Nothing Special   »   [go: up one dir, main page]

US20080193381A1 - Heterodimers of glutamic acid - Google Patents

Heterodimers of glutamic acid Download PDF

Info

Publication number
US20080193381A1
US20080193381A1 US11/936,659 US93665907A US2008193381A1 US 20080193381 A1 US20080193381 A1 US 20080193381A1 US 93665907 A US93665907 A US 93665907A US 2008193381 A1 US2008193381 A1 US 2008193381A1
Authority
US
United States
Prior art keywords
compound
substituted
radionuclide
alkyl
chelate complex
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
US11/936,659
Inventor
John W. Babich
Craig N. Zimmerman
Kevin P. Maresca
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Molecular Insight Pharmaceuticals Inc
Original Assignee
Molecular Insight Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=39365345&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20080193381(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to US11/936,659 priority Critical patent/US20080193381A1/en
Application filed by Molecular Insight Pharmaceuticals Inc filed Critical Molecular Insight Pharmaceuticals Inc
Assigned to MOLECULAR INSIGHT PHARMACEUTICALS, INC. reassignment MOLECULAR INSIGHT PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BABICH, JOHN W., MARESCA, KEVIN P., ZIMMERMAN, CRAIG N.
Publication of US20080193381A1 publication Critical patent/US20080193381A1/en
Assigned to NEXBANK, SSB, A TEXAS-CHARTERED SAVINGS BANK, AS COLLATERAL AGENT reassignment NEXBANK, SSB, A TEXAS-CHARTERED SAVINGS BANK, AS COLLATERAL AGENT GRANT OF SECURITY INTEREST IN PATENT RIGHTS Assignors: MOLECULAR INSIGHT PHARMACEUTICALS, INC.
Assigned to MOLECULAR INSIGHT PHARMACEUTICALS, INC. reassignment MOLECULAR INSIGHT PHARMACEUTICALS, INC. MERGER (SEE DOCUMENT FOR DETAILS). Assignors: MOLECULAR INSIGHT PHARMACEUTICALS, INC.
Priority to US13/271,549 priority patent/US9309193B2/en
Priority to US13/294,677 priority patent/US8487129B2/en
Assigned to MOLECULAR INSIGHT PHARMACEUTICALS, INC. reassignment MOLECULAR INSIGHT PHARMACEUTICALS, INC. RELEASE OF PATENT SECURITY INTEREST Assignors: NEXBANK, SSB (AS COLLATERAL AGENT)
Priority to US15/068,841 priority patent/US10640461B2/en
Priority to US15/337,867 priority patent/US9878980B2/en
Priority to US15/794,539 priority patent/US10131627B2/en
Priority to US16/156,289 priority patent/US10647666B2/en
Priority to US16/870,288 priority patent/US20210070695A1/en
Priority to US17/099,440 priority patent/US20210070696A1/en
Priority to US17/238,535 priority patent/US20210246103A1/en
Priority to US17/982,182 priority patent/US20230095637A1/en
Granted legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
    • C07C275/06—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton
    • C07C275/16—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton being further substituted by carboxyl groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/385—Haptens or antigens, bound to carriers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/001—Acyclic or carbocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
    • C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C275/24—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/30—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
    • C07F1/005—Compounds containing elements of Groups 1 or 11 of the Periodic Table without C-Metal linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
    • C07F13/005—Compounds without a metal-carbon linkage

Definitions

  • NAALADase N-acetylated alpha-linked acidic dipeptidase
  • GCPII glutamate carboxypeptidase II
  • NAAG N-acetylaspartyl-glutamate
  • the enzyme is a type II protein of the co-catalytic class of metallopeptidases, containing two zinc atoms in the active site.
  • NAALADase independent of its characterization in the nervous system, one form of NAALADase was shown to be expressed at high levels in human prostatic adenocarcinomas and was designated the prostate-specific membrane antigen (PSMA).
  • PSMA prostate-specific membrane antigen
  • the NAALADase/PSMA gene is known to produce multiple mRNA splice forms and based on previous immunohistochemical evidence, it has been assumed that the human brain and prostate expressed different isoforms of the enzyme.
  • PSMA Human prostate-specific membrane antigen
  • FOLH1 folate hydrolase I
  • PSMA is a trans-membrane, 750 amino acid type II glycoprotein which is primarily expressed in normal human prostate epithelium but is upregulated in prostate cancer, including metastatic disease.
  • PSMA is a unique exopeptidase with reactivity toward poly-gamma-glutamated folates, capable of sequentially removing the poly-gamma-glutamyl termini. Since PSMA is expressed by virtually all prostate cancers and its expression is further increased in poorly differentiated, metastatic and hormone-refractory carcinomas, it is a very attractive target for prostate imaging and therapy.
  • Developing ligands that interact with PSMA and carry appropriate radionuclides may provide a promising and novel targeting option for the detection, treatment and management of prostate cancer.
  • the radio-immunoconjugate form of the anti-PSMA monoclonal antibody (mAb) 7E11, known as the PROSTASCINT scan, is currently being used to diagnose prostate cancer metastasis and recurrence.
  • mAb monoclonal antibody
  • PROSTASCINT targets the intracellular domain of PSMA and is thought to bind mostly necrotic portions of prostate tumor. 14 More recently, monoclonal antibodies have been developed that bind to the extracellular domain of PSMA and have been radiolabeled and shown to accumulate in PSMA-positive prostate tumor models in animals.
  • One aspect of the present invention relates to compounds of Formula (I)
  • R is a C 6 -C 12 substituted or unsubstituted aryl, a C 6 -C 12 substituted or unsubstituted heteroaryl, a C 1 -C 6 substituted or unsubstituted alkyl or —NR′R′,
  • Q is C(O), O, NR′, S(O) 2 , C(O) 2 (CH2)p
  • Y is C(O), O, NR′, S, S(O) 2 , C(O) 2 (CH2)p
  • Z is H or C 1 -C 4 alkyl
  • m is 0, 1, 2, 3, 4 or 5 n is 0, 1, 2, 3, 4, 5 or 6 p is 0, 1, 2, 3, 4, 5 or 6
  • R′ is H, C(O), S(O) 2 , C(O) 2 , a C 6 -C 12 substituted or unsubstituted aryl, a C 6 -C 12 substituted or unsubstituted heteroaryl or a C 1 -C 6 substituted or unsubstituted alkyl, when substituted, aryl, heteroaryl and alkyl are substituted with halogen, C 6 -C 12 heteroaryl, —NR′R′ or COOZ further wherein (i) at least one of R or R′ is a C 6 -C 12 aryl or C 6 -C 12 heteroaryl substituted with a halogen or (ii) at least one of R or R′ is a C 6 -C 12 heteroaryl or a pharmaceutically acceptable salt
  • Another aspect of the present invention relates to compounds of Formula (Ia)
  • R is a C 6 -C 12 substituted or unsubstituted aryl, a C 6 -C 12 substituted or unsubstituted heteroaryl, a C 1 -C 6 substituted or unsubstituted alkyl or —NR′R′,
  • Q is C(O), O, NR′, S, S(O) 2 , C(O) 2 (CH2)p
  • Y is C(O), O, NR′, S, S(O) 2 , C(O) 2 (CH2)p
  • Z is H or C 1 -C 4 alkyl
  • m is 0, 1, 2, 3, 4 or 5 n 0, 1, 2, 3, 4, 5 or 6 n′ 0, 1, 2, 3, 4, 5 or 6 p is 0, 1, 2, 3, 4, 5 or 6
  • R′ is H, C(O), S(O) 2 , C(O) 2 , a C 6 -C 12 substituted or unsubstituted aryl, a C 6 -C 12 substituted or unsubstituted heteroaryl or a C 1 -C 6 substituted or unsubstituted alkyl, when substituted, aryl, heteroaryl and alkyl are substituted with halogen, C 6 -C 12 heteroaryl, —NR′R′ or COOZ further wherein (i) at least one of R or R′ is a C 6 -C 12 aryl or C 6 -C 12 heteroaryl substituted with at least a halogen or (ii) at least one of R or R′ is a substituted or un
  • n is 0 or 1 and n′ is 0 or 1.
  • the present invention also relates to glutamate-urea-lysine PSMA-binding moieties and their use in diagnostic and therapeutic treatment.
  • the urea-based analogues described here are glutamate-urea- ⁇ or ⁇ -amino acid heterodimer coupled through the ⁇ -NH 2 or ⁇ -NH 2 groups.
  • Radiolabels can be incorporated into the structure through a variety of prosthetic groups attached at the X amino acid side chain via a carbon or hetero atom linkage.
  • the compounds of the present invention can find use as targeting agents and diagnostic and therapeutic agents for the treatment and management of prostate cancer and other diseases related to NAALADase inhibition.
  • FIGS. 1A-1C are HPLC chromatograms respectively of the co-injection of the TC-99m-glu-urea-DpK (Tc-99m-MIP 1008), the rhenium analog, and the rhenium diester complexes.
  • FIGS. 2A-2D show stability of the Tc-99m complex of Glu-urea-DpK (Tc-99m-MIP 1008) at 37° C. in respectively PBS pH 7.2, 0.1 M Cysteine in PBS, 0.1 M DTPA in PBS, and 5% mouse serum in PBS for 6 hours.
  • FIGS. 3A-3B are respective HPLC chromatograms of N—[N—[(S)-1,3-dicarboxypropyl]carbamoyl]-S-3-iodo-L-tyrosine (I-131 DCIT) crude reaction FIG. 3A , top, purified at 2 hours, FIG. 3B , middle and at 2 days FIG. 3C , bottom.
  • FIG. 5 shows I-123 DCIT bound specifically to LnCap cells and not PC3 cells (left set) as is evident by the counts displaceable by nonradiolabeled compound (middle set) or PMPA (right set) in LnCap cells.
  • the histograms show the mean ⁇ SEM, each experiment was performed in duplicate.
  • FIG. 6 is Scatchard Analysis in PSMA Cellular Binding Assay with cold 2- ⁇ 3-[1-Carboxy-2-(4-hydroxy-phenyl)-ethyl]-ureido ⁇ -pentanedioic acid (DCT).
  • DCT cold 2- ⁇ 3-[1-Carboxy-2-(4-hydroxy-phenyl)-ethyl]-ureido ⁇ -pentanedioic acid
  • FIG. 7 shows biological assessments of selected compounds in the PSMA-positive LNCaP cells.
  • FIG. 8 show biological assessments of lead compounds in the PSMA-positive LNCaP cells.
  • FIG. 9 Shows Scatchard Analysis in PSMA Cellular Binding Assay with MIP1072.
  • FIG. 10 shows internalization of I-131-MIP 1072.
  • FIGS. 11A and 11B respectively show stability of I-131 MIP-1072 verses DCT and Phenacetin in rat microsomes for 60 minutes.
  • FIG. 12 shows tissue biodistribution of the I-131 MIP1072 in xenograft tumored mice.
  • FIG. 13 shows inhibition of NAALADase activity from LNCaP cellular lysates.
  • FIG. 14 shows inhibition of NAALADase Activity from LNCaP Cellular lysates.
  • FIG. 15 shows inhibition of NAALADase Activity from LNCaP Cellular lysates.
  • FIG. 16 shows the ability of test compounds to inhibit the binding of a known NAALADase inhibitor, 131I-DCIT, to PSMA on LNCaP cells was examined. Cells were incubated with various concentrations of test compounds and 131I-DCIT for 1 hour then washed and counted to determine IC50 values.
  • FIG. 17 is direct binding analysis of MIP-1072.
  • 123 I-MIP-1072 (3 nM, >1,000 mCi/ ⁇ mole) was incubated with PSMA positive LNCaP cells or PSMA negative PC3 cells (300,000 cells/well), in both the absence and presence of either non-radioactive 10 ⁇ M MIP-1072 or 10 ⁇ M of a specific PSMA inhibitor (PMPA).
  • PMPA specific PSMA inhibitor
  • FIG. 18 shows saturation binding analysis of 123 I-MIP-1072 in LNCaP cells.
  • FIG. 19 shows internalization of 123 I-MIP-1072.
  • FIG. 20 shows uptake of 123 I-MIP-1072 in LNCaP xenograft bearing mice. Tissue biodistribution of 123 I-MIP-1072 (2 ⁇ Ci/mouse, >1,000 mCi/ ⁇ mole) was assessed in selected tissues from LNCaP (PSMA positive) tumor bearing nude mice. Results are expressed as the percent of the injected dose per gram of the selected tissues (% ID/g).
  • FIG. 21 Uptake of 123 I-MIP-1072 in LNCaP and PC3 xenograft bearing mice. Tissue biodistribution of 123 I-MIP-1072 (2 ⁇ Ci/mouse, >1,000 mCi/ ⁇ mole) was assessed in selected tissues from LNCaP (PSMA positive) and PC3 (PSMA negative) tumor bearing nude mice with (Blocked) or without (Normal) pretreatment with 50 mg/kg PMPA.
  • “Pharmaceutically acceptable salt” refers to those salts which retain the biological effectiveness and properties of the free bases and which are obtained by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • Alkyl refers to a straight-chain, branched or cyclic saturated aliphatic hydrocarbon. Typical alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl and the like.
  • the alkyl group may be optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, or alkoxy.
  • R′ substituent it is a lower alkyl of from 1 to 6 carbons, more preferably 1 to 4 carbons.
  • Aryl refers to an aromatic group which has at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups.
  • the aryl group may be optionally substituted with one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxyl, SH, OH, NO 2 , amine, thioether, cyano, alkoxy, alkyl, and amino.
  • substituents selected from the group consisting of halogen, trihalomethyl, hydroxyl, SH, OH, NO 2 , amine, thioether, cyano, alkoxy, alkyl, and amino.
  • Examples of aryl groups include phenyl, napthyl and anthracyl groups. Phenyl and substituted phenyl groups are preferred.
  • Heteroaryl refers to an aryl group having from 1 to 3 heteroatoms as ring atoms, the remainder of the ring atoms being carbon. Heteroatoms include oxygen, sulfur, and nitrogen. Thus, heterocyclic aryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolo, pyrimidyl, pyrazinyl, imidazolyl and the like.
  • the following compounds were all prepared in overall yields ranging from 20-40% following the route depicted in Scheme 1.
  • the first step performed at 0° C. under inert conditions used the di-t-butyl ester of Glutamic acid with CDI in the presence of base to form the intermediate Glu-urea-imidazole derivative 2.
  • This intermediate was activated with MeOTf under basic conditions to afford the methylated imidazole 3, which under inert conditions reacted readily with amines.
  • the tert-butyl ester protecting groups were removed using 20% TFA in DCM for 1 to 4 hour at room temperature. Upon completion of the deprotection, the reactions were concentrated on a rotary evaporator or blown dry with nitrogen and purified on a silica column or recrystallized. The final products were tested in vitro and in vivo.
  • the analogs can be prepared via the isocyanate generated in situ using triphosgene. This approach can be accomplished by either activation of the glutamate residue and coupling with a lysine residue (route A) or by activating the lysine residue and coupling it with the glutamate (route B) as shown in scheme 2 below.
  • reaction is concentrated, diluted with 50 mL ethyl acetate, washed 2N NaHSO4 (2 ⁇ 50 mL), brine (50 mL) and dried over sodium sulfate to yield a yellow oil. Purification by column chromatography to afford the desired product as a clear oil which upon standing solidifies to a white solid (1.9 g, 54%).
  • reaction was concentrated to dryness, diluted with 150 mL ethyl acetate, washed with 2N NaHSO 4 (2 ⁇ 200 mL), brine (150 mL) and dried over sodium sulfate to yield a yellow oil.
  • This oil was purified by column chromatography (SiO 2 ) to afford the desired product as a clear oil which upon standing solidifies to a white solid (12.0 g, 72%).
  • a tether is incorporated onto the side chain of glutamic acid or lysine prior to conjugation to form the urea dimer.
  • the side chain carboxylic acid of one of the glutamic acids is modified into a tether to append a chelator, atom or functional group that is or contains a radionuclide (Scheme 4).
  • the protected intermediate was prepared by reductive amination using pyridine-2-carboxaldehyde as previously described. Treatment with 2M LiOH in MeOH effected hydrolysis of the methyl ester. The methanol was removed and excess DCM:TFA (1:1) was added and the reaction stirred at room temperature overnight. The crude material was converted into the desired Rhenium conjugate following the procedure described above. Preparative HPLC afforded the desired molecule (9.5 mg, 16%).
  • the following compounds were all prepared in overall yields ranging from 20-40% usin the route depicted in Scheme 3.
  • the Z-deprotected Glu-urea-lysine was mixed with the appropriate aldehyde (0.9 equivalents) at room temperature for one hour to form the ⁇ chiff base intermediate.
  • the ⁇ chiff base was reduced using 1 equivalent of sodium triacetoxyborohydride.
  • the compounds were deprotected using 50% TFA in DCM for 1 hour at room temperature. Upon completion, the reactions were concentrated on a rotary evaporator or were blown dry with nitrogen and extracted using methylene chloride and water. The water layer was evaporated to dryness to afford the deprotected product in 40-80% yield.
  • the reaction was diluted with DCM (50 mL) and washed with water (30 mL), 5% aq. Citric acid (30 mL), sat. sodium bicarbonate (30 mL), water (30 mL) and brine (30 mL). The organic layer was dried over sodium sulfate and concentrated to afford the crude product. The product was purified by column chromatography to afford the desired product (303 mg, 0.51 mmol, 49%) as a white foam.
  • phenyl isocyanate (100 mg, 0.84 mmol) was dissolved in DCM (10 mL) 2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid di t-butyl ester (409 mg, 0.84 mmol) was added and stirred for 3 hours.
  • the reaction mixture was evaporated to dryness and the crude mixture was purified via flash column chromatography 2:1 hexanes/ethyl acetate to afford the tert-butyl ester as a white solid which was deprotected using TFA/CH 2 Cl 2 affording the desired product.
  • the rhenium complexes of the SAAC-inhibitors are conveniently isolated from the reactions of the readily available precursor [Net 4 ] 2 [Re(CO) 3 Br 3 ] with the SAAC-inhibitor. Since the donor sets provided by the SAAC terminus are well documented as effective chelators for the ⁇ M(CO) 3 ⁇ +1 core and have been designed to adopt the required facial arrangement about the metal site, the preparations of the complexes were unexceptional.
  • the PEG2 dipyridyl compound, (17R,21S)-11,19-dioxo-1-( yridine-2-yl)-2-( yridine-2-ylmethyl)-dioxa-2,12,18,20-tetraazatricosane-17,21,23-tricarboxylic acid was prepared employing the same general procedure as shown in Scheme 1, using previously prepared and protected 2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid di t-butyl ester.
  • the rhenium ester complex was prepared employing the same procedure as described in the general rhenium experimental.
  • the PEG4 dipyridyl compound (23R,27S)-17,25-dioxo-1-(pyridin-2-yl)-2-(pyridin-2-ylmethyl)-5,8,11,14-tetraoxa-2,18,24,26-tetraazanonacosane-23,27,29-tricarboxylic acid was prepared employing the same general procedure as shown in Scheme A, using previously prepared and protected 2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid di t-butyl ester.
  • the rhenium ester complex was prepared employing the same procedure as described in the general rhenium experimental. The compound was deprotected using the previously described methods to yield the desired product. (5.1 mg, 29.6%) as a white solid.
  • the PEG8 dipyridyl compound, (35R,39S)-29,37-dioxo-1-(pyridin-2-yl)-2-(pyridin-2-ylmethyl)-5,8,11,14,17,20,23,26-octaoxa-2,30,36,38-tetraazahentetracontane-35,39,41-tricarboxylic acid was prepared employing the same general procedure as shown in Scheme A, using previously prepared and protected 2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid di t-butyl ester.
  • the rhenium ester complex was prepared employing the same procedure as described in the general rhenium experimental. The compound was deprotected using the previously described methods to yield the desired product (8.0 mg, 30.4%) as a white solid. ESMS m/z: 1195 (M+H) + .
  • the C11-PAMA compound, (19R,23S)-13,21-dioxo-2-( ⁇ yridine-2-ylmethyl)-2,14,20,22-tetraazapentacosane-1,19,23,25-tetracarboxylic acid was prepared employing the same general procedure as shown in Scheme A, using previously prepared and protected 2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid di t-butyl ester.
  • the rhenium ester complex was prepared employing the same procedure as described in the general rhenium experimental. The compound was deprotected using the previously described methods to yield the desired product (3.0 mg, 75%) as an off-white solid.
  • Table 1 below is a summary of synthesized PSMA inhibitors investigated.
  • the properties of the Group VII metals technetium and rhenium are very similar due to their periodic relationship. It was anticipated that the metals would demonstrate similar reaction chemistry, which is often the case for the tricarbonyl, nitrogen, and thiazole chemistry of these two metals. Likewise, due to their similar size that stabilizes the spin paired d 6 electron configuration of M(I), perrhenate and pertechnetate have very similar reaction behaviors. Synthesizing the rhenium-TECs allowed us a facile route to structurally characterize the products. The periodic relationship between Tc and Re indicates that Tc-99m radiopharmaceuticals can be designed by modeling analogous rhenium complexes.
  • rhenium-TEC complexes were synthesized with macroscopic quantities of rhenium for characterization by conventional methods, including mass-spectrometry, 1 H and 13 C NMR spectrometry. Following purification, the synthesized rhenium complexes were run through a HPLC column for purification and identification of retention times to compare with Tc reaction products. The rhenium-TEC complexes were also crystallized.
  • the rhenium complexes of the SAAC-inhibitors are conveniently isolated from the reactions of the readily available precursors ⁇ Re(CO) 3 (H 2 O) 3 ⁇ +1 and [Net 4 ] 2 [Re(CO) 3 Br 3 ] with the SAAC-inhibitor. Since the donor sets provided by the SAAC terminus are well documented as effective chelators for the ⁇ M(CO) 3 ⁇ +1 core and have been designed to adopt the required facial arrangement about the metal site, the preparations of the complexes were unexceptional.
  • the compounds of the general structure 3 were prepared in overall yields ranging from 20-40% using the general route depicted in Scheme A.
  • the key synthetic intermediate (1) was reacted with the appropriate aldehyde at room temperature in for one hour to form the ⁇ yridi base intermediate.
  • the ⁇ yridi base was not isolated but was reduced in situ with sodium triacetoxyborohydride.
  • the t-butyl ester protecting groups were removed using 50% TFA in DCM for 1 hour at room temperature. Upon completion of the deprotection, the reactions were concentrated on a rotary evaporator and purified by HPLC or flash chromatography to afford the desired products (3) in 40-80% yield.
  • the following compounds of the general structure 8 were prepared in overall yields ranging from 20-60% by the route depicted in Scheme B.
  • the key synthetic intermediate (4) was reacted with the appropriate phenylisocyanate at room temperature to afford the desired protected intermediates (5) in good yields.
  • the t-butyl ester protecting groups were removed in the presence of 50% TFA in DCM for 1 hour at room temperature. Upon completion, the reactions were concentrated on a rotary evaporator purified by HPLC or recrystallization to afford the desired products (6) in 40-90% yield.
  • the stability of the radiolabeled compounds in solution and in serum were determined as a function of time and solution conditions. Specifically, after radiolabeling and isolation, the product was stored at room temperature for 6 h after which HPLC analysis was performed to check for degree of label retention, as well as potential product degradation. The reformation of TcO 4 ⁇ and the presence of the reduced material TcO 2 was analyzed.
  • ligand challenges were performed. Specifically, the stabilities of the 99m Tc complexes were investigated by incubating the HPLC purified complexes in 5% mouse serum at room temperature and 37° C. The ability of competing ligands, such as cysteine and DTPA, to extract Tc-99m from the complexes was studied by incubating the purified complexes with solutions (PBS pH 7.2) containing competing ligands at final concentrations of 0.1 M.
  • solutions PBS pH 7.2
  • the stability of the radiolabeled compound in solution was determined as a function of time. Specifically, after radiolabeling and isolation, the product was stored at room temperature for 48 h after which HPLC analysis was performed to check for degree of label retention, as well as potential product degradation. The reformation of NaI and the presence of the reduced iodates was analyzed. The results of the labeling stability study demonstrated no significant degradation of the I-131 DCIT out to 2 days at room temperature. The results of the study are shown in FIG. 3 .
  • the stability of the radiolabeled compound in solution was determined as a function of time. Specifically, after radiolabeling and isolation, the product was stored at 37° C. for 3 days after which HPLC analysis was performed to check for degree of label retention, as well as potential product degradation. The reformation of NaI and the presence of the reduced iodates was analyzed. The results of the labeling stability study demonstrated no significant degradation of the I-13 11072 out to 3 days at room temperature in DMSO, 10% ethanol/saline, PBS pH 7.2, and 6% ascorbate/3% gentisic acid solution. The results of the study are shown in FIG. 4 .
  • the newly prepared SAAC-urea-Glu conjugates were screened in a human prostate cancer cell binding assay using PSMA-positive, LnCap cells, and PSMA-negative, PC3 cells. Compounds demonstrating specific uptake or binding to PSMA-positive cells will be studied for tumor localization in vivo.
  • LNCaP and PC3 human prostate cancer cells were obtained from American Type Culture Collection, Rockville, Md. LNCaP cells were maintained in RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS). PC3 cells were grown in F12K medium supplemented with 10% FBS. Binding of the radiolabeled compound and competition with cold derivatives to LNCaP and PC-3 cells was performed according to the methods of Tang et al. (Tang, H.; Brown, M.; Ye, Y.; Huang, G.; Zhang, Y.; Wang, Y.; Zhai, H.; Chen, X.; Shen, T.
  • the resulting slurry was then centrifuged at 21,000 ⁇ G for 10 min and the supernatant was collected and injected onto an Agilent LCMS model MSD SL using a 95:5 water:acetonitrile (with 0.1% formic acid) to 40:60 water:acetonitrile (with 0.1% formic acid) gradient and monitoring for the parent ion only in single ion mode.
  • the results, shown in FIGS. 11A and 11B are expressed as degradation of the parent ion with respect to the 0 min time point.
  • MIP-1072 The stability of MIP-1072 was assessed using rat liver microsomes. MIP-1072 (50 ⁇ M) and Phenacetin (100 ⁇ M) were incubated with rat liver microsomes at 37° C. for the indicated time. Phenacetin was used as a control substance that is known to be metabolized. MIP-1072 was not degraded by the rat liver microsomes during the incubation period. However, phenacetin was degraded by 22% after a 60 min incubation.
  • the lead compound, MIP 1072 was I-131-labeled for tissue distribution studies in mice with both LNCaP (PSMA positive) and PC3 (PSMA negative) tumors implanted.
  • the compound was radiolabeled by the route shown below.
  • NAALADase for therapeutic treatments.
  • Diseases that could be receptive to NAALADase treatment include painful and sensory diabetic neuropathy, neuronal damage and prostate cancer, schizophrenia, colorectal cancer, inflammation, amyotrophic lateral schlerosis, or diabetic neuropathy.
  • the present compounds can also be used an analgesic.
  • Guidance for the modeling of such therapeutic treatments can be found in Goodman & Gilman's The Pharmacological Basis of Therapeutics, McGraw Hill, 10 edition, 2001, Pharmaceutical Preformulation and Formulation: A Practical Guide from Candidate Drug Selection to Commercial Dosage Form, CRC, 2001 and Handbook of Pharmaceutical Excipients, AphA Publications, 5 edition, 2005.
  • LNCaP cells (300,000 cells/well) were incubated for 1 hour with 3 nM [ 131 I]-DCIT in the presence of 1-10,000 mM MIP-1072 in RPMI-1640 medium supplemented with 0.5% bovine serum albumin, then washed and counted in a gamma counter. All documents cited in this specification including patent applications are incorporated by reference in their entirety.
  • LNCaP cells or the PSMA negative cell line, PC3 cells, were incubated in RPMI-1640 medium supplemented with 0.5% bovine serum albumin for 1 hour with 3 nM 123 I-MIP-1072 alone, or in the presence of 10 ⁇ M unlabeled MIP-1072, or 10 ⁇ M 2-(phosphonomethyl)-pentanedioic acid (PMPA), a structurally unrelated NAALADase inhibitor. Cells were washed and counted in a gamma counter.
  • PMPA 2-(phosphonomethyl)-pentanedioic acid
  • the affinity constant (K d ) of MIP-1072 was determined by saturation binding analysis ( FIG. 18 ).
  • LNCaP cells were incubated for 1 hour with 30-100,000 pM 131 I-MIP-1072 in HBS (50 mM Hepes, pH 7.5, 0.9% sodium chloride) at either 4° C. or 37° C. in the absence or presence of 10 ⁇ M unlabeled MIP-1072 (to determine non-specific binding). Cells were then washed and the amount of radioactivity was measured on a gamma counter. Specific binding was calculated as the difference between total binding and nonspecific binding.
  • the affinity constant (K d ) of the interaction of MIP-1072 with PSMA on LNCaP cells was determined by saturation binding analysis performed by titrating 123 I-MIP-1072 (3 pM-1,000 nM) in the presence and absence of an excess of non-radiolabeled MIP-1072 (10 ⁇ M).
  • a K d of 4.8 nM, and Bmax of 1,490 fmoles/10 6 cells at 4° C. was determined by nonlinear regression analysis using Graph Pad Prism software ( FIG. 18 ).
  • the K d was not significantly different at 37° C., 8.1 nM.
  • the Bmax was greater at 37° C. than at 4° C.; 1,490 vs. 4,400 fmol/10 6 cells, respectively, indicating internalization of MIP-1072.
  • the results below are representative of two independent analyses.
  • LNCaP cells were incubated in HBS with 100 nM 123 I-MIP-1072 for 0-2 hours at 4 and 37° C. At the indicated time the media was removed and the cells were incubated in mild acid buffer (50 mM glycine, 150 mM NaCl, pH 3.0) at 4° C. for 5 minutes. After the brief incubation the cells were centrifuged at 20,000 ⁇ g for 5 minutes. The supernatant and cell pellet were counted in a gamma counter.
  • mild acid buffer 50 mM glycine, 150 mM NaCl, pH 3.0
  • a quantitative analysis of the tissue distribution of 123 I-MIP-1072 was performed in separate groups of male NCr Nude ⁇ / ⁇ mice bearing PSMA positive LNCaP xenografts (approximately 100-200 mm 3 ) administered via the tail vein as a bolus injection (approximately 2 ⁇ Ci/mouse) in a constant volume of 0.05 ml.
  • Tissues blood, heart, lungs, liver, spleen, kidneys, adrenals, stomach, large and small intestines (with contents), testes, skeletal muscle, bone, brain, adipose, and tumor
  • LLB Model 1282 Wallac Oy, Finland

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Pain & Pain Management (AREA)
  • Epidemiology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Psychiatry (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Microbiology (AREA)
  • Immunology (AREA)
  • Mycology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • Rheumatology (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Nuclear Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pyridine Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Compounds of Formula (Ia)
Figure US20080193381A1-20080814-C00001
wherein R is a C6-C12 substituted or unsubstituted aryl, a C6-C12 substituted or unsubstituted heteroaryl, a C1-C6 substituted or unsubstituted alkyl or —NR′R′,
  • Q is C(O), O, NR′, S, S(O)2, C(O)2 (CH2)p
  • Y is C(O), O, NR′, S, S(O)2, C(O)2 (CH2)p
  • Z is H or C1-C4 alkyl,
  • R′ is H, C(O), S(O)2, C(O)2, a C6-C12 substituted or unsubstituted aryl, a C6-C12 substituted or unsubstituted heteroaryl or a C1-C6 substituted or unsubstituted alkyl, when substituted, aryl, heteroaryl and alkyl are substituted with halogen, C6-C12 heteroaryl, —NR′R′ or COOZ, which have diagnostic and therapeutic properties, such as the treatment and management of prostate cancer and other diseases related to NAALADase inhibition. Radiolabels can be incorporated into the structure through a variety of prosthetic groups attached at the X amino acid side chain via a carbon or hetero atom linkage.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • This application claims priority to U.S. provisional application No. 60/857,490 filed Nov. 8, 2006 and U.S. provisional application No. 60/878,678 filed Jan. 5, 2007, the disclosures of which are incorporated herein by reference in their entireties.
    • BACKGROUND OF THE INVENTION
  • At least 1 million men suffer from prostate cancer and it's estimated that the disease will strike one in six U.S. men between the ages of 60 and 80. There are more than 300,000 new cases of prostate cancer diagnosed each year. Prostate cancer will affect one in six men in the United States, and the mortality from the disease is second only to lung cancer. An estimated $2 billion is currently spent worldwide on surgical, radiation, drug therapy and minimally invasive treatments, $1 billion of the spending in the U.S. There is presently no effective therapy for relapsing, metastatic, androgen-independent prostate cancer. New agents that will enable rapid visualization of prostate cancer and specific targeting to allow radiotherapy present are needed.
  • N-acetylated alpha-linked acidic dipeptidase (NAALADase), also known as glutamate carboxypeptidase II (GCPII) is a neuropeptidase which cleaves N-acetylaspartyl-glutamate (NAAG) into N-acetylaspartate and glutamate in the nervous system, see below, depicting hydrolytic cleavage of NAAG by NAALDase through the tetrahedral intermediate. The enzyme is a type II protein of the co-catalytic class of metallopeptidases, containing two zinc atoms in the active site.
  • Figure US20080193381A1-20080814-C00002
  • Independent of its characterization in the nervous system, one form of NAALADase was shown to be expressed at high levels in human prostatic adenocarcinomas and was designated the prostate-specific membrane antigen (PSMA). The NAALADase/PSMA gene is known to produce multiple mRNA splice forms and based on previous immunohistochemical evidence, it has been assumed that the human brain and prostate expressed different isoforms of the enzyme.
  • Human prostate-specific membrane antigen (PSMA), also known as folate hydrolase I (FOLH1), is a trans-membrane, 750 amino acid type II glycoprotein which is primarily expressed in normal human prostate epithelium but is upregulated in prostate cancer, including metastatic disease. PSMA is a unique exopeptidase with reactivity toward poly-gamma-glutamated folates, capable of sequentially removing the poly-gamma-glutamyl termini. Since PSMA is expressed by virtually all prostate cancers and its expression is further increased in poorly differentiated, metastatic and hormone-refractory carcinomas, it is a very attractive target for prostate imaging and therapy. Developing ligands that interact with PSMA and carry appropriate radionuclides may provide a promising and novel targeting option for the detection, treatment and management of prostate cancer.
  • The radio-immunoconjugate form of the anti-PSMA monoclonal antibody (mAb) 7E11, known as the PROSTASCINT scan, is currently being used to diagnose prostate cancer metastasis and recurrence. Early promising results from various Phase I and II trials have utilized PSMA as a therapeutic target. PROSTASCINT targets the intracellular domain of PSMA and is thought to bind mostly necrotic portions of prostate tumor.14 More recently, monoclonal antibodies have been developed that bind to the extracellular domain of PSMA and have been radiolabeled and shown to accumulate in PSMA-positive prostate tumor models in animals.
  • While monoclonal antibodies hold promise for tumor detection and therapy, there have been limited clinical successes outside of lymphoma because of their low permeability in solid tumors. Low molecular weight mimetics, with higher permeability in solid tumors will have a definite advantage in obtaining high percent per gram and a high percentage of specific binding.
    • SUMMARY OF THE INVENTION
  • One aspect of the present invention relates to compounds of Formula (I)
  • Figure US20080193381A1-20080814-C00003
  • wherein R is a C6-C12 substituted or unsubstituted aryl, a C6-C12 substituted or unsubstituted heteroaryl, a C1-C6 substituted or unsubstituted alkyl or —NR′R′,
    • Q is C(O), O, NR′, S(O)2, C(O)2 (CH2)p Y is C(O), O, NR′, S, S(O)2, C(O)2 (CH2)p
  • Z is H or C1-C4 alkyl,
    m is 0, 1, 2, 3, 4 or 5
    n is 0, 1, 2, 3, 4, 5 or 6
    p is 0, 1, 2, 3, 4, 5 or 6
    R′ is H, C(O), S(O)2, C(O)2, a C6-C12 substituted or unsubstituted aryl, a C6-C12 substituted or unsubstituted heteroaryl or a C1-C6 substituted or unsubstituted alkyl, when substituted, aryl, heteroaryl and alkyl are substituted with halogen, C6-C12 heteroaryl, —NR′R′ or COOZ
    further wherein
    (i) at least one of R or R′ is a C6-C12 aryl or C6-C12 heteroaryl substituted with a halogen or
    (ii) at least one of R or R′ is a C6-C12 heteroaryl
    or a pharmaceutically acceptable salt of the compound of Formula (I).
  • Another aspect of the present invention relates to compounds of Formula (Ia)
  • Figure US20080193381A1-20080814-C00004
  • wherein R is a C6-C12 substituted or unsubstituted aryl, a C6-C12 substituted or unsubstituted heteroaryl, a C1-C6 substituted or unsubstituted alkyl or —NR′R′,
    • Q is C(O), O, NR′, S, S(O)2, C(O)2 (CH2)p Y is C(O), O, NR′, S, S(O)2, C(O)2 (CH2)p
  • Z is H or C1-C4 alkyl,
    m is 0, 1, 2, 3, 4 or 5
    n 0, 1, 2, 3, 4, 5 or 6
    n′ 0, 1, 2, 3, 4, 5 or 6
    p is 0, 1, 2, 3, 4, 5 or 6
    R′ is H, C(O), S(O)2, C(O)2, a C6-C12 substituted or unsubstituted aryl, a C6-C12 substituted or unsubstituted heteroaryl or a C1-C6 substituted or unsubstituted alkyl, when substituted, aryl, heteroaryl and alkyl are substituted with halogen, C6-C12 heteroaryl, —NR′R′ or COOZ further wherein
    (i) at least one of R or R′ is a C6-C12 aryl or C6-C12 heteroaryl substituted with at least
    a halogen or
    (ii) at least one of R or R′ is a substituted or unsubstituted C6-C12 heteroaryl
    or a pharmaceutically acceptable salt of the compound of Formula (I).
  • In a preferred embodiment of the compounds of Formulas (I), (Ia), (II) or (IIa) n is 0 or 1 and n′ is 0 or 1.
  • The present invention also relates to glutamate-urea-lysine PSMA-binding moieties and their use in diagnostic and therapeutic treatment. In one embodiment, the urea-based analogues described here are glutamate-urea-α or β-amino acid heterodimer coupled through the α-NH2 or β-NH2 groups. Radiolabels can be incorporated into the structure through a variety of prosthetic groups attached at the X amino acid side chain via a carbon or hetero atom linkage. The compounds of the present invention can find use as targeting agents and diagnostic and therapeutic agents for the treatment and management of prostate cancer and other diseases related to NAALADase inhibition.
  • Suitable chemical moieties, definitions of chemical moieties, excipients and methods and modes of administration can be found in US Published Application Nos. 2004/0054190 and 2004/0002478 and International Application Nos. WO 02/22627 and WO 03/060523, which are incorporated by reference in their entirety.
    • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIGS. 1A-1C are HPLC chromatograms respectively of the co-injection of the TC-99m-glu-urea-DpK (Tc-99m-MIP 1008), the rhenium analog, and the rhenium diester complexes.
  • FIGS. 2A-2D show stability of the Tc-99m complex of Glu-urea-DpK (Tc-99m-MIP 1008) at 37° C. in respectively PBS pH 7.2, 0.1 M Cysteine in PBS, 0.1 M DTPA in PBS, and 5% mouse serum in PBS for 6 hours.
  • FIGS. 3A-3B are respective HPLC chromatograms of N—[N—[(S)-1,3-dicarboxypropyl]carbamoyl]-S-3-iodo-L-tyrosine (I-131 DCIT) crude reaction FIG. 3A, top, purified at 2 hours, FIG. 3B, middle and at 2 days FIG. 3C, bottom.
  • FIG. 4A-4D are radio-HPLC chromatograms of I-131 MIP 1072 purified; at 3 days in A) DMSO. B) 3% genstisate-6% Ascorbate/Ascorbic acid, C) PBS, pH=7.2, D) 10% Ethanol in Saline at 37° C. As shown above, the I-131-1072 (peak 12 minutes) remained stable throughout the experiments.
  • FIG. 5 shows I-123 DCIT bound specifically to LnCap cells and not PC3 cells (left set) as is evident by the counts displaceable by nonradiolabeled compound (middle set) or PMPA (right set) in LnCap cells. The histograms show the mean ±SEM, each experiment was performed in duplicate.
  • FIG. 6 is Scatchard Analysis in PSMA Cellular Binding Assay with cold 2-{3-[1-Carboxy-2-(4-hydroxy-phenyl)-ethyl]-ureido}-pentanedioic acid (DCT).
  • FIG. 7 shows biological assessments of selected compounds in the PSMA-positive LNCaP cells.
  • FIG. 8 show biological assessments of lead compounds in the PSMA-positive LNCaP cells.
  • FIG. 9 Shows Scatchard Analysis in PSMA Cellular Binding Assay with MIP1072.
  • FIG. 10 shows internalization of I-131-MIP 1072.
  • FIGS. 11A and 11B respectively show stability of I-131 MIP-1072 verses DCT and Phenacetin in rat microsomes for 60 minutes.
  • FIG. 12 shows tissue biodistribution of the I-131 MIP1072 in xenograft tumored mice.
  • FIG. 13 shows inhibition of NAALADase activity from LNCaP cellular lysates.
  • FIG. 14 shows inhibition of NAALADase Activity from LNCaP Cellular lysates.
  • FIG. 15 shows inhibition of NAALADase Activity from LNCaP Cellular lysates.
  • FIG. 16 shows the ability of test compounds to inhibit the binding of a known NAALADase inhibitor, 131I-DCIT, to PSMA on LNCaP cells was examined. Cells were incubated with various concentrations of test compounds and 131I-DCIT for 1 hour then washed and counted to determine IC50 values.
  • FIG. 17 is direct binding analysis of MIP-1072. 123I-MIP-1072 (3 nM, >1,000 mCi/μmole) was incubated with PSMA positive LNCaP cells or PSMA negative PC3 cells (300,000 cells/well), in both the absence and presence of either non-radioactive 10 μM MIP-1072 or 10 μM of a specific PSMA inhibitor (PMPA).
  • FIG. 18 shows saturation binding analysis of 123I-MIP-1072 in LNCaP cells.
  • FIG. 19 shows internalization of 123I-MIP-1072.
  • FIG. 20 shows uptake of 123I-MIP-1072 in LNCaP xenograft bearing mice. Tissue biodistribution of 123I-MIP-1072 (2 μCi/mouse, >1,000 mCi/μmole) was assessed in selected tissues from LNCaP (PSMA positive) tumor bearing nude mice. Results are expressed as the percent of the injected dose per gram of the selected tissues (% ID/g).
  • FIG. 21 Uptake of 123I-MIP-1072 in LNCaP and PC3 xenograft bearing mice. Tissue biodistribution of 123I-MIP-1072 (2 μCi/mouse, >1,000 mCi/μmole) was assessed in selected tissues from LNCaP (PSMA positive) and PC3 (PSMA negative) tumor bearing nude mice with (Blocked) or without (Normal) pretreatment with 50 mg/kg PMPA.
    •  DETAILED DESCRIPTION OF THE INVENTION Definitions
  • “Pharmaceutically acceptable salt” refers to those salts which retain the biological effectiveness and properties of the free bases and which are obtained by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • “Alkyl” refers to a straight-chain, branched or cyclic saturated aliphatic hydrocarbon. Typical alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl and the like. The alkyl group may be optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, or alkoxy. When the alky group is an R′ substituent, it is a lower alkyl of from 1 to 6 carbons, more preferably 1 to 4 carbons.
  • “Aryl” refers to an aromatic group which has at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups. The aryl group may be optionally substituted with one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxyl, SH, OH, NO2, amine, thioether, cyano, alkoxy, alkyl, and amino. Examples of aryl groups include phenyl, napthyl and anthracyl groups. Phenyl and substituted phenyl groups are preferred. “Heteroaryl” refers to an aryl group having from 1 to 3 heteroatoms as ring atoms, the remainder of the ring atoms being carbon. Heteroatoms include oxygen, sulfur, and nitrogen. Thus, heterocyclic aryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolo, pyrimidyl, pyrazinyl, imidazolyl and the like.
    • Synthesis
  • All reactions were carried out in dry glassware under an atmosphere of argon unless otherwise noted. Reactions were purified by column chromatography, under medium pressure using a Biotage SP4 or by preparative high pressure liquid chromatography.
  • 1H NMR was recorded on a Bruker 400 MHz instrument. Spectra are reported as ppm δ and are referenced to the solvent resonances in CDCl3, DMSO-d6 or methanol-d4. All solvents were purchased from Sigma-Aldrich. Reagents were purchased from Sigma Aldrich, Bachem, Akaal, Fisher, Alfa Aesar, Acros and Anaspec. The following abbreviations are used methylene chloride (DCM), ethyl acetate (EA), hexanes (Hex), dichloroethane (DCE), dimethyl formamide (DMF), trifluoroacetic acid (TFA), tetrahydrofuran (THF), carbonyldiimidazole (CDI), dimethylaminopyridine (DMAN), triethylamine (TEA), methyl trifluoromethanesulfonate (MeOTf), (S)-2-Amino-6-(bis-pyridin-2-ylmethyl-amino)-hexanoic acid (dpK), glutamic acid (Glu), diisopropylethylamine (DIEA), benzyloxycarbonyl (CBZ).
    • Synthesis of Intermediates
  • The following compounds were all prepared in overall yields ranging from 20-40% following the route depicted in Scheme 1. The first step, performed at 0° C. under inert conditions used the di-t-butyl ester of Glutamic acid with CDI in the presence of base to form the intermediate Glu-urea-imidazole derivative 2. This intermediate was activated with MeOTf under basic conditions to afford the methylated imidazole 3, which under inert conditions reacted readily with amines. The tert-butyl ester protecting groups were removed using 20% TFA in DCM for 1 to 4 hour at room temperature. Upon completion of the deprotection, the reactions were concentrated on a rotary evaporator or blown dry with nitrogen and purified on a silica column or recrystallized. The final products were tested in vitro and in vivo.
  • Figure US20080193381A1-20080814-C00005
  • L-(S)-2-[(Imidazole-1-carbonyl)-amino]-pentanedioic acid di-tert-butyl ester (2) To a suspension of di-t-butyl glutamate hydrochloride (15.0 g, 51 mmol) in DCM (150 mL) cooled to 0° C. was added TEA (18 mL) and DMAP (250 mg). After stirring for 5 min. CDI (9.0 g, 56 mmol) was added and the reaction was stirred overnight with warming to room temperature. The reaction was diluted with DCM (150 mL) and washed with saturated sodium bicarbonate (60 mL), water (2×100 mL) and brine (100 mL). The organic layer was dried over sodium sulfate and concentrated to afford the crude product as a semi-solid, which slowly solidified upon standing. The crude material was triturated with hexane/ethyl acetate to afford a white solid which was filtered, washed with hexane (100 mL) and dried to afford the desired product (15.9 g, 45 mmol, 88%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.63 (s, 1H), 7.00 (br, 2H), 6.31 (d, 1H), 4.02 (m, 1H), 2.19 (m, 2H), 1.86 (m, 1H), 1.67 (m, 1H), 1.39 (s, 9H), 1.38 (s, 9H). ESMS m/z: 354 (M+H)+.
  • Figure US20080193381A1-20080814-C00006
  • Alternatively, the analogs can be prepared via the isocyanate generated in situ using triphosgene. This approach can be accomplished by either activation of the glutamate residue and coupling with a lysine residue (route A) or by activating the lysine residue and coupling it with the glutamate (route B) as shown in scheme 2 below.
  • Figure US20080193381A1-20080814-C00007
    • L-(S,S)-2-[3-(5-Benzyloxycarbonylamino-1-tert-butoxycarbonyl-pentyl-ureido)-pentanedioic acid di-tert-butyl ester (3)
  • Route A. In a round bottom flask 1.8 mL TEA (13.2 mmol) was combined with 1.8 grams (6 mmol) L-glutamic acid di-tertbutyl ester hydrochloride in 20 mL DCM. This solution is added dropwise over 45 minutes to a solution of 10 mL DCM and triphosgene (0.7 g, 2.2 mmol) at 0° C. After stirring an additional 30 min a solution of H-lys-(Z)-O-t-butyl ester HCl (2.2 g, 6 mmol) containing TEA (1.8 mL, 13 mmol) in 15 mL DCM was added in one portion. The solution was stirred for 1 hour. The reaction is concentrated, diluted with 50 mL ethyl acetate, washed 2N NaHSO4 (2×50 mL), brine (50 mL) and dried over sodium sulfate to yield a yellow oil. Purification by column chromatography to afford the desired product as a clear oil which upon standing solidifies to a white solid (1.9 g, 54%).
  • Route B. In a round bottom flask triphosgene (2.9 g, 10 mmol) is suspended in DCM (50 mL) and stirred at 0° C. A solution of H-Lysine(Z) freebase (9.1 g, 27 mmol) and DIEA (10.4 mL, 60 mmol) DCM (50 mL) was added dropwise to the triphosgene solution over 2.5 hours. After 2.5 hours a solution of L-glutamic acid di-tertbutyl ester hydrochloride (8 g, 27 mmol) containing DEA (10.4 mL, 60 mmol) DCM (50 mL) was added in one portion and allowed to stir for 45 minutes. The reaction was concentrated to dryness, diluted with 150 mL ethyl acetate, washed with 2N NaHSO4 (2×200 mL), brine (150 mL) and dried over sodium sulfate to yield a yellow oil. This oil was purified by column chromatography (SiO2) to afford the desired product as a clear oil which upon standing solidifies to a white solid (12.0 g, 72%). 1H NMR (400 MHz, CDCl3) δ 7.34 (m, 5H), 5.33-5.28 (m, 3H), 5.08 (d, J=7.4 Hz, 2H), 4.38-4.29 (m, 2H), 3.15 (m, 2H), 2.32-2.01 (m, 2H), 1.90-1.50 (m, 8H), 1.43-1.40 (m, 27H, t-Bu's). ESMS m/z: 622 (M+H)+.
  • Figure US20080193381A1-20080814-C00008
  • 2-[3-(5-Amino-1-tert-butoxycarbonyl-pentyl)-ureido]-pentanedioic acid di-tert-butyl ester (4). To a solution of 2-[3-(5-Benzyloxycarbonylamino-1-tert-butoxycarbonyl-pentyl)-ureido]-pentanedioic acid di-tert-butyl ester (630 mg, 1.0 mmol) in ethanol (20 mL) was added ammonium formate (630 mg, 10 eqv) followed by 10% Pd—C and the suspension was allowed to stand with occasional agitation overnight until complete. The reaction was filtered through celite and concentrated to afford the desired product (479 mg, 98%) as a waxy solid. 1H NMR (400 MHz, CDCl3) δ 7.15-6.0 (bm, 4H, NH's), 4.29 (m, 2H), 3.02 (m, 2H), 2.33 (m, 2H), 2.06-1.47 (m, 8H), 1.45-1.40 (m, 27H, t-Bu's). ESMS m/z: 488 (M+H)+.
  • Figure US20080193381A1-20080814-C00009
    • Synthesis of the Glu-Urea-Glu Tether Core Model Compounds.
  • In this series a tether is incorporated onto the side chain of glutamic acid or lysine prior to conjugation to form the urea dimer. In the example below the side chain carboxylic acid of one of the glutamic acids is modified into a tether to append a chelator, atom or functional group that is or contains a radionuclide (Scheme 4).
  • Figure US20080193381A1-20080814-C00010
    • 2-{3-[3-(4-Amino-butylcarbamoyl)-1-methoxycarbonyl-propyl]-ureido}-pentanedioic acid di-tert-butyl ester (28)
  • To a solution of N—BOC Glutamic acid α-methyl ester BOC-Glu(OH)-Ome (960 mg, 3.7 mmol) in DMF (6 mL) cooled to 0° C. was added EDC (845 mg, 1.3 eqv) and TEA (1.3 mL). After stirring for 10 min the mono protected diamine N-CBZ-1,4-diaminobutane hydrochloride salt (1 g, 3.8 mmol) was added and the reaction is allowed to stir overnight with warming to room temperature. The crude reaction was diluted with EA (100 mL) and washed with and washed with water (30 mL), 5% aq. Citric acid (30 mL), sat. sodium bicarbonate (30 mL), water (30 mL) and brine (30 mL). The organic layer was dried over sodium sulfate and concentrated to afford the crude product as a thick syrup (2.1 g). To the obtained syrup was added 4 N HCl in dioxane (10 mL) and the reaction was stirred at room temperature for 3 h. Concentration afforded a waxy solid (1.8 g) as the hydrochloride salt. The salt was coupled to the activated L-(S)-2-[(Imidazole-1-carbonyl)-amino]-pentanedioic acid di-tert-butyl ester (2) as described in the preceding experimental sections to afford the desired fully protected dimer x (1.9 g). This material was suspended in absolute EtOH (20 mL) excess ammonium formate (5 g) added followed by 20% Pd(OH)2 on carbon (100 mg) and the suspension very gently agitated overnight to effect cleavage of the CBZ protection group. Filtration through celite and concentration afforded the desired free amine (1.4 g, 2.7 mmol, 73%, 4 steps). 1H NMR (400 MHz, CDCl3) δ 8.41 (br, 2H), 7.36 9 br, 1H), 6.44 (bs, 1H), 6.37 (bs, 1H), 4.37-4.29 (m, 2H), 3.71 (s, 3H), 3.20-1.50 (m, 16H), 1.45 (s, 9H), 1.43 (s, 9H). ESMS m/z: 517 (M+H)+.
  • Figure US20080193381A1-20080814-C00011
    • Re(CO)3-2-(3-{3-[4-(Bis-pyridin-2-ylmethyl-amino)-butylcarbamoyl]-1-carboxy-propyl}-ureido)-pentanedioic acid[Br] (29) (MIP-1100)
  • The protected intermediate was prepared by reductive amination using pyridine-2-carboxaldehyde as previously described. Treatment with 2M LiOH in MeOH effected hydrolysis of the methyl ester. The methanol was removed and excess DCM:TFA (1:1) was added and the reaction stirred at room temperature overnight. The crude material was converted into the desired Rhenium conjugate following the procedure described above. Preparative HPLC afforded the desired molecule (9.5 mg, 16%). 1H NMR (400 MHz, DMSO-d6) δ 8.78 (m, 2H), 8.31 (br, 1H), 7.95 (m, 2H), 7.59 (m, 2H), 7.39 (m, 2H), 6.60-6.33 (m, 2H), 4.89 (m, 4H), 4.00 (m, 1H), 3.76 (m, 1H), 3.20-1.2 (m, 16H) (3 CO2H not seen). ESMS 842 (M−H)+.
  • Figure US20080193381A1-20080814-C00012
    • Synthesis of the Glu-urea-X-benzyl-Lysine Core Model Compounds.
  • The following compounds were all prepared in overall yields ranging from 20-40% usin the route depicted in Scheme 3. The Z-deprotected Glu-urea-lysine was mixed with the appropriate aldehyde (0.9 equivalents) at room temperature for one hour to form the □chiff base intermediate. The □chiff base was reduced using 1 equivalent of sodium triacetoxyborohydride. The compounds were deprotected using 50% TFA in DCM for 1 hour at room temperature. Upon completion, the reactions were concentrated on a rotary evaporator or were blown dry with nitrogen and extracted using methylene chloride and water. The water layer was evaporated to dryness to afford the deprotected product in 40-80% yield.
  • Figure US20080193381A1-20080814-C00013
  • 4-Trimethylstannanyl-benzaldehyde (5). To a solution of 4-iodobenzaldehyde (1.92 g, 8.27 mmol) in dry dioxane (60 mL) was added hexamethylditin (4.1 mL, 19.8 mmol) followed by Pd(Ph3P)Cl2 (150 mg) and the reaction mixture was heated for 3 h under reflux until judged complete. The reaction was filtered through celite and purified by column chromatography using hexanes/ethyl acetate (9/1) as eluent to afford (2.24 g, 98%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 9.97 (s, 1H), 7.81 (d, J=7.8 Hz, 2H), 7.72 (d, J=7.8 Hz, 2H), 0.29 (s, 9H). ESMS m/z: 268 (Sn-cluster).
  • Figure US20080193381A1-20080814-C00014
  • 2-{3-[1-tert-Butoxycarbonyl-5-(4-trimethylstannanyl-benzylamino)-pentyl]-ureido}-pentanedioic acid di-tert-butyl ester (6). To a solution of 2-[3-(5-Amino-1-tert-butoxycarbonyl-pentyl)-ureido]-pentanedioic acid di-tert-butyl ester (150 mg, 0.31 mmol) in DCE (10 mL) was added 4-Trimethylstannanyl-benzaldehyde (82 mg, 0.31 mmol) followed by sodium triacetoxyborohydride (98 mg, 0.47 mmol) and the reaction was stirred overnight at 40° C. The reaction was concentrated and purified by column chromatography using hexanes/ethyl acetate as eluent to afford the desired product (88 mg, 38%) as a thick syrup which begins to solidify upon standing. 1H NMR (400 MHz, DMSO-d6) δ 7.48 (d, J=7.4 Hz, 2H), 7.30 (d, J=7.4 Hz, 2H), 6.27 (m, 2H, NH's), 3.96 (m, 4H), 2.74 (bm, 2H), 2.21 (m, 2H), 1.87 (m, 2H), 1.65-1.19 (m, 7H), 1.35 (m, 27H, t-Bu's), 0.23 (s, 9H). ESMS m/z: 742 (Sn-cluster).
  • Figure US20080193381A1-20080814-C00015
  • (S,S)-2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid (7) (MIP 1033) The same experimental procedure as depicted in scheme 1, yielded 8% of 2-[3-(5-benzyloxycarbonylamino-1-tert-butoxycarbonyl-pentyl)-ureido]-pentanedioic acid di-tert-butyl ester. The compound was deprotected using the previously described methods and purified by HPLC to afford the desired product. 1H NMR (tri-t-butyl ester of Z-protected amine) (400 MHz, CDCl3,) δ 12.2 (s, 3H), 6.4 (s, 2H), 4.15 (m, 2H), 3.45 (m, 1H), 2.75 (bs, 1H), 2.2 (m, 4H), 1.90 (m, 2H), 1.65 (m, 2H), 1.50 (s, 2H), 1.35 (m, 2H). ESMS m/z: 622 (M−H)#.
  • Figure US20080193381A1-20080814-C00016
  • (S)-2-(3,3-Bis-pyridin-2-ylmethyl-ureido)-pentanedioic acid (8) (MIP 1025). The same experimental procedure as in the general synthesis, yielded 0.65 g, 48% of 2-(3,3-Bis-pyridin-2-ylmethyl-ureido)-pentanedioic acid di-tert-butyl ester. The compound was deprotected using the previously described methods and purified by HPLC to afford the desired product. 1H NMR (400 MHz, DMSO-d6) δ, 12.0 (bs, 2H), 8.68 (d, 2H), 8.00 (m, 2H), 7.41 (d, 4H), 7.14 (d, 1H), 4.73 (d, 4H), 3.96 (s, 1H), 2.18 (m, 2H), 1.80 (m, 2H).
  • Figure US20080193381A1-20080814-C00017
  • (S,S)-2-{3-[3-(Bis-pyridin-2-ylmethyl-amino)-1-carboxy-propyl]-ureido}-pentanedioic acid (9) (MIP 1028). The same experimental procedure as in the general synthesis in scheme 1, yielded 0.16 g, 35% of 2-{3-[3-(Bis-pyridin-2-ylmethyl-amino)-1-carboxy-propyl]-ureido}-pentanedioic acid di-tert-butyl ester. The compound was deprotected using the previously described methods and purified by HPLC to afford the desired product. 1H NMR (400 MHz, DMSO-d6) δ 12.4 (br, 2H), 9.37 (s, 1H), 8.52 (d, 2H), 7.80 (t, 2H), 7.14 (dd, 4H), 6.45 (m, 2H), 4.49 (br, 4H), 4.12 (s, 1H), 4.05 (s, 1H), 3.21 (m, 2H), 2.24 (m, 2H), 1.80 (m, 2H), 1.40 (m, 2H). ESMS m/z: (diethyl ester) 429 (M)+, 451 (M+Na).
  • Figure US20080193381A1-20080814-C00018
  • (S,S)-2-{3-[5-(Bis-pyridin-2-ylmethyl-amino)-1-carboxy-pentyl]-ureido}-pentanedioic acid (10) (MIP 1008). The same experimental procedure as in the general synthesis, yielded 0.09 g, 12% of 2-{3-[5-(Bis-pyridin-2-ylmethyl-amino)-1-carboxy-pentyl]-ureido}-pentanedioic acid di-tert-butyl ester. The compound was deprotected using the previously described methods and purified by HPLC to afford the desired product. 1H NMR (400 MHz, DMSO-d6) δ 12.7 (s, 2H), 8.97 (s, 1H), 8.65 (dd, 2H), 7.91 (dd, 2H), 7.45 (m, 4H), 6.44 (d, 1H), 6.28 (d, 1H), 4.45 (br, 4H), 4.10 (m, 2H), 3.15 (br, 2H), 2.60 (m, 2H), 2.25 (m, 2H), 1.90 (m, 2H), 1.78 (m, 2H), 1.45 (m, 2H).
  • Figure US20080193381A1-20080814-C00019
  • (S)-2-{3-[1-Carboxy-2-(4-iodo-phenyl)-ethyl]-ureido}-pentanedioic acid (11) (MIP-1034). The same experimental procedure as in the general synthesis, yielded 0.038 g, 5% of 2-{3-[1-Carboxy-2-(4-iodo-phenyl)-ethyl]-ureido}-pentanedioic acid di-tert-butyl ester. The compound was deprotected using the previously described methods. 1H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 3H), 7.65 (dd, 2H), 7.05 (dd, 2H), 6.30 (m, 2H), 4.25 (s, 1H), 4.05 (s, 1H), 2.90 (m, 2H), 2.2 (m, 2H), 1.80 (m, 2H). ESMS m/z: 429 (M)+, 451 (M+Na).
  • Figure US20080193381A1-20080814-C00020
  • (S,S)-2-{3-[1-Carboxy-5-(2-iodo-benzylamino)-pentyl]-ureido}-pentanedioic acid (12) (MIP 1035). The same general procedure, using the previously prepared and protected 2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid di t-butyl ester. The compound was deprotected using the previously described methods (5.5 mg, 66%). 1H NMR (400 MHz, DMSO-d6) δ 12.4 (s, 3H), 8.8 (s, 1H), 7.94 (m, 1H), 7.5 (m, 1H), 7.16 (t, 1H), 6.38 (m, 2H), 4.15 (m, 5H), 3.06 (s, 2H), 2.85 (s, 1H), 2.2 (m, 2H), 1.90 (m, 1H), 1.70 (m, 2H), 1.50 (s, 2H), 1.35 (m, 2H). ESMS m/z: 536 (M+H)+.
  • Figure US20080193381A1-20080814-C00021
  • (S,S)-2-{3-[1-Carboxy-5-(3-iodo-benzylamino)-pentyl]-ureido}-pentanedioic (13) (MIP 1089). The same general procedure, using previously prepared and protected 2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid di-t-butyl ester. The compound was deprotected using the previously described methods (4.1 mg, 53%). 1H NMR (400 MHz, DMSO-d6) δ 12.4 (s, 3H), 8.7 (s, 2H), 7.9 (s, 1H), 7.8 (d, 1H), 7.44 (d, 1H), 7.22 (t, 1H), 6.25 (s, 2H), 4.09 (m, 5H), 2.89 (s, 1H), 2.75 (s, 1H), 2.2 (d, 2H), 1.90 (m, 2H), 1.65 (m, 2H), 1.40 (m, 2H).
  • Figure US20080193381A1-20080814-C00022
  • (S,S)-2-{3-[1-Carboxy-5-(4-iodo-benzylamino)-pentyl]-ureido}-pentanedioic (14) (MIP 1072). The same general procedure, using previously prepared and protected 2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid di t-butyl ester. The compound was deprotected using the previously described methods (12 mg, 66%). 1H NMR (400 MHz, DMSO-d6) δ 12.4 (bs, 3H), 8.8 (br, 1H), 7.8 (d, 2H), 7.27 (d, 2H), 6.35 (br, 2H), 4.1 (m, 4H), 2.89 (m, 2H), 2.2 (d, 2H), 1.90 (m, 2H), 1.65 (m, 4H), 1.35 (m, 2H). ESMS m/z: 536 (M+H)+.
  • Figure US20080193381A1-20080814-C00023
  • (S,S)-2-{3-[1-Carboxy-5-(4-fluoro-benzylamino)-pentyl]-ureido}-pentanedioic (15) (MIP 1090). The same general procedure, using previously prepared and protected 2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid di t-butyl ester. The compound was deprotected using the previously described methods. 1H NMR (400 MHz, DMSO-d6) δ 12.4 (br, 3H), 8.7 (br, 1H), 7.5 (m, 2H), 7.3 (m, 2H), 6.35 (m, 2H), 4.1 (m, 4H), 2.9 (m, 2H), 2.2 (d, 2H), 1.90 (m, 2H), 1.60 (m, 4H), 1.35 (m, 2H). ESMS m/z: 428 (M+H)+, 450 (M+Na).
  • Figure US20080193381A1-20080814-C00024
  • (S,S)-2-{3-[1-Carboxy-5-(4-bromo-benzylamino)-pentyl]-ureido}-pentanedioic (16) (MIP 1094). The same general procedure, using previously prepared and protected 2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid di t-butyl ester. 1HNMR (tri t-butyl ester) (400 MHz, CDCl3) δ 7.52 (d, 2H), 7.32 (d, 2H), 6.28 (m, 2H), 3.98 (m, 2H), 2.55 (t, 2H), 2.48 (t, 2H), 2.22 (m, 2H), 1.85 (m, 2H), 1.62 (m, 2H), 1.45 (m, 2H), 1.37 (s, 27H), 1.28 (m, 2H) ESMS m/z: 642 (M+H)+. The compound was deprotected using the previously described methods. ESMS m/z: 474 (M+H)+.
  • Figure US20080193381A1-20080814-C00025
  • (S,S)-2-{3-[1-Carboxy-5-(4-iodo-benzoylamino)-pentyl]-ureido}-pentanedioic acid (17) (MIP 1044). The same general procedure, using previously prepared and protected 2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid di t-butyl ester. The compound was deprotected using the previously described methods. 1H NMR (400 MHz, DMSO-d6) δ 12.4 (s, 3H), 8.45 (s, 1H), 7.8 (dd, 2H), 7.6 (dd, 2H), 6.3 (s, 2H), 5.75 (s, 1H), 4.1 (m, 4H), 3.2 (s, 2H), 2.25 (d, 2H), 1.90 (m, 1H), 1.65 (m, 2H), 1.4 (m, 2H).
  • Figure US20080193381A1-20080814-C00026
    • 2-{3-[1-carboxy-5-(4-iodo-benzenesulfonylamino)-pentyl]-ureido}-pentanedioic acid (18). (MIP 1097)
  • In a round bottom flask 2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid di t-butyl ester (300 mg, 0.62 mmol) is suspended in water (10 mL) and 1,4 dioxane (10 mL) and TEA (1.75 mL, 1.25 mmol) was added followed by 4-iodo-benzenesulfonyl chloride and the mixture stirred overnight at 50° C. The reaction mixture was evaporated to dryness, taken up in DCM and chromatographed over silica gel to afford the desired product (375 mg, 80%) as a clear oil. The compound was deprotected using the previously described methods followed by HPLC purification to afford the desired product MIP-1097 as a whiter solid (270 grams, 90% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.97 (d, 2H), 7.68 (t, 1H), 7.53 (d, 2H), 6.35 (dd, 2H), 4.10 (m, 1H), 4.00 (m, 1H), 2.65 (m, 2H), 2.22 (m, 2H), 1.9 (m, 1H), 1.7 (m, 1H), 1.55 (m, 1H), 1.45 (m, 1H), 1.35 (m, 2H), 1.25 (m, 2H), (3 CO2H not seen). ESMS m/z: 565 (M+H)+.
  • Figure US20080193381A1-20080814-C00027
    • 2-(3-{1-Carboxy-5-[3-(4-iodo-phenyl)-ureido]-pentyl}-ureido)-pentanedioic acid (19) (MIP 1095)
  • In a round bottom flask 4-iodo-phenyl isocyanate (100 mg, 0.41 mmol) is dissolved in DCM (10 mL) containing TEA (0.057 mL, 0.4 mmol). 2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid di t-butyl ester (200 mg, 0.41 mmol) was added and stirred for 3 hours. The reaction mixture was evaporated to dryness and the crude mixture taken up in methanol (5 mL). Dropwise addition to water (20 mL) afforded a white precipitate which was collected and washed with water (20 mL) and dried to afford the desired tri-tert butyl ester as a white solid which was deprotected directly using the previously described method to afford the desired product (158 mg, 53%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.5 (d, 2H), 7.22 (d, 2H), 6.3 (t, 2H), 6.16 (t, 1H), 4.05 (m, 2H), 3.05 (m, 2H), 2.24 (m, 2H), 1.9 (m, 1H), 1.68 (m, 2H), 1.52 (m, 1H), 1.38 (m, 2H), 1.28 (m, 2H), (3 CO2H not seen). ESMS m/z: 565 (M+H)+.
  • Figure US20080193381A1-20080814-C00028
    • Synthesis of Glu-Urea-β-Phenyl Glycines (±)-3-Amino-3-(3-iodo-phenyl)-propionic acid (20)
  • Malonic acid (2.2 g, 21.5 mmol) and 3-iodobenzaldehyde (5 g, 21.5 mmol) were suspended in ethanol (50 mL) and ammonium acetate (1.66 g, 21.5 mmol) was added and the reaction heated to a reflux overnight. The reaction was cooled to room temperature filtered and washed with ethanol followed by ether and dried to afford the product (3.4 g, 11.6 mmol, 54%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.80 (s, 1H), 7.64 (dd, J=7.8 Hz, 1H), 7.42 (dd, J=7.6 Hz, 1H), 7.16 (dd, J=7.8 Hz, 1H), 7.14 (dd, J=7.6 Hz, 1H), 4.21 (m, 1H), 2.36 (m, 2H).
  • Figure US20080193381A1-20080814-C00029
    • (±)-3-Amino-3-(3-iodo-phenyl)-propionic acid methyl ester (21)
  • To a suspension of (±)-3-Amino-3-(3-iodo-phenyl)-propionic acid (3.1 g, 10.6 mmol) in methanol was added thionyl chloride (0.95 mL, 12.7 mmol) and the reaction was stirred at room temperature overnight. Concentration followed by trituration with ether gives a white solid. The solid is filtered, washed with ether and dried to afford the desired product (3.5 g, 10 mmol, 95%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.79 (br, 2H), 8.01 (s, 1H), 7.74 (d, J=8.1 Hz, 1H). 7.57 (d, J=7.8 Hz, 1H), 7.21 (dd, J=8.1, 7.8 Hz, 1H), 4.56 (br, 1H), 3.54 (s, 3H), 3.23-3.17 (m, 1H), 3.04-2.98 (m, 1H).
  • Figure US20080193381A1-20080814-C00030
    • (S,R) and (S,S)-2-{3-[1-(3-Iodo-phenyl)-2-methoxycarbonyl-ethyl]-ureido}-pentanedioic acid di-tert-butyl ester (22)
  • 2-[(Imidazole-1-carbonyl)-amino]-pentanedioic acid di-tert-butyl ester (370 mg, 1.05 mmol) was dissolved in DCE (10 mL) and cooled to 0° C. MeoTf (142 μL, 1.25 mmol) was added and the reaction was allowed to proceed for 20 min. (±)-3-Amino-3-(3-iodo-phenyl)-propionic acid methyl ester (356 mg, 1.045 mmol) was added and the reaction was allowed to warm to room temperature and then warmed to 55° C. and stirred overnight. The reaction was diluted with DCM (50 mL) and washed with water (30 mL), 5% aq. Citric acid (30 mL), sat. sodium bicarbonate (30 mL), water (30 mL) and brine (30 mL). The organic layer was dried over sodium sulfate and concentrated to afford the crude product. The product was purified by column chromatography to afford the desired product (303 mg, 0.51 mmol, 49%) as a white foam. 1H NMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.29 (s, 1H), 7.07-7.02 (m, 1H), 5.74 (br, 1H), 5.17 (br, 2H), 4.30 (m, 1H), 3.63 (s, 1.5H), 3.62 (s, 1.5H), 2.88-2.76 (m, 2H), 2.38-2.24 (m, 2H), 2.10-2.00 (m, 1H), 1.90-1.80 (m, 1H), 1.46 (s, 9H), 1.44 (s, 9H).
  • Figure US20080193381A1-20080814-C00031
    • (S,R) and (S,S)-2-{3-[2-Carboxy-1-(3-iodo-phenyl)-ethyl]-ureido}-pentanedioic acid (23)
  • To a solution of (±)2-{3-[1-(3-Iodo-phenyl)-2-methoxycarbonyl-ethyl]-ureido}-pentanedioic acid di-tert-butyl ester (289 mg, 0.49 mmol) was dissolved in methanol (3 mL) and 2M LiOH (0.5 mL) was added and the reqaction stirred at room temperature overnight. The reaction was diluted with water (20 mL) and the organic layer was extracted with ethyl acetate (2×20 mL) then acidified with 1N HCl to pH ˜2. The aqueous layer was extracted with ethyl acetate (3×20 mL), dried over sodium sulfate and concentrated to afford the crude product (206 mg, 0.36 mmol, 73%) as a white solid. To the crude material was added DCM (2 mL) followed by TFA (2 mL) and the reaction was stirred at room temperature overnight. Concentration followed by recrystallization from ethyl acetate afforded the desired product (22 mg, 0.047 mmol, 10%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.39 (br, 3H), 7.64 (br, 1H), 7.56 (m, 1H), 7.30 (bm, 1H), 7.10 (bm, 1H), 6.72 (bm, 1H), 6.34 (bm, 1H), 4.94 (br, 1H), 4.03 (bm, 1H), 2.64 (br, 2H), 2.20 (br, 2H), 1.86 (br, 1H), 1.71 (br, 1H). ESMS m/z: 463 (M−H)+.
  • Figure US20080193381A1-20080814-C00032
  • (S,S)-2-{3-[1-Carboxy-5-(2-chloro-benzylamino)-pentyl]-ureido}-pentanedioic (7) (MIP-1137). The same general procedure as shown in Scheme 1, using previously prepared and protected 2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid di-t-butyl ester. The compound was deprotected using the previously described methods to yield the desired product (100 mg, 45%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.0 (br, 3H), 7.63 (d, 1H), 7.2 (m, 2H), 7.15 (d, 1H), 6.30 (d, 2H), 4.1 (m, 4H), 2.9 (br, 2H), 2.2 (m, 2H), 1.90 (m, 2H), 1.60 (m, 4H), 1.35 (m, 2H). ESMS m/z: 444 (M+H)+.
  • Figure US20080193381A1-20080814-C00033
  • (S,S)-2-{3-[1-Carboxy-5-(3-chloro-benzylamino)-pentyl]-ureido}-pentanedioic (8) (MIP 1131). The same general procedure as shown in Scheme 1, using previously prepared and protected 2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid di t-butyl ester. The compound was deprotected using the previously described methods to yield the desired product (200 mg, 90%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.9 (br, 3H), 7.6 (s, H), 7.43 (m, 3H), 6.39 (br, 2H), 4.1 (m, 4H), 2.9 (br, 2H), 2.2 (m, 2H), 1.90 (m, 2H), 1.60 (m, 4H), 1.35 (m, 2H). ESMS m/z: 444 (M+H)+.
  • Figure US20080193381A1-20080814-C00034
  • (S,S)-2-{3-[1-Carboxy-5-(4-chloro-benzylamino)-pentyl]-ureido}-pentanedioic (9) (MIP 1135). The same general procedure as shown in Scheme 1, using previously prepared and protected 2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid di t-butyl ester. The compound was deprotected using the previously described methods to yield the desired product as (10 mg, 66%) as an off-white solid. ESMS m/z: 444 (M+H)+.
  • Figure US20080193381A1-20080814-C00035
  • (S)-2-(3-((R)-5-(benzylamino)-1-carboxypentyl)ureido)pentanedioic acid (10). (MIP-1106). The same general procedure as shown in Scheme 1, using previously prepared and protected 2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid di t-butyl ester. The compound was deprotected using the previously described methods to yield the desired product (5 mg, 47%) as an off-white solid. ESMS m/z: 410 (M+H)+.
  • Figure US20080193381A1-20080814-C00036
    • 2-(3-{1-Carboxy-5-[3-(phenyl)-ureido}-pentyl]-ureido)-pentanedioic acid (11) (MIP 1111)
  • In a round bottom flask phenyl isocyanate (100 mg, 0.84 mmol) was dissolved in DCM (10 mL) 2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid di t-butyl ester (409 mg, 0.84 mmol) was added and stirred for 3 hours. The reaction mixture was evaporated to dryness and the crude mixture was purified via flash column chromatography 2:1 hexanes/ethyl acetate to afford the tert-butyl ester as a white solid which was deprotected using TFA/CH2Cl2 affording the desired product. 1H NMR (400 MHz, DMSO-d6) δ 12.5 (s, 3H), 8.54 (s, 1H), 7.40 (dd, 2H), 7.26 (dd, 2H), 6.30 (t, 2H), 6.17 (t, 1H), 4.05 (m, 2H), 3.05 (m, 2H), 2.44 (m, 2H), 1.90 (m, 1H), 1.68 (m, 2H) 1.52 (m, 1H). 1.40 (m, 2H). 1.29 (m, 2H). ESMS m/z: 439 (M+H)+.
  • Figure US20080193381A1-20080814-C00037
    • 2-(3-{1-Carboxy-5-[3-(4-bromo-phenyl)-ureido]-pentyl}-ureido)-pentanedioic acid (12) (MIP 1129)
  • In a round bottom flask 4-bromo-phenyl isocyanate (100 mg, 0.50 mmol) was dissolved in DCM (10 mL). 2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid di t-butyl ester (246 mg, 0.50 mmol) was added and stirred for 3 hours. The reaction mixture was evaporated to dryness and the crude mixture was purified via flash column chromatography 2:1 hexanes/ethyl acetate to afford the tert-butyl ester as a white solid which was deprotected using TFA/CH2Cl2 affording the desired product
  • 1H NMR (400 MHz, DMSO-d6) δ 12.5 (s, 3H), 8.55 (s, 1H), 7.35 (d, 4H), 6.30 (t, 2H), 6.18 (t, 1H), 4.08 (m, 2H), 3.05 (m, 2H), 2.22 (m, 2H), 1.90 (m, 1H), 1.68 (m, 2H), 1.52 (m, 1H), 1.40 (m, 2H), 1.30 (m, 2H). ESMS m/z: 518 (M+H)+.
  • Figure US20080193381A1-20080814-C00038
    • 2-(3-{1-Carboxy-5-[3-(4-chloro-phenyl)-ureido]-pentyl}-ureido)-pentanedioic acid (13) (MIP 1110)
  • In a round bottom flask 4-chloro-phenyl isocyanate (100 mg, 0.65 mmol) was dissolved in DCM (10 mL) 2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid, di-t-butyl ester (318 mg, 0.65 mmol) was added and stirred for 3 hours. The reaction mixture was evaporated to dryness and the crude mixture was purified via flash column chromatography 2:1 hexanes/ethyl acetate to afford the tert-butyl ester as a white solid (470 mg, 96%) which was deprotected using TFA/CH2Cl2 affording the desired product
  • 1H NMR (400 MHz, DMSO-d6) δ 12.5 (s, 3H), 8.35 (s, 1H), 7.40 (dd, 2H), 7.19 (dd, 2H), 6.30 (t, 2H), 6.10 (t, 1H), 4.08 (m, 2H), 3.05 (m, 2H), 2.32 (m, 2H), 1.90 (m, 1H), 1.68 (m, 2H), 1.52 (m, 1H), 1.40 (m, 2H), 1.30 (m, 2H). ESMS m/z: 474 (M+H)+.
  • Figure US20080193381A1-20080814-C00039
  • (S)-2-(3-((R)-1-carboxy-5-(
    Figure US20080193381A1-20080814-P00001
    yridine
    Figure US20080193381A1-20080814-P00001
    ne-1-ylmethylamino)pentyl)ureido)pentanedioic acid. (14) (MIP-1108). The same general procedure as shown in Scheme A, using previously prepared and protected 2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid di t-butyl ester. The compound was deprotected using the previously described methods to yield the desired product (51 mg, 70%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.9 (br, 3H), 7.95 (m, 5H), 7.6 (m, 2H), 6.35 (br, 2H), 4.1 (m, 4H), 2.9 (br, 2H), 2.55 (m, 2H), 2.25 (m, 2H), 1.70 (m, 4H), 1.3 (m, 2H). ESMS m/z: 460 (M+H)+.
  • Figure US20080193381A1-20080814-C00040
  • 2-(3-{1-Carboxy-5-[3-(3-iodo-benzyl)-ureido]-pentyl}-ureido)-pentanedioic acid (15) (MIP-101). The same general procedure as shown in Scheme 2, using previously prepared and protected 2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid di t-butyl ester. The compound was deprotected using the previously described methods to yield the desired product. ESMS m/z: 579 (M+H)+.
  • Figure US20080193381A1-20080814-C00041
  • (19S,23S)-2-(4-iodobenzyl)-1-(4-iodophenyl)-13,21-dioxo-2,14,20,22-tetraazapentacosane-19,23,25-tricarboxylic acid (16) (MIP-1130). The same general procedure as shown in Scheme A, using previously prepared and protected 2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid di t-butyl ester. The compound was deprotected using the previously described methods to yield the desired product (8.3 mg, 10%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.8 (d), 7.3 (d), 6.3 (dd), 4.25 (br), 4.05 (m), 2.97 (m), 2.85 (br), 2.22 (m), 2.05 (m), 0.90 (m), 1.64 (m), 1.48 (m), 1.35 (m), 1.2 (m). ESMS m/z: 936 (M+H)+.
  • Figure US20080193381A1-20080814-C00042
    • Rhenium General Experimental:
  • The rhenium complexes of the SAAC-inhibitors are conveniently isolated from the reactions of the readily available precursor [Net4]2[Re(CO)3Br3] with the SAAC-inhibitor. Since the donor sets provided by the SAAC terminus are well documented as effective chelators for the {M(CO)3}+1 core and have been designed to adopt the required facial arrangement about the metal site, the preparations of the complexes were unexceptional.
  • The {Re(I)(CO)3}+ system followed similar reaction chemistry to that of the Tc-99m tricarbonyl core. The use of [Net4]2[ReBr3(CO)3], as the starting material led to facile formation of the fac-{Re(CO)3(L)3} core. The [Net4]2[ReBr3(CO)3] was readily derived from the [ReBr(CO)5]. The synthesis of the Re(I) complexes was accomplished by reacting [Net4]2[ReBr3(CO)3] with the appropriate TEC ligand in the ratio of 1:1.2 in 10 ml of methanol. The reaction was allowed to heat at 80° C. for 4 hours. After cooling all of the following reaction products were all purified using a small silica column with yields ranging from 10-30%.
  • Figure US20080193381A1-20080814-C00043
    • Glu-urea-Lys-PEG2-ReDP:
  • [Re(CO)3{(17R,21S)-11,19-dioxo-1-(
    Figure US20080193381A1-20080814-P00001
    I yridine-2-yl)-2-(
    Figure US20080193381A1-20080814-P00001
    yridine-2-ylmethyl)-5,8-dioxa-2,12,18,20-tetraazatricosane-17,21,23-tricarboxylic acid}][Br]. (17) (MIP-1133). The PEG2 dipyridyl compound, (17R,21S)-11,19-dioxo-1-(
    Figure US20080193381A1-20080814-P00001
    yridine-2-yl)-2-(
    Figure US20080193381A1-20080814-P00001
    yridine-2-ylmethyl)-dioxa-2,12,18,20-tetraazatricosane-17,21,23-tricarboxylic acid was prepared employing the same general procedure as shown in Scheme 1, using previously prepared and protected 2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid di t-butyl ester. The rhenium ester complex was prepared employing the same procedure as described in the general rhenium experimental. The compound was deprotected using the previously described methods to yield the desired product (2 mg, 20%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.8 (d), 8.00 (dd), 7.55 (d), 7.42 (dd), 6.45 (s), 3.95 (m), 3.4-3.6 (m), 2.45 (m), 1.25 (m), 1.1 (m), 0.8 (m). ESMS m/z: 931 (M+H)+.
    • Glu-urea-Lys-PEG4—ReDP:
  • [Re(CO)3{(23R,27S)-17,25-dioxo-1-(pyridin-2-yl)-2-(pyridin-2-ylmethyl)-5,8,11,14-tetraoxa-2,18,24,26-tetraazanonacosane-23,27,29-tricarboxylic acid}][Br]. (18) (KM11-200). The PEG4 dipyridyl compound (23R,27S)-17,25-dioxo-1-(pyridin-2-yl)-2-(pyridin-2-ylmethyl)-5,8,11,14-tetraoxa-2,18,24,26-tetraazanonacosane-23,27,29-tricarboxylic acid was prepared employing the same general procedure as shown in Scheme A, using previously prepared and protected 2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid di t-butyl ester. The rhenium ester complex was prepared employing the same procedure as described in the general rhenium experimental. The compound was deprotected using the previously described methods to yield the desired product. (5.1 mg, 29.6%) as a white solid. ESMS m/z: 1019 (M+H)+.
    • Glu-urea-Lys-PEG8—ReDP:
  • [Re(CO)3{(35R,39S)-29,37-dioxo-1-(□yridine-2-yl)-2-(□yridine-2-ylmethyl)-5,8,11,14,17,20,23,26-octaoxa-2,30,36,38-tetraazahentetracontane-35,39,41-tricarboxylic acid}][Br]. (19) (MIP-1132). The PEG8 dipyridyl compound, (35R,39S)-29,37-dioxo-1-(pyridin-2-yl)-2-(pyridin-2-ylmethyl)-5,8,11,14,17,20,23,26-octaoxa-2,30,36,38-tetraazahentetracontane-35,39,41-tricarboxylic acid was prepared employing the same general procedure as shown in Scheme A, using previously prepared and protected 2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid di t-butyl ester. The rhenium ester complex was prepared employing the same procedure as described in the general rhenium experimental. The compound was deprotected using the previously described methods to yield the desired product (8.0 mg, 30.4%) as a white solid. ESMS m/z: 1195 (M+H)+.
    • Glu-urea-Lys-C11PAMA-Re:
  • [Re(CO)3{(19R,23S)-13,21-dioxo-2-(□yridine-2-ylmethyl)-2,14,20,22-tetraazapentacosane-1,19,23,25-tetracarboxylic acid}] (20) (MIP-1109). The C11-PAMA compound, (19R,23S)-13,21-dioxo-2-(□yridine-2-ylmethyl)-2,14,20,22-tetraazapentacosane-1,19,23,25-tetracarboxylic acid was prepared employing the same general procedure as shown in Scheme A, using previously prepared and protected 2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid di t-butyl ester. The rhenium ester complex was prepared employing the same procedure as described in the general rhenium experimental. The compound was deprotected using the previously described methods to yield the desired product (3.0 mg, 75%) as an off-white solid. ESMS m/z: 922 (M+H)+.
  • Figure US20080193381A1-20080814-C00044
  • Table 1 below is a summary of synthesized PSMA inhibitors investigated.
    • Table 1
  • TABLE 1
    Summary of in vitro cell binding data of the additional or
    retested Glu-Urea-Lys derivatives.
    Compound
    MIP # X Description IC50 (nM)
    — — PMPA  10
    1033 — Glu-urea-Lys 498
    1137 2-Cl 2-Cl-benzyl 245
    1131 3-Cl 3-Cl-benzyl 277
    1135 4-Cl 4-Cl-benzyl  2
    1106 H Des-halo benzyl 2960 
    1111 H Des-halo diurea  12
    1129 4-Br 4-Br-diurea  2
    1110 4-Cl 4-Cl-diurea  4
    1108 — 2-naphyl 154
    1101 3-I 3-I-diurea  10
    1130 4-di-I C11 4-di-iodo 300
    1133 — PEG2Re 227
    KM11-200 — PEG4Re NA
    1132 — PEG8Re 1747 
    1109 — C11PAMA-Re 696
    1027 4-I 4-I-benzoyl   3*
    1095 4-I 4-I-diurea  10*
    • β-Amino Acid Analogs
  • β-amino acid analogs of MIP-1072, MIP-1095, MIP-1027 specifically but the extension to other analogs such as the technetium conjugates as well as other halogen analogs is very desirable. We have no new examples to support this claim at this time.
  • MIP-1072 β-amino acid analogs
  • Figure US20080193381A1-20080814-C00045
  • MIP-1095 β-amino acid analogs
  • Figure US20080193381A1-20080814-C00046
    • Synthesis of {Re(CO)3}+1 Core Model Complexes
  • The properties of the Group VII metals technetium and rhenium are very similar due to their periodic relationship. It was anticipated that the metals would demonstrate similar reaction chemistry, which is often the case for the tricarbonyl, nitrogen, and thiazole chemistry of these two metals. Likewise, due to their similar size that stabilizes the spin paired d6 electron configuration of M(I), perrhenate and pertechnetate have very similar reaction behaviors. Synthesizing the rhenium-TECs allowed us a facile route to structurally characterize the products. The periodic relationship between Tc and Re indicates that Tc-99m radiopharmaceuticals can be designed by modeling analogous rhenium complexes.
  • Some of the new compounds were synthesized with macroscopic quantities of rhenium for characterization by conventional methods, including mass-spectrometry, 1H and 13C NMR spectrometry. Following purification, the synthesized rhenium complexes were run through a HPLC column for purification and identification of retention times to compare with Tc reaction products. The rhenium-TEC complexes were also crystallized.
  • The rhenium complexes of the SAAC-inhibitors are conveniently isolated from the reactions of the readily available precursors {Re(CO)3(H2O)3}+1 and [Net4]2[Re(CO)3Br3] with the SAAC-inhibitor. Since the donor sets provided by the SAAC terminus are well documented as effective chelators for the {M(CO)3}+1 core and have been designed to adopt the required facial arrangement about the metal site, the preparations of the complexes were unexceptional.
    • GENERAL EXPERIMENTAL
  • The {Re(I)(CO)3}+ system followed similar reaction chemistry to that of the Tc-99m tricarbonyl core. The use of [Net4]2[ReBr3(CO)3], as the starting material led to facile formation of the fac-{Re(CO)3(L)3} core. The [Net4]2[ReBr3(CO)3] was readily derived from the [ReBr(CO)5]. The synthesis of the Re(I) complexes was accomplished by reacting [Net4]2[ReBr3(CO)3] with the appropriate TEC ligand in the ratio of 1:1.2 in 10 ml of methanol. The reaction was allowed to heat at 80° C. for 4 hours. After cooling all of the following reaction products were all purified using a small silica column with yields ranging from 10-30%.
  • [Re(CO)3(2-{3-[3-(Bis-pyridin-2-ylmethyl-amino)-1-carboxy-propyl]-ureido}-pentanediethyl ester)][Br] (24). 1H NMR (400 MHz, DMSO-d6) δ 8.65 (dd, 2H), 7.85 (dd, 2H), 7.7 (dd, 4H), 7.25 (dd, 2H), 6.42 (dd, 1H), 6.0 (dd, 1H), 4.5 (m, 2H), 4.16 (m, 2H), 3.80 (m, 4H), 2.45 (m, 2H), 2.0 (dd, 2H), 1.5 (m, 4H), 1.25 (m, 6H). ESMS m/z: 812-815.
  • Figure US20080193381A1-20080814-C00047
  • [Re(CO)3(2-{3-[5-(Bis-pyridin-2-ylmethyl-amino)-1-carboxy-pentyl]-ureido}-pentanedioic acid)][Br] (25) (MIP 1029). 1H NMR (400 MHz, DMSO-d6) δ 12.6 (s, 2H), 8.91 (s, 1H), 8.63 (dd, 2H), 7.85 (dd, 2H), 7.75 (dd, 4H), 7.3 (dd, 2H), 6.44 (d, H), 6.28 (d, 1H), 4.45 (s, 2H), 4.10 (m, 2H), 3.15 (s, 1H), 2.60 (m, 2H), 2.25 (m, 2H), 1.90 (m, 1H), 1.78 (m, 2H), 1.45 (m, 2H). ESMS m/z: 770-774.
  • Figure US20080193381A1-20080814-C00048
  • 2-{3-[1-Carboxy-5-(carboxymethyl-pyridin-2-ylmethyl-amino)-pentyl]-ureido}-pentanedioic acid (26). The same general procedure, using the previously prepared and protected 2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid di t-butyl ester. The compound was deprotected using the previously described methods (2.2 mg, 65%). 1H NMR (400 MHz, DMSO-d6) δ 8.65 (d, 1H), 7.91 (dd, 1H), 7.56 (d, 1H), 7.45 (dd, 1H), 6.31 (m, 2H), 4.34 (s, 2H), 4.08 (m, 4H), 3.10 (m, 2H), 2.24 (m, 2H), 1.95 (m, 1H), 1.68 (m, 4H), 1.5 (m, 1H), 1.22 (m, 2H). ESMS m/z: 469 (M+H)+. M+1 469.
  • [Re(CO)3(2-{3-[1-Carboxy-5-(carboxymethyl-pyridin-2-ylmethyl-amino)-pentyl]-ureido}-pentanedioic acid)] (27). 1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, 1H), 8.13 (dd, 1H), 7.69 (d, 1H), 7.57 (dd, 1H), 6.45 (m, 2H), 4.75 (m, 1H), 4.50 (m, 1H), 4.20 (m, 2H), 3.61 (m, 4H), 3.15 (m, 2H), 2.38 (m, 1H), 2.0 (m, 2H), 1.75 (m, 4H), 1.62 (m, 1H), 1.25 (m, 2H). ESMS m/z 779-782 (M+2Na)+.
  • Figure US20080193381A1-20080814-C00049
    • Synthesis of Glu-Urea-Lys(N-benzyl-X) analogs (3)
  • The compounds of the general structure 3 were prepared in overall yields ranging from 20-40% using the general route depicted in Scheme A. The key synthetic intermediate (1) was reacted with the appropriate aldehyde at room temperature in for one hour to form the □yridi base intermediate. The □yridi base was not isolated but was reduced in situ with sodium triacetoxyborohydride. The t-butyl ester protecting groups were removed using 50% TFA in DCM for 1 hour at room temperature. Upon completion of the deprotection, the reactions were concentrated on a rotary evaporator and purified by HPLC or flash chromatography to afford the desired products (3) in 40-80% yield.
  • Figure US20080193381A1-20080814-C00050
    • Synthesis of Glu-Urea-Ureido(Phenyl-X) Analogs
  • The following compounds of the general structure 8 were prepared in overall yields ranging from 20-60% by the route depicted in Scheme B. The key synthetic intermediate (4) was reacted with the appropriate phenylisocyanate at room temperature to afford the desired protected intermediates (5) in good yields. The t-butyl ester protecting groups were removed in the presence of 50% TFA in DCM for 1 hour at room temperature. Upon completion, the reactions were concentrated on a rotary evaporator purified by HPLC or recrystallization to afford the desired products (6) in 40-90% yield.
  • Figure US20080193381A1-20080814-C00051
    • Preparation and Characterization of the Radio-labeled Complexes Technetium-99m Labeling
  • Preparation of the 99mTc-labeled complexes were achieved by addition of 100 μL of a solution containing [99mTc(CO)3(H2O)3]+ to 500 μL of 10−4 M solutions of the inhibitor-SAAC. The mixtures were heated at 70° C. for 30 min. The products were analyzed for their radiochemical purity by reverse-phase HPLC.
  • The stability of the radiolabeled compounds in solution and in serum were determined as a function of time and solution conditions. Specifically, after radiolabeling and isolation, the product was stored at room temperature for 6 h after which HPLC analysis was performed to check for degree of label retention, as well as potential product degradation. The reformation of TcO4 − and the presence of the reduced material TcO2 was analyzed.
  • To assist in predicting the in vivo stability, ligand challenges were performed. Specifically, the stabilities of the 99mTc complexes were investigated by incubating the HPLC purified complexes in 5% mouse serum at room temperature and 37° C. The ability of competing ligands, such as cysteine and DTPA, to extract Tc-99m from the complexes was studied by incubating the purified complexes with solutions (PBS pH 7.2) containing competing ligands at final concentrations of 0.1 M.
  • The results of the labeling competition studies demonstrated no degradation of the Tc-99m-complexes out to 6 hours in the serum or the competing ligands study. The results of the incubation at 37° C. after 6 hours are shown in FIG. 2.
    • Iodinations of DCT
  • Preparation of the iodine-131 labeled compound N—[N—[(S)-1,3-dicarboxypropyl]carbamoyl]-S-3-iodo-L-tyrosine (I-131-DCIT) was achieved by addition of 100 ul of [I-131] NaI in 0.1 N NaOH to a PBS (pH 7.2) solution containing DCT (1 mg/mL) in an Iodogen tube™ (Fisher Scientific, Pierce). The mixture was vortexed for 3 minutes and stored at room temperature for 20 minutes.
  • The stability of the radiolabeled compound in solution was determined as a function of time. Specifically, after radiolabeling and isolation, the product was stored at room temperature for 48 h after which HPLC analysis was performed to check for degree of label retention, as well as potential product degradation. The reformation of NaI and the presence of the reduced iodates was analyzed. The results of the labeling stability study demonstrated no significant degradation of the I-131 DCIT out to 2 days at room temperature. The results of the study are shown in FIG. 3.
  • Preparation of the iodine-131 labeled compound 2-{3-[1-Carboxy-5-(4-iodo-benzoylamino)-pentyl]-ureido}-pentanedioic acid (I-131-MIP 1072) was achieved by addition of 100 ul of [I-131] NaI in 0.1 N NaOH with 30 μl methanol with 0.5% acetic acid to a PBS (pH 7.2) solution containing MIP 1072 (1 mg/mL) in an IODOGEN TUBE (Fisher Scientific). The mixture was vortexed for 3 minutes and stored at room temperature for 20 minutes.
  • The stability of the radiolabeled compound in solution was determined as a function of time. Specifically, after radiolabeling and isolation, the product was stored at 37° C. for 3 days after which HPLC analysis was performed to check for degree of label retention, as well as potential product degradation. The reformation of NaI and the presence of the reduced iodates was analyzed. The results of the labeling stability study demonstrated no significant degradation of the I-13 11072 out to 3 days at room temperature in DMSO, 10% ethanol/saline, PBS pH 7.2, and 6% ascorbate/3% gentisic acid solution. The results of the study are shown in FIG. 4.
    • Biological Characterization of SAAC-Urea-Glutamate Conjugates
  • The newly prepared SAAC-urea-Glu conjugates were screened in a human prostate cancer cell binding assay using PSMA-positive, LnCap cells, and PSMA-negative, PC3 cells. Compounds demonstrating specific uptake or binding to PSMA-positive cells will be studied for tumor localization in vivo.
  • In vitro cold screening assays verses 1-131 DCIT. LNCaP and PC3 human prostate cancer cells were obtained from American Type Culture Collection, Rockville, Md. LNCaP cells were maintained in RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS). PC3 cells were grown in F12K medium supplemented with 10% FBS. Binding of the radiolabeled compound and competition with cold derivatives to LNCaP and PC-3 cells was performed according to the methods of Tang et al. (Tang, H.; Brown, M.; Ye, Y.; Huang, G.; Zhang, Y.; Wang, Y.; Zhai, H.; Chen, X.; Shen, T. Y.; Tenniswood, M., Prostate targeting ligands based on N-acetylated alpha-linked acidic dipeptidase, Biochem. Biophys. Res. Commun. 2003, 307, 8-14) with appropriate modifications. Cells were plated in 12-well plates at approximately 4×105 cells/well and incubated for 48 hours in a humidified incubator at 37° C./5% carbon dioxide prior to addition of compound. Each unique SAAC-urea-Glu conjugate was prepared and diluted in serum-free cell culture medium containing 0.5% bovine serum albumin (BSA) in combination with 3 nM I-131 DCIT (known inhibitor). Total binding was determined by incubating I-131 DCIT without test compound. Plates were incubated at room temperature for 1 hour. Cells were removed from the plates by gently pipetting and transferred to eppendorf tubes. Samples were microcentrifuged for 15 seconds at 10K×g. The medium was aspirated and the pellet was washed twice by dispersal in fresh assay medium followed by microcentrifugation. Cell binding of I-131 DCIT was determined by counting the cell pellet in an automated gamma counter. Nonspecific binding was determined as the counts associated with the cells after incubating with 2 uM nonradiolabeled compound or 2-phosphonomethyl-pentanedioic acid (PMPA). The control compounds are depicted below.
  • Figure US20080193381A1-20080814-C00052
  • The two key compounds for the binding assays, are shown above: the I-DCIT (Kozikowski et al) and 2-Phosphonomethyl-pentanedioic acid (PMPA-right), a potent inhibitor with IC50=6 nM.
  • (ii) In vitro dose screening. I-131 DCIT bound specifically to LnCap cells and not PC3 cells as is evident by the counts displaceable by nonradiolabeled compound or PMPA in LnCap cells only (FIG. 5). Binding constants were determined by incubating LnCap cells with various amounts of nonradiolabeled DCIT in the presence of a constant amount of I-131 DCIT and dividing by the specific activity of each solution to determine the number of fmoles compound bound (FIG. 6). The Kd was determined to be 264 nM and Bmax was 254 fmoles. Compounds MIP-1008 and MIP-1033 which at 2 uM competed with I-131 DCIT for binding to LnCap cells, were retested at various doses to determine IC-50 values (FIGS. 7 and 8). While MIP-1072, MIP-1095, and MIP-1097 displayed IC50 values<50 nm compounds MIP-1008 and MIP-1033 exhibited IC-50s of 98 nM and 497 nM, respectively. Compounds MIP-1025, MIP-1028, and MIP-1029 did not compete for binding (Table 1).
  • In order to confirm the results of the Scatchard analysis of FIG. 7 indicating MIP-1072 internalization into LNCaP cells, the rate of uptake of MIP-1072 in LNCaP cells was monitored. Each well was dosed with 100 nM MIP-1072 (2 uCi/well) at 4° C. and 37° C. Binding to PSMA reached equilibrium after 15 min as evidenced by the plateau in the curve at 4° C. The cells incubated at 37° C. continued to internalize MIP-1072 after equilibrium had been reached. This result, FIG. 10, confirms the Scatchard and indicates that MIP-1072 is indeed internalized.
  • (iii) Microsome Assay Experimental
  • Pooled male rat liver microsomes (1 mg/mL, BD Biosciences), NADPH regenerating system (1.3 mM NADP, 3.3 mM glucose 6-phosphate and 0.4 U/mL glucose 6-phosphate dehydrogenase, BD Biosciences) and test compound (50 μM MIP-1072, 50 μM DCT, and 100 μM phenacetin) were added to 0.1 M potassium phosphate buffer (pH 7.4) in order to monitor the catastrophic degradation of the test compounds. The mixture was incubated at 37° C. and at the indicated time (0, 15, 60 min) the reaction was stopped by the addition of an equal volume of ice cold methanol (500 μL). The resulting slurry was then centrifuged at 21,000×G for 10 min and the supernatant was collected and injected onto an Agilent LCMS model MSD SL using a 95:5 water:acetonitrile (with 0.1% formic acid) to 40:60 water:acetonitrile (with 0.1% formic acid) gradient and monitoring for the parent ion only in single ion mode. The results, shown in FIGS. 11A and 11B, are expressed as degradation of the parent ion with respect to the 0 min time point.
  • The stability of MIP-1072 was assessed using rat liver microsomes. MIP-1072 (50 μM) and Phenacetin (100 μM) were incubated with rat liver microsomes at 37° C. for the indicated time. Phenacetin was used as a control substance that is known to be metabolized. MIP-1072 was not degraded by the rat liver microsomes during the incubation period. However, phenacetin was degraded by 22% after a 60 min incubation.
  • The lead compound, MIP 1072, was I-131-labeled for tissue distribution studies in mice with both LNCaP (PSMA positive) and PC3 (PSMA negative) tumors implanted. The compound was radiolabeled by the route shown below.
  • Figure US20080193381A1-20080814-C00053
  • The tissue biodistribution results, were consistent with the in-vitro data, and demonstrated significant uptake in the LNCaP (PSMA positive) tumors. The results also displayed a high degree of specificity with very little activity in the PC3 (PSMA negative) tumors. A graph depicting the mice distribution is shown below (FIG. 12).
  • The biological assessment using N—[N—[(S)-1,3-dicarboxypropyl]carbamoyl]-S-3-iodo-L-tyrosine (I-131-DCIT) verses “cold” complexes proved to be a rapid first screen, followed by dose curves to determine accurate IC50 values. The lead series of compounds that exhibited IC50 values<50 nM. In vivo data of the lead series demonstrated high affinity, with 3% ID/g accumulating in the LNCaP tumors, and high specificity with the LNCaP-to-PC3 ratio exceeding 15-to 1.
    • LNCaP Cell Lysis Protocol
    • 2 confluent T75 Flasks
    • Wash cells off the plate by pipetting up and down with media.
    • Wash with 0.32 M sucrose, re-centrifuge
    • Re-suspend cell pellet in 1 mL 50 mM Tris-HCl, pH 7.4, 0.5% Triton X-100
    • Centrifuge at 14000 rpm for 1 min to precipitate nuclei
    • Remove supernatant and divide into 50 uL aliquots
    • Store at −80 C
    Protein Assay:
    • Bio-Rad Protein Standard II-1.44 mg/ml
    • Since using detergent in lysis step, make working reagent, A′ by adding 20 uL of
    • reagent S to each 1 mL of reagent A that will be needed for the run. (If a precipitate forms, warm and vortex)
    • Prepare 5 protein dilutions—0, 0.2, 0.4, 0.8, 1.6 mg/mL
    • Also prepare 1/10, 1/100, and 1/1000 dilutions of the unknown
    • Combine 25 μL standard/unknown, 100 μL A′, 800 μL reagent B in duplicate. Mix
    • After ˜15 min measure absorbance at 750 nM
    NAALADase Assay:
    • Rxn Buffer: 50 mM Tris-HCl, pH 7.4, 20 mM CoCl2, 32 mM NaCl
    • Make cold NAAG (100 mM stock) dilute 1/100 in Rxn Buffer for 1 mM
    • Combine 600 uL buffer and LNCaP cell lysate (200 μg) Pre-incubate 37 C for 3 min
    • Pre-incubate Rxn Buffer and LNCaP cell lysate for 3 min at 37 C
    • Add 6 μL of 1 mM NAAG (for 1 μM final conc) spiked with 1,000,000 CPM of 3H-NAAG (100 μL of 1 mM NAAG+10 μL of 3H-NAAG (10 μCi)). For competition add PMPA.
    • Incubate for 30 min
    • At indicated time, stop reaction by removing 100 uL of the reaction-mix and adding an equal volume of ice cold 0.25 M KH2PO4, pH 4.3 to stop the rxn
    • Apply ½ of mixture to 250 mg AG 50W-X4 cation exchange column (200-400 mesh, H+ form, swell resin with DI H2O prior to use). Save the other ½ for counting.
    • Wash column with 500 μL 1:1 Rxn Buffer/0.25MKH2PO4
    • Elute with 3M KCl (1.5 mL)
    • Count 100 uL of the load, elution and reaction (diluted 1:6) to minimize quenching
  • Notes:
    • Time=0 control values will be subtracted from experimental time points
    • Results expressed as pmol 3H-glutamate formed/min/mg protein
    • Grant says inc only 10 min to ensure linearity, although Luthi-Carter, et al (J Pharm Exp Therap 1998 286(2)) says 2 hours still no effect on linearity and less than 20% of the substrate consumed
    Therapeutic Treatments
  • Compounds of the present can be used to inhibit NAALADase for therapeutic treatments. Diseases that could be receptive to NAALADase treatment include painful and sensory diabetic neuropathy, neuronal damage and prostate cancer, schizophrenia, colorectal cancer, inflammation, amyotrophic lateral schlerosis, or diabetic neuropathy. The present compounds can also be used an analgesic. Guidance for the modeling of such therapeutic treatments can be found in Goodman & Gilman's The Pharmacological Basis of Therapeutics, McGraw Hill, 10 edition, 2001, Pharmaceutical Preformulation and Formulation: A Practical Guide from Candidate Drug Selection to Commercial Dosage Form, CRC, 2001 and Handbook of Pharmaceutical Excipients, AphA Publications, 5 edition, 2005.
    • Competitive Binding of Analogs (FIG. 16)
  • The ability of non-radioactive analogs to compete with 131I-DCIT for binding to PSMA was tested in the PSMA positive human prostate cancer cell line, LNCaP cells. LNCaP cells (300,000 cells/well) were incubated for 1 hour with 3 nM [131I]-DCIT in the presence of 1-10,000 mM MIP-1072 in RPMI-1640 medium supplemented with 0.5% bovine serum albumin, then washed and counted in a gamma counter. All documents cited in this specification including patent applications are incorporated by reference in their entirety.
    • Direct Binding and Internalization of MIP-1072
  • The direct binding of 123I-MIP-1072 to prostate cancer cells was examined (FIG. 17). LNCaP cells, or the PSMA negative cell line, PC3 cells, were incubated in RPMI-1640 medium supplemented with 0.5% bovine serum albumin for 1 hour with 3 nM 123I-MIP-1072 alone, or in the presence of 10 μM unlabeled MIP-1072, or 10 μM 2-(phosphonomethyl)-pentanedioic acid (PMPA), a structurally unrelated NAALADase inhibitor. Cells were washed and counted in a gamma counter.
  • The affinity constant (Kd) of MIP-1072 was determined by saturation binding analysis (FIG. 18). LNCaP cells were incubated for 1 hour with 30-100,000 pM 131I-MIP-1072 in HBS (50 mM Hepes, pH 7.5, 0.9% sodium chloride) at either 4° C. or 37° C. in the absence or presence of 10 μM unlabeled MIP-1072 (to determine non-specific binding). Cells were then washed and the amount of radioactivity was measured on a gamma counter. Specific binding was calculated as the difference between total binding and nonspecific binding. The affinity constant (Kd) of the interaction of MIP-1072 with PSMA on LNCaP cells was determined by saturation binding analysis performed by titrating 123I-MIP-1072 (3 pM-1,000 nM) in the presence and absence of an excess of non-radiolabeled MIP-1072 (10 μM). A Kd of 4.8 nM, and Bmax of 1,490 fmoles/106 cells at 4° C. was determined by nonlinear regression analysis using Graph Pad Prism software (FIG. 18). The Kd was not significantly different at 37° C., 8.1 nM. The Bmax, however, was greater at 37° C. than at 4° C.; 1,490 vs. 4,400 fmol/106 cells, respectively, indicating internalization of MIP-1072. The results below are representative of two independent analyses.
  • The ability of MIP-1072 to internalize in LNCaP cells was confirmed by an acid wash assay (FIG. 19). LNCaP cells were incubated in HBS with 100 nM 123I-MIP-1072 for 0-2 hours at 4 and 37° C. At the indicated time the media was removed and the cells were incubated in mild acid buffer (50 mM glycine, 150 mM NaCl, pH 3.0) at 4° C. for 5 minutes. After the brief incubation the cells were centrifuged at 20,000×g for 5 minutes. The supernatant and cell pellet were counted in a gamma counter. In order to confirm the results of the saturation binding analysis indicating MIP-1072 internalization into LNCaP cells, we monitored the rate of uptake of MIP-1072 in LNCaP cells. Each well was dosed with 100 nM MIP-1072 (2 uCi/well) at 4° C. and 37° C. Binding to PSMA reached equilibrium after 15 min as evidenced by the plateau in the curve at 4° C. The cells incubated at 37° C. continued to internalize MIP-1072 after equilibrium had been reached. The results show a time dependent, acid insensitive increase in radioactivity associated with the pellet at 37° C. but not at 4° C., indicating that 123I-MIP-1072 is internalized at 37° C. but not at 4° C. (FIG. 19).
    • Tumor Uptake and Tissue Distribution of 123I-MIP-1072
  • A quantitative analysis of the tissue distribution of 123I-MIP-1072 was performed in separate groups of male NCr Nude−/− mice bearing PSMA positive LNCaP xenografts (approximately 100-200 mm3) administered via the tail vein as a bolus injection (approximately 2 μCi/mouse) in a constant volume of 0.05 ml. The animals (n=5/time point) were euthanized by asphyxiation with carbon dioxide at 0.25, 1, 2, 4, 8, and 24 hours post injection. Tissues (blood, heart, lungs, liver, spleen, kidneys, adrenals, stomach, large and small intestines (with contents), testes, skeletal muscle, bone, brain, adipose, and tumor) were dissected, excised, weighed wet, transferred to plastic tubes and counted in an automated γ-counter (LKB Model 1282, Wallac Oy, Finland). To compare uptake of 123I-MIP-1072 in LNCaP versus PC3 tumors, and to demonstrate that the compound was on mechanism via competition with 2-(phosphonomethyl)-pentanedioic acid (PMPA), some mice bearing either LNCaP or PC3 xenografts were pretreated with 50 mg/kg PMPA 5 minutes prior to injection with 123I-MIP-1072 and selected tissues were harvested at 1 hour post injection. MIP-1072, uptake and exposure was greatest in the kidney and LNCaP xenograft which express high levels of PSMA. Peak uptake in the kidney was 158±46% ID/g at 2 hours and the LNCaP xenograft was 17±6% ID/g at 1 hours (FIG. 20). Uptake in these target tissues was rapid, whereas the washout was slower in the LNCaP xenograft. 123I-MIP-1072 was demonstrated to be on mechanism in vivo as evidenced by the localization to PSMA expressing LNCaP tumors but not PC3 tumors which do not express PSMA (FIG. 21). In addition, both the tumor and kidneys were blocked by pretreating the mice with PMPA, a potent inhibitor of PSMA.

Claims (67)

1. A compound of Formula (I)
Figure US20080193381A1-20080814-C00054
wherein R is a C6-C12 substituted or unsubstituted aryl, a C6-C2 substituted or unsubstituted heteroaryl, a C1-C6 substituted or unsubstituted alkyl or —NR′R′,
Q is C(O), O, NR′, S, S(O)2, C(O)2 (CH2)p
Y is C(O), O, NR′, S, S(O)2, C(O)2 (CH2)p
Z is H or C1-C4 alkyl,
m is 0, 1, 2, 3, 4 or 5
n is 0, 1, 2, 3, 4, 5 or 6
p is 0, 1, 2, 3, 4, 5 or 6
R′ is H, C(O), S(O)2, C(O)2, a C6-C12 substituted or unsubstituted aryl, a C6-C12 substituted or unsubstituted heteroaryl or a C1-C6 substituted or unsubstituted alkyl, when substituted, aryl, heteroaryl and alkyl are substituted with halogen, C6-C12 heteroaryl, —NR′R′ or COOZ
further wherein
(i) at least one of R or R′ is a C6-C12 aryl or C6-C12 heteroaryl substituted with a halogen or
(ii) at least one of R or R′ is a C6-C12 heteroaryl
or a pharmaceutically acceptable salt of the compound of Formula (I).
2. The compound of claim 1, wherein the halogen is a radiohalogen, I-123, I-125, I-131, I-124, Br-75, Br-77, or F-18.
3. The compound of claim 1, wherein
n is 0 or 1
m is 0, 1, 2, 3 or 4
Q is NR′
Y is C(O) or CH2 and
R is a C6-C12 substituted or substituted aryl.
4. The compound of claim 3, wherein R is a phenyl moiety substituted with a halogen.
5. The compound of claim 4, wherein the compound is:
Figure US20080193381A1-20080814-C00055
Figure US20080193381A1-20080814-C00056
Figure US20080193381A1-20080814-C00057
Figure US20080193381A1-20080814-C00058
wherein the carboxy groups of any of the above compounds can be substituted with C1-C4 alkyl and
X is selected from the group consisting of halogen, radiohalogen, I-123, I-125, I-131, I-124, Br-75, Br-77, and F-18.
6. The compound of claim 4, wherein the compound is:
Figure US20080193381A1-20080814-C00059
Figure US20080193381A1-20080814-C00060
Figure US20080193381A1-20080814-C00061
7. The compound of claim 1, wherein
n is 0 or 1
m is 0, 1, 2, 3 or 4
Q is NR′
Y is C(O) or CH2 and
R is a —CH2(CH2)1-4CHNR′R′ and
R′ is a C1-C2 alkyl substituted with a pyridine or carboxy group.
8. The compound of claim 1, wherein the compound is
Figure US20080193381A1-20080814-C00062
wherein the carboxy groups of any of the above compounds can be substituted with C1-C4 alkyl.
9. The compound of claim 1, wherein
n is 0 or 1
m is 0
Q is CH2
Y is CH2 and
R is —NR′R′ and
R′ is a C1-C2 alkyl substituted with a pyridine or carboxy group.
10. The compound of claim 9, wherein the compound is
Figure US20080193381A1-20080814-C00063
wherein the carboxy groups of any of the above compounds can be substituted with C1-C4 alkyl.
11. A compound of claim 1, wherein the compound is:
Figure US20080193381A1-20080814-C00064
wherein the carboxy groups of the above compounds can be substituted with C1-C4 alkyl.
12. The compound of claim 1, wherein the compounds is of the Formula (II):
Figure US20080193381A1-20080814-C00065
13. A radionuclide chelate complex comprising the compound or salt of claim 1.
14. The radionuclide chelate complex of claim 13, wherein the radionuclide is an imaging radionuclide.
15. The radionuclide chelate complex of claim 13, wherein the radionuclide is a therapeutic radionuclide.
16. The radionuclide chelate complex of claim 14, wherein the radionuclide is a (technetium-99m)Tc(CO)3 chelate complex or (rhenium-186/188)Re(CO)3 chelate complex.
17. The radionuclide chelate complex of claim 16, wherein the radionuclide is
Figure US20080193381A1-20080814-C00066
Figure US20080193381A1-20080814-C00067
wherein the carboxy groups of any of the above compounds can be substituted with C1-C4 alkyl.
18. A glutamate-urea-lysine PSMA-binding whose IC50 inhibition of PSMA is less than 20 nM, wherein the glutamate-urea-lysine PSMA-binding moiety is a glutamate-urea-α or β-amino acid heterodimer coupled through the α-NH2 or β-NH2 groups.
19. The compound of claim 18 in which the PSMA-binding moiety and the radio-imaging moiety are conjugated via an amide, ester, amine, or ether linkage.
20. A method of imaging one or more organs or tissues or both of a mammal comprising administering to a mammal an effective amount of a glutamate-urea-lysine PSMA-binding moiety conjugated to a radio-imaging moiety and obtaining an image of one or more organs or tissues or both of the mammal, wherein the glutamate-urea-lysine PSMA-binding moiety is a glutamate-urea-α or β-amino acid heterodimer coupled through the α-NH2 or β-NH2 groups.
21. The method of claim 20, wherein the one or more organs or tissues or both includes prostate tissue, kidney tissue, brain tissue, vascular tissue, or tumor tissue.
22. A kit comprising: (i) compound comprising a glutamate-urea-lysine PSMA-binding moiety conjugated to a metal chelating moiety, and (ii) radionuclide.
23. The kit of claim 21, wherein the radionuclide is selected from technetium-99m, rhenium-186, rhenium-188 or combinations thereof.
24. A method of staging a pathological condition associated with one or more organs or tissues or both of a mammal comprising: (i) administering to a mammal an effective amount of a compound comprising a glutamate-urea-lysine PSMA-binding moiety conjugated to a radio-imaging moiety, (ii) obtaining an image of the one or more organs or tissues or both of said mammal; (iii) determining from said image the amount of PSMA which is present in the one or more organs or tissues or both of said mammal, and (iv) utilizing the amount determined and a control amount to arrive at a stage of the pathological condition, wherein the glutamate-urea-lysine PSMA-binding moiety is a glutamate-urea-α or β-amino acid heterodimer coupled through the α-NH2 or β-NH2 groups.
25. The method of claim 24, wherein the pathological condition is selected from the group consisting of cancer, prostate cancer, angiogenesis, heart failure, cardiomyopathy, lung disease, kidney dysfunction, renal failure, inflammation, atherosclerosis, vulnerable arterial plaques or neoplasm.
26. A method of monitoring a mammal's response to therapy for a pathological condition associated with one or more organs or tissues or both of the mammal comprising (i) administering to a mammal an effective amount of a compound comprising a glutamate-urea-lysine PSMA-binding moiety conjugated to a radio-imaging moiety, (ii) obtaining an image of the one or more organs or tissues or both of the mammal, (iii) determining from said image the amount of peptidase which is present in the one or more organs or tissues or both of the mammal, and (iv) utilizing the amount determined and a control amount to gauge the mammal's response, if any, to a therapy, wherein the glutamate-urea-lysine PSMA-binding moiety is a glutamate-urea-α or β-amino acid heterodimer coupled through the α-NH2 or β-NH2 groups.
27. The method of claim 26, wherein the control amount is obtained from an amount found in a group of normal subjects.
28. The method of claim 26, wherein the control amount is obtained from a baseline amount found in the one or more organs of said mammal.
29. A method of quantifying expression of a peptidase in one or more organs or tissues or both of a mammal comprising administering to a mammal an effective amount of a compound including a peptidase-binding moiety conjugated to a radio-imaging moiety, obtaining an image of the one or more organs or tissues or both of the mammal; quantifying from the image and a series of standard images an amount of expression of the peptidase in the one or more organs or tissues or both of the mammal.
30. A method of treating a patient with painful and sensory diabetic neuropathy, neuronal damage and prostate cancer, schizophrenia, colorectal cancer, inflammation, amyotrophic lateral schlerosis, or diabetic neuropathy comprising administering to the patient a therapeutically effective amount of a glutamate-urea-lysine PSMA-binding moiety, wherein the glutamate-urea-lysine PSMA-binding moiety is a glutamate-urea-α or β-amino acid heterodimer coupled through the α-NH2 or β-NH2 groups.
31. A method of treating a patient in need of an analgesic comprising administering to the patient a therapeutically effective amount of a glutamate-urea-lysine PSMA-binding moiety, wherein the glutamate-urea-lysine PSMA-binding moiety is a glutamate-urea-α or β-amino acid heterodimer coupled through the α-NH2 or β-NH2 groups.
32. A compound of Formula (Ia)
Figure US20080193381A1-20080814-C00068
wherein R is a C6-C12 substituted or unsubstituted aryl, a C6-C12 substituted or unsubstituted heteroaryl, a C1-C6 substituted or unsubstituted alkyl or —NR′R′,
Q is C(O), O, NR′, S, S(O)2, C(O)2 (CH2)p
Y is C(O), O, NR′, S, S(O)2, C(O)2 (CH2)p
Z is H or C1-C4 alkyl,
m is 0, 1, 2, 3, 4 or 5
n is 0, 1, 2, 3, 4, 5 or 6
n′ is 0, 1, 2, 3, 4, 5 or 6
p is 0, 1, 2, 3, 4, 5 or 6
R′ is H, C(O), S(O)2, C(O)2, a C6-C12 substituted or unsubstituted aryl, a C6-C12 substituted or unsubstituted heteroaryl or a C1-C6 substituted or unsubstituted alkyl, when substituted, aryl, heteroaryl and alkyl are substituted with halogen, C6-C12 heteroaryl, —NR′R′ or COOZ
further wherein
(i) at least one of R or R′ is a C6-C12 aryl or C6-C12 heteroaryl substituted with at least a halogen or
(ii) at least one of R or R′ is a substituted or unsubstituted C6-C12 heteroaryl
or a pharmaceutically acceptable salt of the compound of Formula (I).
33. The compound of claim 32, wherein the halogen is a radiohalogen, I-123, I-125, I-131, I-124, Br-75, Br-77, or F-18.
34. The compound of claim 32, wherein
n is 0 or 1
n′ is 0 or 1
m is 0, 1, 2, 3 or 4
Q is NR′
Y is C(O) or CH2 and
R is a C6-C12 substituted or substituted aryl.
35. The compound of claim 34, wherein R is a phenyl moiety substituted with a halogen.
36. The compound of claim 32, wherein
n is 0 or 1
n′ is 0 or 1
m is 0, 1, 2, 3 or 4
Q is NR′
Y is C(O) or CH2 and
R is a —CH2(CH2)1-4CHNR′R′ and
R′ is a C1-C2 alkyl substituted with a pyridine or carboxy group.
37. The compound of claim 36, wherein the compound is
Figure US20080193381A1-20080814-C00069
wherein the carboxy groups of any of the above compounds can be substituted with C1-C4 alkyl.
38. The compound of claim 32, wherein
n is 0 or 1
n′ is 0 or 1
m is 0, 1, 2, 3 or 4
Q is CH2
Y is CH2 and
R is —NR′R′ and
R′ is a C1-C2 alkyl substituted with a pyridine or carboxy group.
39. The compound of claim 38, wherein the compound is
Figure US20080193381A1-20080814-C00070
Figure US20080193381A1-20080814-C00071
wherein the carboxy groups of any of the above compounds can be substituted with C1-C4 alkyl.
40. The compound of claim 32, wherein the compounds is of the Formula (Iia):
Figure US20080193381A1-20080814-C00072
41. A radionuclide chelate complex comprising the compound or salt of claim 31.
42. The radionuclide chelate complex of claim 44, wherein the radionuclide is an imaging radionuclide.
43. The radionuclide chelate complex of claim 44, wherein the radionuclide is a therapeutic radionuclide.
44. The radionuclide chelate complex of claim 45, wherein the radionuclide is a (technetium-99m)Tc(CO)3 chelate complex or (rhenium-186/188)Re(CO)3 chelate complex.
45. The compound of claim 1, wherein the compound is of Formula Iib:
Figure US20080193381A1-20080814-C00073
wherein -Y-R is selected from the group consisting of:
Figure US20080193381A1-20080814-C00074
and H;
wherein X is selected from the group consisting of: I, Br, Cl, F, and H.
46. The compound of claim 45, wherein the compound is of the following structure:
Figure US20080193381A1-20080814-C00075
wherein X is selected from the group consisting of:
Figure US20080193381A1-20080814-C00076
47. The compound of claim 45, wherein the compound is of the following structure:
Figure US20080193381A1-20080814-C00077
wherein X is selected from the group consisting of:
Figure US20080193381A1-20080814-C00078
48. The compound of claim 45 selected from the group consisting of:
Figure US20080193381A1-20080814-C00079
(S)-2-(3-((S)-5-amino-1-carboxypentyl)ureido)pentanedioic acid,
Figure US20080193381A1-20080814-C00080
(S,S)-2-{3-[1-Carboxy-5-(2-chloro-benzylamino)-pentyl]-ureido}-pentanedioic acid,
Figure US20080193381A1-20080814-C00081
(S,S)-2-{3-[1-Carboxy-5-(3-chloro-benzylamino)-pentyl]-ureido}-pentanedioic acid,
Figure US20080193381A1-20080814-C00082
(S,S)-2-{3-[1-Carboxy-5-(4-chloro-benzylamino)-pentyl]-ureido}-pentanedioic acid,
Figure US20080193381A1-20080814-C00083
(S)-2-(3-((R)-5-(benzylamino)-1-carboxypentyl)ureido)pentanedioic acid,
Figure US20080193381A1-20080814-C00084
2-(3-{1-Carboxy-5-[3-(phenyl)-ureido]-pentyl}-ureido)-pentanedioic acid,
Figure US20080193381A1-20080814-C00085
2-(3-{1-Carboxy-5-[3-(4-bromo-phenyl)-ureido]-pentyl}-ureido)-pentanedioic acid;
Figure US20080193381A1-20080814-C00086
2-(3-{1-Carboxy-5-[3-(4-chloro-phenyl)-ureido]-pentyl}-ureido)-pentanedioic acid;
Figure US20080193381A1-20080814-C00087
(S)-2-(3-((R)-1-carboxy-5-(□pyridine-1-ylmethylamino)pentyl)ureido)pentanedioic acid; and
Figure US20080193381A1-20080814-C00088
2-(3-{1-Carboxy-5-[3-(3-iodo-benzyl)-ureido]-pentyl}-ureido)-pentanedioic acid.
49. The compound according to claim 1, selected from the group consisting of:
Figure US20080193381A1-20080814-C00089
50. The compound according to claim 32, selected from the group consisting of:
Figure US20080193381A1-20080814-C00090
51. A radionuclide chelate complex comprising the compound or salt of claim 45.
52. The radionuclide chelate complex of claim 57, wherein the radionuclide is an imaging radionuclide.
53. The radionuclide chelate complex of claim 57, wherein the radionuclide is a therapeutic radionuclide.
54. The radionuclide chelate complex of claim 51, wherein the radionuclide is a (technetium-99m)Tc(CO)3 chelate complex or (rhenium-186/188)Re(CO)3 chelate complex.
55. A compound of formula III:
Figure US20080193381A1-20080814-C00091
wherein
L is a bond, an optionally substituted alkyl, alkenyl, or alkynyl of C1-C15, or —[(CH2)qO]s—, wherein q and s are independently an integer of 1 to 10;
E is —NR′R′,
Q is C(O), O, NR′, S, S(O)2, C(O)2 (CH2)p
Y is C(O), O, NR′, S, S(O)2, C(O)2 (CH2)p
Z is H or C1-C4 alkyl,
m is 0, 1, 2, 3, 4 or 5
n is 0, 1, 2, 3, 4, 5 or 6
n′ is 0, 1, 2, 3, 4, 5 or 6
p is 0, 1, 2, 3, 4, 5 or 6
R′ is independently H, C(O), S(O)2, C(O)2, a C6-C12 substituted or unsubstituted aryl, a C6-C12 substituted or unsubstituted heteroaryl or a C1-C14 substituted or unsubstituted alkyl, when substituted, aryl, heteroaryl and alkyl are substituted with halogen, C6-C12 heteroaryl, —NR′R′ or COOZ.
or a pharmaceutically acceptable salt thereof.
56. A radionuclide chelate complex comprising the compound or salt of claim 55.
57. The compound of claim 55, wherein the compound is of the following structure:
Figure US20080193381A1-20080814-C00092
wherein n is an integer of 0 to 9.
58. The compound of claim 57, wherein n is 9 and the compound is (19S,23S)-2-(4-iodobenzyl)-1-(4-iodophenyl)-13,21-dioxo-2,14,20,22-tetraazapentacosane-19,23,25-tricarboxylic acid.
59. The compound of claim 55, wherein the compound is of the following structure:
Figure US20080193381A1-20080814-C00093
wherein n is 2, 4, or 8.
60. A radionuclide chelate complex comprising the compound of claim 59 of the following structure:
Figure US20080193381A1-20080814-C00094
wherein n is 2, 4 or 8 or a salt thereof.
61. The radionuclide chelate complex of claim 60 of the following structure:
[Re(CO)3 {(17R,21S)-11,19-dioxo-1-(ÿyridine-2-yl)-2-(ÿyridine-2-ylmethyl)-5,8-dioxa-2,12,18,20-tetraazatricosane-17,21,23-tricarboxylic acid}][Br];
[Re(CO)3 {(23R,27S)-17,25-dioxo-1-(pyridin-2-yl)-2-(pyridin-2-ylmethyl)-5,8,11,14-tetraoxa-2,18,24,26-tetraazanonacosane-23,27,29-tricarboxylic acid}][Br]; and
[Re(CO)3 {(35R,39S)-29,37-dioxo-1-(ÿyridine-2-yl)-2-(ÿyridine-2-ylmethyl)-5,8,11,14,17,20,23,26-octaoxa-2,30,36,38-tetraazahentetracontane-35,39,41-tricarboxylic acid}][Br] or a salt thereof.
62. The compound of claim 55 of the following structure:
Figure US20080193381A1-20080814-C00095
63. A radionuclide chelate complex comprising a salt form of the compound of claim 62 of the following structure:
Figure US20080193381A1-20080814-C00096
[Re(CO)3 {(19R,23S)-13,21-dioxo-2-(ÿyridine-2-ylmethyl)-2,14,20,22-tetraazapentacosane-1,19,23,25-tetracarboxylic acid}].
64. A radionuclide chelate complex of claim 13, wherein the radionuclide is a radio copper.
65. A radionuclide chelate complex of claim 41, wherein the radionuclide is a radio copper.
66. A radionuclide chelate complex of claim 51, wherein the radionuclide is a radio copper.
67. A radionuclide chelate complex comprising the compound or salt of claim 32 selected from the following structures:
Figure US20080193381A1-20080814-C00097
Figure US20080193381A1-20080814-C00098
US11/936,659 2006-11-08 2007-11-07 Heterodimers of glutamic acid Granted US20080193381A1 (en)

Priority Applications (11)

Application Number Priority Date Filing Date Title
US11/936,659 US20080193381A1 (en) 2006-11-08 2007-11-07 Heterodimers of glutamic acid
US13/271,549 US9309193B2 (en) 2006-11-08 2011-10-12 Heterodimers of glutamic acid
US13/294,677 US8487129B2 (en) 2006-11-08 2011-11-11 Heterodimers of glutamic acid
US15/068,841 US10640461B2 (en) 2006-11-08 2016-03-14 Heterodimers of glutamic acid
US15/337,867 US9878980B2 (en) 2006-11-08 2016-10-28 Heterodimers of glutamic acid
US15/794,539 US10131627B2 (en) 2006-11-08 2017-10-26 Heterodimers of glutamic acid
US16/156,289 US10647666B2 (en) 2006-11-08 2018-10-10 Heterodimers of glutamic acid
US16/870,288 US20210070695A1 (en) 2006-11-08 2020-05-08 Heterodimers of glutamic acid
US17/099,440 US20210070696A1 (en) 2006-11-08 2020-11-16 Heterodimers of glutamic acid
US17/238,535 US20210246103A1 (en) 2006-11-08 2021-04-23 Heterodimers of glutamic acid
US17/982,182 US20230095637A1 (en) 2006-11-08 2022-11-07 Heterodimers of Glutamic Acid

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US85749006P 2006-11-08 2006-11-08
US87867807P 2007-01-05 2007-01-05
US11/936,659 US20080193381A1 (en) 2006-11-08 2007-11-07 Heterodimers of glutamic acid

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US13/271,549 Division US9309193B2 (en) 2006-11-08 2011-10-12 Heterodimers of glutamic acid
US13/294,677 Continuation US8487129B2 (en) 2006-11-08 2011-11-11 Heterodimers of glutamic acid

Publications (1)

Publication Number Publication Date
US20080193381A1 true US20080193381A1 (en) 2008-08-14

Family

ID=39365345

Family Applications (11)

Application Number Title Priority Date Filing Date
US11/936,659 Granted US20080193381A1 (en) 2006-11-08 2007-11-07 Heterodimers of glutamic acid
US13/271,549 Active 2027-12-08 US9309193B2 (en) 2006-11-08 2011-10-12 Heterodimers of glutamic acid
US13/294,677 Active US8487129B2 (en) 2006-11-08 2011-11-11 Heterodimers of glutamic acid
US15/068,841 Active US10640461B2 (en) 2006-11-08 2016-03-14 Heterodimers of glutamic acid
US15/337,867 Active US9878980B2 (en) 2006-11-08 2016-10-28 Heterodimers of glutamic acid
US15/794,539 Active US10131627B2 (en) 2006-11-08 2017-10-26 Heterodimers of glutamic acid
US16/156,289 Active US10647666B2 (en) 2006-11-08 2018-10-10 Heterodimers of glutamic acid
US16/870,288 Abandoned US20210070695A1 (en) 2006-11-08 2020-05-08 Heterodimers of glutamic acid
US17/099,440 Abandoned US20210070696A1 (en) 2006-11-08 2020-11-16 Heterodimers of glutamic acid
US17/238,535 Abandoned US20210246103A1 (en) 2006-11-08 2021-04-23 Heterodimers of glutamic acid
US17/982,182 Pending US20230095637A1 (en) 2006-11-08 2022-11-07 Heterodimers of Glutamic Acid

Family Applications After (10)

Application Number Title Priority Date Filing Date
US13/271,549 Active 2027-12-08 US9309193B2 (en) 2006-11-08 2011-10-12 Heterodimers of glutamic acid
US13/294,677 Active US8487129B2 (en) 2006-11-08 2011-11-11 Heterodimers of glutamic acid
US15/068,841 Active US10640461B2 (en) 2006-11-08 2016-03-14 Heterodimers of glutamic acid
US15/337,867 Active US9878980B2 (en) 2006-11-08 2016-10-28 Heterodimers of glutamic acid
US15/794,539 Active US10131627B2 (en) 2006-11-08 2017-10-26 Heterodimers of glutamic acid
US16/156,289 Active US10647666B2 (en) 2006-11-08 2018-10-10 Heterodimers of glutamic acid
US16/870,288 Abandoned US20210070695A1 (en) 2006-11-08 2020-05-08 Heterodimers of glutamic acid
US17/099,440 Abandoned US20210070696A1 (en) 2006-11-08 2020-11-16 Heterodimers of glutamic acid
US17/238,535 Abandoned US20210246103A1 (en) 2006-11-08 2021-04-23 Heterodimers of glutamic acid
US17/982,182 Pending US20230095637A1 (en) 2006-11-08 2022-11-07 Heterodimers of Glutamic Acid

Country Status (16)

Country Link
US (11) US20080193381A1 (en)
EP (5) EP2942065B1 (en)
JP (2) JP5606737B2 (en)
CN (2) CN103922998A (en)
BR (1) BRPI0718700B8 (en)
CA (1) CA2669127C (en)
CY (1) CY1116610T1 (en)
DK (1) DK2097111T3 (en)
ES (4) ES2684322T3 (en)
HK (2) HK1200164A1 (en)
HU (3) HUE059645T2 (en)
PL (3) PL3699162T3 (en)
PT (2) PT3699162T (en)
SI (1) SI2097111T1 (en)
TW (1) TWI492761B (en)
WO (1) WO2008058192A2 (en)

Cited By (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090061010A1 (en) * 2007-03-30 2009-03-05 Massachusetts Institute Of Technology Cancer cell targeting using nanoparticles
US20100069426A1 (en) * 2008-06-16 2010-03-18 Zale Stephen E Therapeutic polymeric nanoparticles with mTor inhibitors and methods of making and using same
US20100068286A1 (en) * 2008-06-16 2010-03-18 Greg Troiano Drug Loaded Polymeric Nanoparticles and Methods of Making and Using Same
US20100104655A1 (en) * 2008-06-16 2010-04-29 Zale Stephen E Therapeutic Polymeric Nanoparticles Comprising Vinca Alkaloids and Methods of Making and Using Same
US20100216804A1 (en) * 2008-12-15 2010-08-26 Zale Stephen E Long Circulating Nanoparticles for Sustained Release of Therapeutic Agents
US20100226986A1 (en) * 2008-12-12 2010-09-09 Amy Grayson Therapeutic Particles Suitable for Parenteral Administration and Methods of Making and Using Same
US20100324008A1 (en) * 2007-08-17 2010-12-23 Purdue Research Foundation Psma binding ligand-linker conjugates and methods for using
US20110064657A1 (en) * 2007-06-26 2011-03-17 The Johns Hopkins University Labeled inhibitors of prostate specific membrane antigen (psma), biological evaluation, and use as imaging agents
US20110142760A1 (en) * 2008-08-01 2011-06-16 The Johns Hopkins University Psma-binding agents and uses thereof
US8211473B2 (en) 2009-12-11 2012-07-03 Bind Biosciences, Inc. Stable formulations for lyophilizing therapeutic particles
US8518963B2 (en) 2009-12-15 2013-08-27 Bind Therapeutics, Inc. Therapeutic polymeric nanoparticle compositions with high glass transition temperature or high molecular weight copolymers
US8709483B2 (en) 2006-03-31 2014-04-29 Massachusetts Institute Of Technology System for targeted delivery of therapeutic agents
WO2014078484A1 (en) * 2012-11-15 2014-05-22 Endocyte, Inc. Conjugates for treating diseases caused by psma expressing cells
WO2014127365A1 (en) * 2013-02-15 2014-08-21 Case Western Reserve University Psma ligands and uses thereof
US8906381B2 (en) 2008-10-12 2014-12-09 Massachusetts Institute Of Technology Immunonanotherapeutics that provide IGG humoral response without T-cell antigen
US8932595B2 (en) 2008-10-12 2015-01-13 Massachusetts Institute Of Technology Nicotine immunonanotherapeutics
US8986655B2 (en) 2009-05-19 2015-03-24 The Regents Of The University Of California Compositions, devices, and methods related to prostate-specific membrane antigen
WO2015057692A1 (en) * 2013-10-14 2015-04-23 The Johns Hopkins University Prostate-specific membrane antigen-targeted photosensitizers for photodynamic therapy
US9217129B2 (en) 2007-02-09 2015-12-22 Massachusetts Institute Of Technology Oscillating cell culture bioreactor
US9267937B2 (en) 2005-12-15 2016-02-23 Massachusetts Institute Of Technology System for screening particles
US9333179B2 (en) 2007-04-04 2016-05-10 Massachusetts Institute Of Technology Amphiphilic compound assisted nanoparticles for targeted delivery
US9381477B2 (en) 2006-06-23 2016-07-05 Massachusetts Institute Of Technology Microfluidic synthesis of organic nanoparticles
WO2016112382A3 (en) * 2015-01-09 2016-09-29 The Johns Hopkins University Intranasal administration of glutamate carboxypeptidase (gcp-ii) inhibitors
US9474717B2 (en) 2007-10-12 2016-10-25 Massachusetts Institute Of Technology Vaccine nanotechnology
US9492400B2 (en) 2004-11-04 2016-11-15 Massachusetts Institute Of Technology Coated controlled release polymer particles as efficient oral delivery vehicles for biopharmaceuticals
US9878980B2 (en) 2006-11-08 2018-01-30 Molecular Insight Pharmaceuticals, Inc. Heterodimers of glutamic acid
US9877923B2 (en) 2012-09-17 2018-01-30 Pfizer Inc. Process for preparing therapeutic nanoparticles
US9895378B2 (en) 2014-03-14 2018-02-20 Pfizer Inc. Therapeutic nanoparticles comprising a therapeutic agent and methods of making and using the same
US9951324B2 (en) 2010-02-25 2018-04-24 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10112974B2 (en) 2014-08-24 2018-10-30 Max-Planck-Gesellschaft Zur Foerderung Der Wissenschaften E.V. Method for the production of 18F-labeled active esters and their application exemplified by the preparation of a PSMA-specific PET-tracer
US10188759B2 (en) 2015-01-07 2019-01-29 Endocyte, Inc. Conjugates for imaging
US10207005B2 (en) 2013-02-15 2019-02-19 Case Western Reserve University Photodynamic therapy composition
WO2019157037A1 (en) 2018-02-06 2019-08-15 The Johns Hopkins University Psma targeted radiohalogenated urea-polyaminocarboxylates for cancer radiotherapy
US10398791B2 (en) 2013-10-18 2019-09-03 Deutsches Krebsforschungszentrum Labeled inhibitors of prostate specific membrane antigen (PSMA), their use as imaging agents and pharmaceutical agents for the treatment of prostate cancer
US10434194B2 (en) 2013-06-20 2019-10-08 Case Western Reserve University PSMA targeted nanobubbles for diagnostic and therapeutic applications
US10736974B2 (en) 2014-10-22 2020-08-11 The Johns Hopkins University Scaffolds and multifunctional intermediates for imaging PSMA and cancer therapy
US10905762B2 (en) 2011-02-04 2021-02-02 Case Western Reserve University Targeted nanoparticle conjugates
US11202836B2 (en) 2018-03-23 2021-12-21 Case Western Reserve University PSMA targeted conjugate compounds and uses thereof
WO2022101352A1 (en) 2020-11-12 2022-05-19 Abx Advanced Biochemical Compounds Gmbh Ligands of prostate specific membrane antigen (psma) containing heteroaromatic linker building blocks
CN114786734A (en) * 2019-11-21 2022-07-22 费罗诺娃私人有限公司 Magnetic tracer compositions
US11975074B2 (en) 2013-02-15 2024-05-07 Case Western Reserve University Photodynamic therapy composition
US11998620B2 (en) 2021-11-09 2024-06-04 Case Western Reserve University PSMA targeted compounds and uses thereof
US12083191B2 (en) 2009-10-19 2024-09-10 Case Western Reserve University Composition and methods for imaging cells
US12133901B2 (en) 2020-01-21 2024-11-05 Case Western Reserve University PSMA ligand targeted compounds and uses thereof

Families Citing this family (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6528499B1 (en) 2000-04-27 2003-03-04 Georgetown University Ligands for metabotropic glutamate receptors and inhibitors of NAALADase
EP1745802A1 (en) * 2005-07-20 2007-01-24 Kreatech Biotechnology B.V. Method of conjugating therapeutic compounds to cell targeting moieties via metal complexes
RU2498798C2 (en) 2008-01-09 2013-11-20 Моликьюлар Инсайт Фармасьютикалз, Инк. Carbonic anhydrase ix inhibitors
JP2011525180A (en) * 2008-06-16 2011-09-15 バインド バイオサイエンシズ インコーポレイテッド Method for the manufacture of targeted drugs functionalized with diblock copolymers for use in the production of therapeutically targeted nanoparticles
WO2010065906A2 (en) 2008-12-05 2010-06-10 Molecular Insight Pharmaceuticals, Inc. Ca-ix specific radiopharmaceuticals for the treatment and imaging of cancer
WO2010065899A2 (en) 2008-12-05 2010-06-10 Molecular Insight Pharmaceuticals, Inc. Technetium-and rhenium-bis(heteroaryl)complexes and methods of use thereof
CA2745918C (en) * 2008-12-05 2017-10-10 Molecular Insight Pharmaceuticals, Inc. Technetium- and rhenium-bis(heteroaryl) complexes and methods of use thereof
US8465725B2 (en) 2009-06-15 2013-06-18 Molecular Insight Pharmaceuticlas, Inc. Process for production of heterodimers of glutamic acid
JPWO2011052676A1 (en) * 2009-10-30 2013-03-21 住友大阪セメント株式会社 Exhaust gas purification device for internal combustion engine
EP2338892A1 (en) * 2009-12-18 2011-06-29 Bayer Schering Pharma Aktiengesellschaft Prostate specific membrane antigen inhibitors
JP2011206049A (en) 2010-03-08 2011-10-20 Sumio Sugano Necrosis marker and use thereof
JP5843338B2 (en) * 2011-08-05 2016-01-13 モレキュラ インサイト ファーマシューティカルズ インコーポレイテッド Radiolabeled prostate-specific membrane antigen inhibitor
CA2860504A1 (en) 2012-01-06 2013-07-11 Molecular Insight Pharmaceuticals Metal complexes of poly(carboxyl)amine-containing ligands having an affinity for carbonic anhydrase ix
PL2943227T3 (en) 2013-01-14 2018-02-28 Molecular Insight Pharmaceuticals, Inc. Triazine based radiopharmaceuticals and radioimaging agents
JP6908964B2 (en) * 2013-10-18 2021-07-28 ピーエスエムエー ディベロップメント カンパニー，エルエルシー Combination therapy with PSMA ligand conjugate
WO2015057250A1 (en) 2013-10-18 2015-04-23 Psma Development Company, Llc Combination therapies with psma ligand conjugates
WO2015073896A2 (en) 2013-11-15 2015-05-21 Psma Development Company, Llc Biomarkers for psma targeted therapy for prostate cancer
EP3193914B1 (en) * 2014-09-08 2021-01-20 Molecular Insight Pharmaceuticals, Inc. Organ protection in psma-targeted radionuclide therapy of prostate cancer
AU2016333334B2 (en) 2015-09-30 2019-07-25 Deutsches Krebsforschungszentrum 18F-tagged inhibitors of prostate specific membrane antigen (PSMA) and their use as imaging agents for prostate cancer
KR101639599B1 (en) 2015-11-09 2016-07-14 서울대학교산학협력단 Peptide thiourea derivatives, their radioisotope labeled compounds and pharmaceutical composition for treatment or diagnosis of prostate cancer comprising the same as an active ingredient
CA3049470A1 (en) 2016-01-10 2017-07-13 The University Of British Columbia 18/19f-labelled compounds which target the prostate specific membrane antigen
WO2017184231A1 (en) 2016-04-20 2017-10-26 Dow Corning Corporation Lithium alkylsiliconate composition, coating, and method of making same
FI127538B (en) * 2016-06-22 2018-08-31 Dextech Medical Ab Modified dextran conjugates
KR20230043239A (en) * 2016-06-23 2023-03-30 코넬 유니버시티 Double targeted constructs to affect tumor kill
AU2017290664B2 (en) * 2016-06-28 2021-08-05 Cornell University 18F-labeled triazole containing PSMA inhibitors
EP3609541A4 (en) 2017-04-05 2021-04-07 Cornell University Trifunctional constructs with tunable pharmacokinetics useful in imaging and anti-tumor therapies
CA3065133A1 (en) * 2017-06-09 2018-12-13 Gemoab Monoclonals Gmbh Targeting modules for universal chimeric antigen receptor expressing immune cells and use in the treatment of cancer, infections and autoimmune disorders
EP3853213A4 (en) * 2018-09-21 2022-07-06 Endocyte, Inc. Shielding agents and their use
CA3115806A1 (en) * 2018-10-11 2020-04-16 Progenics Pharmaceuticals, Inc Combination therapy for treating metastatic prostate cancer
RU2697519C1 (en) * 2018-10-15 2019-08-15 Общество с ограниченной ответственностью "Изварино Фарма" Peptide agent comprising a psma-binding ligand based on a urea derivative, a method for production thereof and use thereof for preparing a conjugate with a drug and diagnostic agent
WO2020139012A1 (en) * 2018-12-27 2020-07-02 (주)퓨쳐켐 Carboxylic acid-introduced psma-targeting compound and use thereof
DK3917626T3 (en) * 2019-01-30 2023-08-28 Technische Univ Muenchen Klinikum Rechts Der Isar PSMA-BINDING DUAL-MODE RADIOTRACER AND THERAPEUTICS
CA3144094A1 (en) 2019-06-21 2020-12-24 Provincial Health Services Authority Radiolabeled compounds targeting the prostate-specific membrane antigen
WO2021202376A1 (en) 2020-03-30 2021-10-07 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Method for blocking uptake of prostate-specific membrane antigen (psma)-targeted radionuclides by exocrine organs
CN111548305B (en) * 2020-05-12 2021-08-31 北京师范大学 Quinoline compound for targeting PSMA (patterned middle molecular weight ligands) and preparation method thereof
CN112209970B (en) * 2020-10-21 2021-10-29 北京师范大学 Preparation method and application of technetium-99 m labeled isonitrile-containing glutamic acid-urea derivative
WO2024150132A1 (en) 2023-01-10 2024-07-18 Sun Pharma Advanced Research Company Limited Ligand-drug conjugates

Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3527789A (en) * 1967-10-06 1970-09-08 Shell Oil Co Production of poly(lower)alkyl alkenepolycarboxylates
US4885136A (en) * 1986-10-17 1989-12-05 Katayama Chemical Works Co., Ltd. Method of anticorrosive treatment for soft water boilers
US4888136A (en) * 1988-05-02 1989-12-19 Witco Corporation New flame retardant compositions of matter and cellulosic products containing same
US5442088A (en) * 1991-04-06 1995-08-15 Hoechst Aktiengesellschaft Process for the preparation of phosphorus-containing L-amino acids, their derivatives and intermediates for this process
US5672592A (en) * 1996-06-17 1997-09-30 Guilford Pharmaceuticals Inc. Certain phosphonomethyl-pentanedioic acid derivatives thereof
US5739123A (en) * 1994-06-21 1998-04-14 Zambon Group S.P.A. Phosphinic acid derivatives with metallopeptidase inhibitory activity
US5795877A (en) * 1996-12-31 1998-08-18 Guilford Pharmaceuticals Inc. Inhibitors of NAALADase enzyme activity
US5824662A (en) * 1996-09-27 1998-10-20 Guilford Pharmaceuticals Inc. Treatment of global and focal ischemia using naaladase inhibitors
US6071965A (en) * 1996-06-17 2000-06-06 Guilford Pharmaceuticals Inc. Phosphinic alkanoic acid derivatives
US6479470B1 (en) * 1999-04-28 2002-11-12 Georgetown University Ligands for metabotropic glutamate receptors and inhibitors of NAALAdase
US6528499B1 (en) * 2000-04-27 2003-03-04 Georgetown University Ligands for metabotropic glutamate receptors and inhibitors of NAALADase
US20040054190A1 (en) * 2002-01-10 2004-03-18 Johns Hopkins University Imaging agents and methods of imaging NAALADase or PSMA
US20060155146A1 (en) * 2005-01-13 2006-07-13 Lenges Christian P Rheology control agents
US20060155021A1 (en) * 2005-01-13 2006-07-13 Lenges Christian P Coating compositions containing rheology control agents
US20060198785A1 (en) * 2003-04-15 2006-09-07 Santos Isabel R Bifunctional tridentate pyrazolyl containing ligands for re and tc tricarbonyl complexes
US20110008253A1 (en) * 2009-06-15 2011-01-13 Molecular Insight Pharmaceuticals, Inc. Process for production of heterodimers of glutamic acid

Family Cites Families (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6011021A (en) 1996-06-17 2000-01-04 Guilford Pharmaceuticals Inc. Methods of cancer treatment using naaladase inhibitors
US6046180A (en) 1996-06-17 2000-04-04 Guilford Pharmaceuticals Inc. NAALADase inhibitors
US6025344A (en) 1996-06-17 2000-02-15 Guilford Pharmaceuticals Inc. Certain dioic acid derivatives useful as NAALADase inhibitors
US5902817A (en) 1997-04-09 1999-05-11 Guilford Pharmaceuticals Inc. Certain sulfoxide and sulfone derivatives
TR199901173T2 (en) 1996-09-27 1999-07-21 Guilford Pharmaceuticals, Inc. Methods and compositions of NAALADase for the treatment of glutamate abnormality and regulation of neuronal activity in vivo.
US5962521A (en) 1997-04-04 1999-10-05 Guilford Pharmaceuticals Inc. Hydroxamic acid derivatives
ZA983930B (en) 1997-05-14 1999-11-08 Lilly Co Eli Excitatory amino acid receptor modulators.
US6228888B1 (en) 1999-07-01 2001-05-08 Guilford Pharmaceuticals Inc. Methods for treating anxiety, anxiety disorders and memory impairment using naaladase inhibitors
JP4846199B2 (en) * 2002-03-11 2011-12-28 モレキュラ インサイト ファーマシューティカルズ インコーポレイテッド Technetium-diviridine complex and method of use thereof
DE60328513D1 (en) * 2002-11-07 2009-09-03 Newsouth Innovations Pty Ltd INDUCTION OF MITOCHONDRIAL PERMEABILITY TRANSITION
DE602004027631D1 (en) * 2003-04-15 2010-07-22 Mallinckrodt Inc BIFUNCTIONAL TRIDENTATES PYRAZOLYL-CONTAINING LIGANDS FOR RE, TC AND MN TRICARBONYL COMPLEXES
WO2006093991A1 (en) * 2005-03-02 2006-09-08 The Cleveland Clinic Foundation Compounds which bind psma and uses thereof
EP2942065B1 (en) 2006-11-08 2018-06-27 Molecular Insight Pharmaceuticals, Inc. Heterodimers of glutamic acid
WO2009002529A2 (en) * 2007-06-26 2008-12-31 The Johns Hopkins University Labeled inhibitors of prostate specific membrane antigen (psma), biological evaluation, and use as imaging agents
PT2187965T (en) * 2007-08-17 2020-01-17 Purdue Research Foundation Psma binding ligand-linker conjugates and methods for using
CA3131469A1 (en) 2009-03-19 2010-09-23 The Johns Hopkins University Psma-targeting compounds and uses thereof
JP5843338B2 (en) 2011-08-05 2016-01-13 モレキュラ インサイト ファーマシューティカルズ インコーポレイテッド Radiolabeled prostate-specific membrane antigen inhibitor
PE20211760A1 (en) 2013-10-18 2021-09-07 Deutsches Krebsforsch MARKED MEMBRANE-SPECIFIC PROSTATIC ANTIGEN (PSMA) INHIBITORS INCLUDING CARBOXYL GROUPS AND A MODIFIED BINDER REGION, IMAGING AGENTS, AND UNDERSTANDING PHARMACEUTICAL AGENTS
EP3193914B1 (en) 2014-09-08 2021-01-20 Molecular Insight Pharmaceuticals, Inc. Organ protection in psma-targeted radionuclide therapy of prostate cancer

Patent Citations (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3527789A (en) * 1967-10-06 1970-09-08 Shell Oil Co Production of poly(lower)alkyl alkenepolycarboxylates
US4885136A (en) * 1986-10-17 1989-12-05 Katayama Chemical Works Co., Ltd. Method of anticorrosive treatment for soft water boilers
US4888136A (en) * 1988-05-02 1989-12-19 Witco Corporation New flame retardant compositions of matter and cellulosic products containing same
US5442088A (en) * 1991-04-06 1995-08-15 Hoechst Aktiengesellschaft Process for the preparation of phosphorus-containing L-amino acids, their derivatives and intermediates for this process
US5739123A (en) * 1994-06-21 1998-04-14 Zambon Group S.P.A. Phosphinic acid derivatives with metallopeptidase inhibitory activity
US5672592A (en) * 1996-06-17 1997-09-30 Guilford Pharmaceuticals Inc. Certain phosphonomethyl-pentanedioic acid derivatives thereof
US5880112A (en) * 1996-06-17 1999-03-09 Guilford Pharmaceuticals Inc. Naaladase inhibitors
US6071965A (en) * 1996-06-17 2000-06-06 Guilford Pharmaceuticals Inc. Phosphinic alkanoic acid derivatives
US5824662A (en) * 1996-09-27 1998-10-20 Guilford Pharmaceuticals Inc. Treatment of global and focal ischemia using naaladase inhibitors
US5795877A (en) * 1996-12-31 1998-08-18 Guilford Pharmaceuticals Inc. Inhibitors of NAALADase enzyme activity
US6479470B1 (en) * 1999-04-28 2002-11-12 Georgetown University Ligands for metabotropic glutamate receptors and inhibitors of NAALAdase
US20040002478A1 (en) * 1999-04-28 2004-01-01 Kozikowski Alan P. Ligands for metabotropic glutamate receptors and inhibitors of NAALADase
US7381745B2 (en) * 1999-04-28 2008-06-03 Georgetown University Ligands for metabotropic glutamate receptors and inhibitors of NAALADase
US20080176821A1 (en) * 1999-04-28 2008-07-24 Georgetown University Ligands for metabotropic glutamate receptors and inhibitors of naaladase
US6528499B1 (en) * 2000-04-27 2003-03-04 Georgetown University Ligands for metabotropic glutamate receptors and inhibitors of NAALADase
US20040054190A1 (en) * 2002-01-10 2004-03-18 Johns Hopkins University Imaging agents and methods of imaging NAALADase or PSMA
US20060198785A1 (en) * 2003-04-15 2006-09-07 Santos Isabel R Bifunctional tridentate pyrazolyl containing ligands for re and tc tricarbonyl complexes
US20060155146A1 (en) * 2005-01-13 2006-07-13 Lenges Christian P Rheology control agents
US20060155021A1 (en) * 2005-01-13 2006-07-13 Lenges Christian P Coating compositions containing rheology control agents
US20110008253A1 (en) * 2009-06-15 2011-01-13 Molecular Insight Pharmaceuticals, Inc. Process for production of heterodimers of glutamic acid

Cited By (144)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9492400B2 (en) 2004-11-04 2016-11-15 Massachusetts Institute Of Technology Coated controlled release polymer particles as efficient oral delivery vehicles for biopharmaceuticals
US9267937B2 (en) 2005-12-15 2016-02-23 Massachusetts Institute Of Technology System for screening particles
US8802153B2 (en) 2006-03-31 2014-08-12 Massachusetts Institute Of Technology System for targeted delivery of therapeutic agents
US8709483B2 (en) 2006-03-31 2014-04-29 Massachusetts Institute Of Technology System for targeted delivery of therapeutic agents
US9381477B2 (en) 2006-06-23 2016-07-05 Massachusetts Institute Of Technology Microfluidic synthesis of organic nanoparticles
US10640461B2 (en) 2006-11-08 2020-05-05 Molecular Insight Pharmaceuticals, Inc. Heterodimers of glutamic acid
US9878980B2 (en) 2006-11-08 2018-01-30 Molecular Insight Pharmaceuticals, Inc. Heterodimers of glutamic acid
US10647666B2 (en) 2006-11-08 2020-05-12 Molecular Insight Pharmaceuticals, Inc. Heterodimers of glutamic acid
US10131627B2 (en) 2006-11-08 2018-11-20 Molecular Insight Pharmaceuticals, Inc. Heterodimers of glutamic acid
US9217129B2 (en) 2007-02-09 2015-12-22 Massachusetts Institute Of Technology Oscillating cell culture bioreactor
US8603499B2 (en) * 2007-03-30 2013-12-10 Bind Therapeutics, Inc. Cancer cell targeting using nanoparticles
US8603500B2 (en) * 2007-03-30 2013-12-10 Bind Therapeutics, Inc. Cancer cell targeting using nanoparticles
US20090061010A1 (en) * 2007-03-30 2009-03-05 Massachusetts Institute Of Technology Cancer cell targeting using nanoparticles
US8246968B2 (en) * 2007-03-30 2012-08-21 Bind Biosciences, Inc. Cancer cell targeting using nanoparticles
US9333179B2 (en) 2007-04-04 2016-05-10 Massachusetts Institute Of Technology Amphiphilic compound assisted nanoparticles for targeted delivery
US9044468B2 (en) * 2007-06-26 2015-06-02 The Johns Hopkins University Labeled inhibitors of prostate specific membrane antigen (PSMA), biological evaluation, and use as imaging agents
US20110064657A1 (en) * 2007-06-26 2011-03-17 The Johns Hopkins University Labeled inhibitors of prostate specific membrane antigen (psma), biological evaluation, and use as imaging agents
US10039845B2 (en) 2007-06-26 2018-08-07 The Johns Hopkins University Labeled inhibitors of prostate specific membrane antigen (PSMA) biological evaluation, and use of imaging agents
US9694091B2 (en) 2007-06-26 2017-07-04 The Johns Hopkins University Labeled inhibitors of prostate specific membrane antigen (PSMA) biological evaluation, and use of imaging agents
US10828282B2 (en) 2007-08-17 2020-11-10 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10624970B2 (en) 2007-08-17 2020-04-21 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10517956B2 (en) 2007-08-17 2019-12-31 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10624969B2 (en) 2007-08-17 2020-04-21 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10517957B2 (en) 2007-08-17 2019-12-31 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10485878B2 (en) 2007-08-17 2019-11-26 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10406240B2 (en) 2007-08-17 2019-09-10 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10624971B2 (en) 2007-08-17 2020-04-21 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US8907058B2 (en) 2007-08-17 2014-12-09 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10646581B2 (en) 2007-08-17 2020-05-12 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US9193763B2 (en) 2007-08-17 2015-11-24 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US11083710B2 (en) 2007-08-17 2021-08-10 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10046054B2 (en) 2007-08-17 2018-08-14 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US20100324008A1 (en) * 2007-08-17 2010-12-23 Purdue Research Foundation Psma binding ligand-linker conjugates and methods for using
US11298341B2 (en) 2007-08-17 2022-04-12 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US11318121B2 (en) 2007-08-17 2022-05-03 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US11369590B2 (en) 2007-08-17 2022-06-28 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US11504357B2 (en) 2007-08-17 2022-11-22 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US11717514B2 (en) 2007-08-17 2023-08-08 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US20120004293A1 (en) * 2007-09-28 2012-01-05 Zale Stephen E Cancer Cell Targeting Using Nanoparticles
US10071056B2 (en) * 2007-09-28 2018-09-11 Pfizer Inc. Cancer cell targeting using nanoparticles
US9295727B2 (en) * 2007-09-28 2016-03-29 Bind Therapeutics, Inc. Cancer cell targeting using nanoparticles
US8603501B2 (en) * 2007-09-28 2013-12-10 Bind Therapeutics, Inc. Cancer cell targeting using nanoparticles
US20140235706A1 (en) * 2007-09-28 2014-08-21 Bind Therapeutics, Inc. Cancer cell targeting using nanoparticles
US20130172406A1 (en) * 2007-09-28 2013-07-04 Bind Biosciences, Inc. Cancer Cell Targeting Using Nanoparticles
US8273363B2 (en) * 2007-09-28 2012-09-25 Bind Biosciences, Inc. Cancer cell targeting using nanoparticles
US8236330B2 (en) * 2007-09-28 2012-08-07 Bind Biosciences, Inc. Cancer cell targeting using nanoparticles
US20110224288A1 (en) * 2007-09-28 2011-09-15 Zale Stephen E Cancer Cell Targeting Using Nanoparticles
US9526702B2 (en) 2007-10-12 2016-12-27 Massachusetts Institute Of Technology Vaccine nanotechnology
US10736848B2 (en) 2007-10-12 2020-08-11 Massachusetts Institute Of Technology Vaccine nanotechnology
US9474717B2 (en) 2007-10-12 2016-10-25 Massachusetts Institute Of Technology Vaccine nanotechnology
US11547667B2 (en) 2007-10-12 2023-01-10 Massachusetts Institute Of Technology Vaccine nanotechnology
US9539210B2 (en) 2007-10-12 2017-01-10 Massachusetts Institute Of Technology Vaccine nanotechnology
US20100068286A1 (en) * 2008-06-16 2010-03-18 Greg Troiano Drug Loaded Polymeric Nanoparticles and Methods of Making and Using Same
US9579284B2 (en) 2008-06-16 2017-02-28 Pfizer Inc. Therapeutic polymeric nanoparticles with mTOR inhibitors and methods of making and using same
US8603534B2 (en) 2008-06-16 2013-12-10 Bind Therapeutics, Inc. Drug loaded polymeric nanoparticles and methods of making and using same
US8609142B2 (en) 2008-06-16 2013-12-17 Bind Therapeutics, Inc. Drug loaded polymeric nanoparticles and methods of making and using same
US8613951B2 (en) 2008-06-16 2013-12-24 Bind Therapeutics, Inc. Therapeutic polymeric nanoparticles with mTor inhibitors and methods of making and using same
US8613954B2 (en) 2008-06-16 2013-12-24 Bind Therapeutics, Inc. Drug loaded polymeric nanoparticles and methods of making and using same
US20100104655A1 (en) * 2008-06-16 2010-04-29 Zale Stephen E Therapeutic Polymeric Nanoparticles Comprising Vinca Alkaloids and Methods of Making and Using Same
US8617608B2 (en) 2008-06-16 2013-12-31 Bind Therapeutics, Inc. Drug loaded polymeric nanoparticles and methods of making and using same
US8420123B2 (en) 2008-06-16 2013-04-16 Bind Biosciences, Inc. Drug loaded polymeric nanoparticles and methods of making and using same
US8623417B1 (en) 2008-06-16 2014-01-07 Bind Therapeutics, Inc. Therapeutic polymeric nanoparticles with mTOR inhibitors and methods of making and using same
US8318208B1 (en) 2008-06-16 2012-11-27 Bind Biosciences, Inc. Drug loaded polymeric nanoparticles and methods of making and using same
US8206747B2 (en) 2008-06-16 2012-06-26 Bind Biosciences, Inc. Drug loaded polymeric nanoparticles and methods of making and using same
US8293276B2 (en) 2008-06-16 2012-10-23 Bind Biosciences, Inc. Drug loaded polymeric nanoparticles and methods of making and using same
US9351933B2 (en) 2008-06-16 2016-05-31 Bind Therapeutics, Inc. Therapeutic polymeric nanoparticles comprising vinca alkaloids and methods of making and using same
US9375481B2 (en) 2008-06-16 2016-06-28 Bind Therapeutics, Inc. Drug loaded polymeric nanoparticles and methods of making and using same
US8663700B2 (en) 2008-06-16 2014-03-04 Bind Therapeutics, Inc. Drug loaded polymeric nanoparticles and methods of making and using same
US9393310B2 (en) 2008-06-16 2016-07-19 Bind Therapeutics, Inc. Drug loaded polymeric nanoparticles and methods of making and using same
US20100069426A1 (en) * 2008-06-16 2010-03-18 Zale Stephen E Therapeutic polymeric nanoparticles with mTor inhibitors and methods of making and using same
US8318211B2 (en) 2008-06-16 2012-11-27 Bind Biosciences, Inc. Therapeutic polymeric nanoparticles comprising vinca alkaloids and methods of making and using same
US8652528B2 (en) 2008-06-16 2014-02-18 Bind Therapeutics, Inc. Drug loaded polymeric nanoparticles and methods of making and using same
US9579386B2 (en) 2008-06-16 2017-02-28 Pfizer Inc. Drug loaded polymeric nanoparticles and methods of making and using same
US12070513B2 (en) * 2008-08-01 2024-08-27 The Johns Hopkins Universty PSMA-binding agents and uses thereof
US20110142760A1 (en) * 2008-08-01 2011-06-16 The Johns Hopkins University Psma-binding agents and uses thereof
US20160114060A1 (en) * 2008-08-01 2016-04-28 The Johns Hopkins University Psma-binding agents and uses thereof
US20220088229A1 (en) * 2008-08-01 2022-03-24 The Johns Hopkins University Psma-binding agents and uses thereof
US8778305B2 (en) * 2008-08-01 2014-07-15 The Johns Hopkins University PSMA-binding agents and uses thereof
US10500292B2 (en) 2008-08-01 2019-12-10 The Johns Hopkins University PSMA-binding agents and uses thereof
US9226981B2 (en) * 2008-08-01 2016-01-05 The Johns Hopkins University PSMA-binding agents and uses thereof
US9861713B2 (en) * 2008-08-01 2018-01-09 The Johns Hopkins University PSMA-binding agents and uses thereof
US20140369931A1 (en) * 2008-08-01 2014-12-18 The Johns Hopkins University Psma-binding agents and uses thereof
US8932595B2 (en) 2008-10-12 2015-01-13 Massachusetts Institute Of Technology Nicotine immunonanotherapeutics
US8906381B2 (en) 2008-10-12 2014-12-09 Massachusetts Institute Of Technology Immunonanotherapeutics that provide IGG humoral response without T-cell antigen
US20100226986A1 (en) * 2008-12-12 2010-09-09 Amy Grayson Therapeutic Particles Suitable for Parenteral Administration and Methods of Making and Using Same
US8563041B2 (en) 2008-12-12 2013-10-22 Bind Therapeutics, Inc. Therapeutic particles suitable for parenteral administration and methods of making and using same
US8905997B2 (en) 2008-12-12 2014-12-09 Bind Therapeutics, Inc. Therapeutic particles suitable for parenteral administration and methods of making and using same
US20110217377A1 (en) * 2008-12-15 2011-09-08 Zale Stephen E Long Circulating Nanoparticles for Sustained Release of Therapeutic Agents
US20100216804A1 (en) * 2008-12-15 2010-08-26 Zale Stephen E Long Circulating Nanoparticles for Sustained Release of Therapeutic Agents
US9198874B2 (en) 2008-12-15 2015-12-01 Bind Therapeutics, Inc. Long circulating nanoparticles for sustained release of therapeutic agents
US9308179B2 (en) 2008-12-15 2016-04-12 Bind Therapeutics, Inc. Long circulating nanoparticles for sustained release of therapeutic agents
US8986655B2 (en) 2009-05-19 2015-03-24 The Regents Of The University Of California Compositions, devices, and methods related to prostate-specific membrane antigen
US12083191B2 (en) 2009-10-19 2024-09-10 Case Western Reserve University Composition and methods for imaging cells
US8603535B2 (en) 2009-12-11 2013-12-10 Bind Therapeutics, Inc. Stable formulations for lyophilizing therapeutic particles
US8956657B2 (en) 2009-12-11 2015-02-17 Bind Therapeutics, Inc. Stable formulations for lyophilizing therapeutic particles
US8211473B2 (en) 2009-12-11 2012-07-03 Bind Biosciences, Inc. Stable formulations for lyophilizing therapeutic particles
US8637083B2 (en) 2009-12-11 2014-01-28 Bind Therapeutics, Inc. Stable formulations for lyophilizing therapeutic particles
US9498443B2 (en) 2009-12-11 2016-11-22 Pfizer Inc. Stable formulations for lyophilizing therapeutic particles
US9872848B2 (en) 2009-12-11 2018-01-23 Pfizer Inc. Stable formulations for lyophilizing therapeutic particles
US8357401B2 (en) 2009-12-11 2013-01-22 Bind Biosciences, Inc. Stable formulations for lyophilizing therapeutic particles
US8916203B2 (en) 2009-12-11 2014-12-23 Bind Therapeutics, Inc. Stable formulations for lyophilizing therapeutic particles
US8912212B2 (en) 2009-12-15 2014-12-16 Bind Therapeutics, Inc. Therapeutic polymeric nanoparticle compositions with high glass transition temperature or high molecular weight copolymers
US9295649B2 (en) 2009-12-15 2016-03-29 Bind Therapeutics, Inc. Therapeutic polymeric nanoparticle compositions with high glass transition temperature or high molecular weight copolymers
US8518963B2 (en) 2009-12-15 2013-08-27 Bind Therapeutics, Inc. Therapeutic polymeric nanoparticle compositions with high glass transition temperature or high molecular weight copolymers
US9835572B2 (en) 2009-12-15 2017-12-05 Pfizer Inc. Therapeutic polymeric nanoparticle compositions with high glass transition temperature or high molecular weight copolymers
US9951324B2 (en) 2010-02-25 2018-04-24 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US11155800B2 (en) 2010-02-25 2021-10-26 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10557128B2 (en) 2010-02-25 2020-02-11 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US12091693B2 (en) 2010-02-25 2024-09-17 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10905762B2 (en) 2011-02-04 2021-02-02 Case Western Reserve University Targeted nanoparticle conjugates
US9877923B2 (en) 2012-09-17 2018-01-30 Pfizer Inc. Process for preparing therapeutic nanoparticles
US10912840B2 (en) 2012-11-15 2021-02-09 Endocyte, Inc. Conjugates for treating diseases caused by PSMA expressing cells
WO2014078484A1 (en) * 2012-11-15 2014-05-22 Endocyte, Inc. Conjugates for treating diseases caused by psma expressing cells
US9636413B2 (en) 2012-11-15 2017-05-02 Endocyte, Inc. Conjugates for treating diseases caused by PSMA expressing cells
US9782493B2 (en) 2012-11-15 2017-10-10 Endocyte, Inc. Conjugates for treating diseases caused by PSMA expressing cells
US9889199B2 (en) 2013-02-15 2018-02-13 Case Western Reserve University PSMA ligands and uses thereof
US10709794B2 (en) 2013-02-15 2020-07-14 Case Western Reserve University Photodynamic therapy composition
WO2014127365A1 (en) * 2013-02-15 2014-08-21 Case Western Reserve University Psma ligands and uses thereof
US11975074B2 (en) 2013-02-15 2024-05-07 Case Western Reserve University Photodynamic therapy composition
US10363313B2 (en) 2013-02-15 2019-07-30 Case Western Reserve University PSMA ligands and uses thereof
US10207005B2 (en) 2013-02-15 2019-02-19 Case Western Reserve University Photodynamic therapy composition
US10434194B2 (en) 2013-06-20 2019-10-08 Case Western Reserve University PSMA targeted nanobubbles for diagnostic and therapeutic applications
WO2015057692A1 (en) * 2013-10-14 2015-04-23 The Johns Hopkins University Prostate-specific membrane antigen-targeted photosensitizers for photodynamic therapy
US10232058B2 (en) 2013-10-14 2019-03-19 The Johns Hopkins University Prostate-specific membrane antigen-targeted photosensitizers for photodynamic therapy
US11931430B2 (en) 2013-10-18 2024-03-19 Novartis Ag Labeled inhibitors of prostate specific membrane antigen (PSMA) as agents for the treatment of prostate cancer
US10471160B2 (en) 2013-10-18 2019-11-12 Deutsches Krebsforschungszentrum Labeled inhibitors of prostate specific membrane antigen (PSMA), their use as imaging agents and pharmaceutical agents for the treatment of prostate cancer
US10398791B2 (en) 2013-10-18 2019-09-03 Deutsches Krebsforschungszentrum Labeled inhibitors of prostate specific membrane antigen (PSMA), their use as imaging agents and pharmaceutical agents for the treatment of prostate cancer
US11045564B2 (en) 2013-10-18 2021-06-29 Deutsches Krebsforschungszentrum Labeled inhibitors of prostate specific membrane antigen (PSMA) as agents for the treatment of prostate cancer
US11951190B2 (en) 2013-10-18 2024-04-09 Novartis Ag Use of labeled inhibitors of prostate specific membrane antigen (PSMA), as agents for the treatment of prostate cancer
US10071100B2 (en) 2014-03-14 2018-09-11 Pfizer Inc. Therapeutic nanoparticles comprising a therapeutic agent and methods of making and using the same
US9895378B2 (en) 2014-03-14 2018-02-20 Pfizer Inc. Therapeutic nanoparticles comprising a therapeutic agent and methods of making and using the same
US10112974B2 (en) 2014-08-24 2018-10-30 Max-Planck-Gesellschaft Zur Foerderung Der Wissenschaften E.V. Method for the production of 18F-labeled active esters and their application exemplified by the preparation of a PSMA-specific PET-tracer
US10736974B2 (en) 2014-10-22 2020-08-11 The Johns Hopkins University Scaffolds and multifunctional intermediates for imaging PSMA and cancer therapy
US11911488B2 (en) 2014-10-22 2024-02-27 The Johns Hopkins Universty Scaffolds and multifunctional intermediates for imaging PSMA and cancer therapy
US10898596B2 (en) 2015-01-07 2021-01-26 Endocyte, Inc. Conjugates for imaging
US10188759B2 (en) 2015-01-07 2019-01-29 Endocyte, Inc. Conjugates for imaging
WO2016112382A3 (en) * 2015-01-09 2016-09-29 The Johns Hopkins University Intranasal administration of glutamate carboxypeptidase (gcp-ii) inhibitors
US11813340B2 (en) 2018-02-06 2023-11-14 The Johns Hopkins University PSMA targeted radiohalogenated urea-polyaminocarboxylates for cancer radiotherapy
WO2019157037A1 (en) 2018-02-06 2019-08-15 The Johns Hopkins University Psma targeted radiohalogenated urea-polyaminocarboxylates for cancer radiotherapy
US11202836B2 (en) 2018-03-23 2021-12-21 Case Western Reserve University PSMA targeted conjugate compounds and uses thereof
CN114786734A (en) * 2019-11-21 2022-07-22 费罗诺娃私人有限公司 Magnetic tracer compositions
US12133901B2 (en) 2020-01-21 2024-11-05 Case Western Reserve University PSMA ligand targeted compounds and uses thereof
WO2022101352A1 (en) 2020-11-12 2022-05-19 Abx Advanced Biochemical Compounds Gmbh Ligands of prostate specific membrane antigen (psma) containing heteroaromatic linker building blocks
US11998620B2 (en) 2021-11-09 2024-06-04 Case Western Reserve University PSMA targeted compounds and uses thereof

Also Published As

Publication number Publication date
EP2942065B1 (en) 2018-06-27
PL2942065T3 (en) 2018-11-30
US8487129B2 (en) 2013-07-16
CN101778910A (en) 2010-07-14
US20120269726A1 (en) 2012-10-25
EP2097111A4 (en) 2012-07-11
US20180111895A1 (en) 2018-04-26
TWI492761B (en) 2015-07-21
PL3699162T3 (en) 2022-10-31
EP3699162B1 (en) 2022-06-29
TW200836765A (en) 2008-09-16
US20120208988A1 (en) 2012-08-16
US20170044098A1 (en) 2017-02-16
DK2097111T3 (en) 2015-08-24
HK1200164A1 (en) 2015-07-31
WO2008058192A3 (en) 2008-09-12
US10131627B2 (en) 2018-11-20
US20160279235A1 (en) 2016-09-29
BRPI0718700A2 (en) 2013-12-31
HUE039199T2 (en) 2018-12-28
WO2008058192A2 (en) 2008-05-15
JP5606737B2 (en) 2014-10-15
SI2097111T1 (en) 2016-02-29
EP4023624A1 (en) 2022-07-06
US20210246103A1 (en) 2021-08-12
AU2007316391A1 (en) 2008-05-15
ES2547481T3 (en) 2015-10-06
PT3699162T (en) 2022-10-11
BRPI0718700B1 (en) 2023-10-10
EP3335736B1 (en) 2020-12-30
JP2015044807A (en) 2015-03-12
EP2942065A1 (en) 2015-11-11
CN103922998A (en) 2014-07-16
US20210070695A1 (en) 2021-03-11
US10647666B2 (en) 2020-05-12
ES2847275T3 (en) 2021-08-02
HUE026216T2 (en) 2016-05-30
ES2926912T3 (en) 2022-10-31
US9309193B2 (en) 2016-04-12
US20190276393A1 (en) 2019-09-12
BRPI0718700B8 (en) 2023-11-07
EP2097111A2 (en) 2009-09-09
CA2669127C (en) 2016-09-13
US20210070696A1 (en) 2021-03-11
HK1257260A1 (en) 2019-10-18
CA2669127A1 (en) 2008-05-15
PT2097111E (en) 2015-11-03
EP3699162A1 (en) 2020-08-26
CN101778910B (en) 2014-05-28
JP5936659B2 (en) 2016-06-22
US9878980B2 (en) 2018-01-30
HUE059645T2 (en) 2022-12-28
EP2097111B1 (en) 2015-07-15
US20230095637A1 (en) 2023-03-30
US10640461B2 (en) 2020-05-05
ES2684322T3 (en) 2018-10-02
CY1116610T1 (en) 2017-03-15
PL2097111T3 (en) 2016-01-29
EP3335736A1 (en) 2018-06-20
JP2010509358A (en) 2010-03-25

Similar Documents

Publication Publication Date Title
US20210246103A1 (en) Heterodimers of glutamic acid
US9238631B2 (en) Radiolabeled amino acids for diagnostic imaging
AU2007316391B2 (en) Heterodimers of glutamic acid

Legal Events

Date Code Title Description
AS Assignment

Owner name: MOLECULAR INSIGHT PHARMACEUTICALS, INC., MASSACHUS

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BABICH, JOHN W.;ZIMMERMAN, CRAIG N.;MARESCA, KEVIN P.;REEL/FRAME:020879/0157

Effective date: 20080429

AS Assignment

Owner name: NEXBANK, SSB, A TEXAS-CHARTERED SAVINGS BANK, AS C

Free format text: GRANT OF SECURITY INTEREST IN PATENT RIGHTS;ASSIGNOR:MOLECULAR INSIGHT PHARMACEUTICALS, INC.;REEL/FRAME:026347/0233

Effective date: 20110520

AS Assignment

Owner name: MOLECULAR INSIGHT PHARMACEUTICALS, INC., MASSACHUS

Free format text: MERGER;ASSIGNOR:MOLECULAR INSIGHT PHARMACEUTICALS, INC.;REEL/FRAME:026396/0273

Effective date: 20110519

STCB Information on status: application discontinuation

Free format text: EXPRESSLY ABANDONED -- DURING PUBLICATION PROCESS

AS Assignment

Owner name: MOLECULAR INSIGHT PHARMACEUTICALS, INC., MASSACHUS

Free format text: RELEASE OF PATENT SECURITY INTEREST;ASSIGNOR:NEXBANK, SSB (AS COLLATERAL AGENT);REEL/FRAME:029660/0618

Effective date: 20130118