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

US20020133019A1 - Thioflavin derivatives for use in antemortem diagnosis of alzheimer's disease and vivo imaging and prevention of amyloid deposition - Google Patents

Thioflavin derivatives for use in antemortem diagnosis of alzheimer's disease and vivo imaging and prevention of amyloid deposition Download PDF

Info

Publication number
US20020133019A1
US20020133019A1 US09/935,767 US93576701A US2002133019A1 US 20020133019 A1 US20020133019 A1 US 20020133019A1 US 93576701 A US93576701 A US 93576701A US 2002133019 A1 US2002133019 A1 US 2002133019A1
Authority
US
United States
Prior art keywords
group
compound
amyloid
lower alkyl
independently
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.)
Abandoned
Application number
US09/935,767
Other languages
English (en)
Inventor
William Klunk
Chester Mathis
Yanming Wang
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.)
University of Pittsburgh
Original Assignee
Individual
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
Priority to US09/935,767 priority Critical patent/US20020133019A1/en
Application filed by Individual filed Critical Individual
Assigned to PITTSBURGH, UNIVERSITY OF reassignment PITTSBURGH, UNIVERSITY OF ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KLUNK, WILLIAM E., MATHIS, CHESTER A., JR., WANG, YANMING
Publication of US20020133019A1 publication Critical patent/US20020133019A1/en
Priority to US10/388,173 priority patent/US7270800B2/en
Priority to US10/859,600 priority patent/US7351401B2/en
Priority to US11/828,554 priority patent/US7854920B2/en
Priority to US12/046,070 priority patent/US20080154042A1/en
Priority to US12/971,886 priority patent/US8404213B2/en
Priority to US13/310,243 priority patent/US20120095235A1/en
Priority to US13/779,063 priority patent/US8911707B2/en
Priority to US14/571,082 priority patent/US9808541B2/en
Priority to US14/595,949 priority patent/US9833458B2/en
Priority to US15/726,314 priority patent/US10137210B2/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • 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
    • A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds
    • 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
    • A61P25/28—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C07D277/66—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2 with aromatic rings or ring systems directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present invention relates to the identification of compounds that are suitable for imaging amyloid deposits in living patients. More specifically, the present invention relates to a method of imaging amyloid deposits in brain in vivo to allow antemortem diagnosis of Alzheimer's Disease. The present invention also relates to therapeutic uses for such compounds.
  • AD Alzheimer's Disease
  • McKhann et al., Neurology 34: 939 (1984) It is the most common cause of dementia in the United States.
  • AD can strike persons as young as 40-50 years of age, yet, because the presence of the disease is difficult to determine without dangerous brain biopsy, the time of onset is unknown.
  • the prevalence of AD increases with age, with estimates of the affected population reaching as high as 40-50% by ages 85-90.
  • AD Alzheimer's disease
  • NP neuritic plaques
  • NFT neurofibrillary tangles
  • neuronal loss along with a variety of other findings.
  • Post-mortem slices of brain tissue of victims of Alzheimer's disease exhibit the presence of amyloid in the form of proteinaceous extracellular cores of the neuritic plaques that are characteristic of AD.
  • amyloid cores of these neuritic plaques are composed of a protein called the ⁇ -amyloid (A ⁇ ) that is arranged in a predominately beta-pleated sheet configuration.
  • a ⁇ ⁇ -amyloid
  • Neuritic plaques are an early and invariant aspect of the disease. Mann et al., J. Neurol. Sci. 89: 169; Mann, Mech. Ageing Dev. 31: 213 (1985); Terry et al., J. Neuropathol. Exp. Neurol 46: 262 (1987).
  • Amyloid-containing neuritic plaques are a prominent feature of selective areas of the brain in AD as well as Down's Syndrome and in persons homozygous for the apolipoprotein E4 allele who are very likely to develop AD.
  • AD Alzheimer's disease
  • Radiolabeled A ⁇ peptide has been used to label diffuse, compact and neuritic type plaques in sections of AD brain. See Maggio et al., WO 93/04194. However, these peptides share all of the disadvantages of antibodies. Specifically, peptides do not normally cross the blood-brain barrier in amounts necessary for imaging and because these probes react with diffuse plaques, they may not be specific for AD.
  • amyloid-binding compounds will have therapeutic potential in AD and type 2 diabetes mellitus. Morphological reactions including, reactive astrocytosis, dystrophic neurites, activated microglia cells, synapse loss, and full complement activation found around neuritic plaques all signify that neurotoxic and cell degenerative processes are occurring in the areas adjacent to these A ⁇ deposits. Joachim et al., Am. J. Pathol. 135: 309 (1989); Masliah et al., loc. cit. 137: 1293 (1990); Lue and Rogers, Dementia 3: 308 (1992). A ⁇ -induced neurotoxicity and cell degeneration has been reported in a number of cell types in vitro.
  • Thioflavin T is a basic dye first described as a selective amyloid dye in 1959 by Vassar and Culling ( Arch. Pathol. 68: 487 (1959)). Schwartz et al. ( Zbl. Path. 106: 320 (1964)) first demonstrated the use of Thioflavin S, an acidic dye, as an amyloid dye in 1964. The properties of both Thioflavin T and Thioflavin S have since been studied in detail. Kelenyi J. Histochem. Cytochem. 15: 172 (1967); Burns et al. J. Path. Bact. 94:337 (1967); Guntern et al. Experientia 48: 8 (1992); LeVine Meth. Enzymol.
  • Thioflavin S is commonly used in the post-mortem study of amyloid deposition in AD brain where it has been shown to be one of the most sensitive techniques for demonstrating senile plaques. Vallet et al. Acta Neuropathol. 83: 170 (1992). Thioflavin T has been frequently used as a reagent to study the aggregation of soluble amyloid proteins into beta-sheet fibrils. LeVine Prot. Sci. 2: 404 (1993). Quaternary amine derivatives related to Thioflavin T have been proposed as amyloid imaging agents, although no evidence of brain uptake of these agents has been presented. Caprathe et aL U.S. Pat. No. 6,001,331.
  • amyloid binding compounds which enter the brain and bind selectively to amyloid.
  • amyloid binding compounds that are non-toxic and bioavailable and, consequently, can be used in therapeutics.
  • an amyloid binding compound having one of structures A-E:
  • Z is S, NR′, O or C(R′) 2 in which case the correct tautomeric form of the heterocyclic ring becomes an indole in which R′ is H or a lower alkyl group:
  • Y is NR 1 R 2 , OR 2 , or SR 2 ;
  • N or R is not a quaternary amine
  • amyloid binding compound having one of structures F-J or a water soluble, non-toxic salt thereof:
  • each Q is independently selected from one of the following structures:
  • Z is S, O, NR′, or C(R′) 2 in which R′ is H or a lower alkyl group
  • Y is NR 1 R 2 , OR 2 , or SR 2 ;
  • M is selected from the group consisting of Tc and Re;
  • M is selected from the group consisting of Tc and Re;
  • R 15 independently is selected from one of:
  • amyloid binding, chelating compound (with or without a chelated metal group) or a water soluble, non-toxic salt thereof of the form:
  • R 15 independently is selected from one of:
  • Z is S, NR′, O, or C(R′) 2 in which R′ is H or a lower alkyl group
  • Y is NR 1 R 2 , OR 26 , or SR 26 ;
  • M* is 99m Tc
  • R 15 independently is selected from one of the following:
  • R 15 independently is selected from one of the following:
  • Z is S, NR′, O, or C(R′) 2 in which R′ is H or a lower alkyl group
  • Y is NR 1 R 2 , OR 2 , or SR 2 ;
  • M* is 99m Tc
  • a chelating group (with chelated metal group) of the form W-L* or V-W-L*, wherein V is selected from the group consisting of —COO—, —CO—, —CH 2 O— and —CH 2 NH—; W is
  • R 15 independently is selected from one of the following:
  • R 15 independently is selected from one of the following:
  • Z is S, NR′, O, or C(R′) 2 in which R′ is H or a lower alkyl group
  • Y is NR 1 R 2 , OR 2 , or SR 2 ;
  • At least one of the substituents R 3 -R 14 is selected from the group consisting of CN, OCH 3 , OH and NH 2 .
  • amyloid binding compounds of the present invention bind to A ⁇ with a dissociation constant (K D ) between 0.0001 and 10.0 ⁇ M when measured by binding to synthetic A ⁇ peptide or Alzheimer's Disease brain tissue.
  • K D dissociation constant
  • Another embodiment of the invention relates to a method for synthesizing the amyloid binding compounds of the present invention having at least one of the substituents R 1 -R 14 selected from the group consisting of 131 I, 125 I, 123 I, 76 Br, 75 Br, 18 F, and 19 F, comprising the step of labeling the amyloid binding compound wherein at least one of the substituents R 1 -R 14 is a tri-alkyl tin, by reaction of the compound with a 131 I, 125 I, 123 I, 76 Br, 75 Br, 18 F, or 19 F containing substance.
  • a further embodiment of the present invention relates to a pharmaceutical composition for in vivo imaging of amyloid deposits, comprising (a) an amyloid binding compound chosen from the structures A-E or F-J, and (b) a pharmaceutically acceptable carrier.
  • an in vivo method for detecting amyloid deposits in a subject comprising the steps of: (a) administering a detectable quantity of a pharmaceutical composition comprising the labeled amyloid binding compound, and detecting the binding of the compound to amyloid deposit in the subject.
  • the amyloid deposit is located in the brain of a subject.
  • the subject is suspected of having a disease or syndrome selected from the group consisting of Alzheimer's Disease, familial Alzheimer's Disease, Down's Syndrome and homozygotes for the apolipoprotein E4 allele.
  • the detecting is selected from the group consisting of gamma imaging, magnetic resonance imaging and magnetic resonance spectroscopy.
  • the gamma imaging is either PET or SPECT.
  • the pharmaceutical composition is administered by intravenous injection.
  • the ratio of (i) binding of the compound to a brain area other than the cerebellum to (ii) binding of the compound to the cerebellum, in a subject is compared to the ratio in a normal subject.
  • Anther embodiment relates to a method of detecting amyloid deposits in biopsy or post-mortem human or animal tissue comprising the steps of: (a) incubating formalin-fixed or fresh-frozen tissue with a solution of an amyloid binding compound of the present invention to form a labeled deposit and then, (b) detecting the labeled deposits.
  • the solution is composed of 25-100% ethanol, with the remainder of the solution being water, wherein the solution is saturated with an amyloid binding compound according to the present invention.
  • the solution is composed of an aqueous buffer (such as tris or phosphate) containing 0-50% ethanol, wherein the solution contains 0.0001 to 100 ⁇ M of an amyloid binding compound according to the present invention.
  • the detecting is effected by microscopic techniques selected from the group consisting of bright-field, fluorescence, laser-confocal, and cross-polarization microscopy.
  • a further embodiment relates to a method of quantifying the amount of amyloid in biopsy or post-mortem tissue comprising the steps of: a) incubating a radiolabeled derivative of an amyloid binding compound of the present invention with a homogenate of biopsy or post-mortem tissue, wherein at least one of the substituents R 1 -R 14 of the compound is labeled with a radiolabel selected from the group consisting of 125 I, 3 H, and a carbon-containing substituent as specified by the amyloid binding compound structures A-E or F-J, wherein at least one carbon is 14 C, b) separating the tissue-bound from the tissue-unbound radiolabeled derivative of an amyloid binding compound of the present invention, c) quantifying the tissue-bound radiolabeled derivative of an amyloid binding compound of the present invention, and d) converting the units of tissue-bound radiolabeled derivative of an amyloid binding compound of the present invention to units of micrograms of amyloid per 100 mg of tissue
  • the radiolabeled derivative of the amyloid binding compound of the present invention or a water soluble, non-toxic salt thereof is according to one of the formulae A-E below:
  • Z is S, NR′, O or C(R′) 2 in which case the correct tautomeric form of the heterocyclic ring becomes an indole in which R′ is H or a lower alkyl group:
  • Y is NR 1 R 2 , OR 2 , or SR 2 ;
  • group is not a quaternary amine
  • each Q is independently selected from one of the following structures:
  • Y is NR 1 R 2 , OR 2 , or SR 2 ;
  • [0117] is not a quaternary amine
  • M is selected from the group consisting of Tc and Re;
  • M is selected from the group consisting of Tc and Re;
  • R 15 independently is selected from one of the following:
  • R 15 independently is selected from the following:
  • Z is S, NR′, O, or C(R′) 2 in which R′ is H or a lower alkyl group
  • Y is NR 1 R 2 , OR 2 , or SR 2 ;
  • Another embodiment relates to a method of distinguishing an Alzheimer's disease brain from a normal brain comprising the steps of: a) obtaining tissue from (i) the cerebellum and (ii) another area of the same brain other than the cerebellum, from normal subjects and from subjects suspected of having Alzheimer's disease; b) incubating the tissues with a radiolabeled derivative of a thioflavin amyloid binding compound according to the present invention so that amyloid in the tissue binds with the radiolabeled derivative of an amyloid binding compound of the present invention; c) quantifying the amount of amyloid bound to the radiolabeled derivative of an amyloid binding compound of the present invention according to the above recited method; d) calculating the ratio of the amount of amyloid in the area of the brain other than the cerebellum to the amount of amyloid in the cerebellum; e) comparing the ratio for amount of amyloid in the tissue from normal subjects with ratio for amount of amyloid in tissue from subjects suspected of having Alzheimer
  • FIG. 1 Shows the structures of a Thioflavin S and Thioflavin T;
  • FIG. 2 Shows the structures of two thioflavin derivatives according to the invention
  • FIG. 3 Shows four serial sections of fluorescent dyed brain frontal cortex of an AD patient
  • FIG. 4 Shows proposed sites of binding of Chrysamine G and Thioflavin T in ⁇ -sheet fibrils
  • FIG. 5 Shows competition assay using Chrysamine G, Thioflavin S and Thioflavin T, and derivatives of the present invention (BTA-0, BTA-1 and BTA-2);
  • FIG. 6 Shows time course radioactivity in the frontal cortex of baboons injected with labeled BTA-1, 6-Meo-BTA-1 and 6-Me-BTA-1;
  • FIG. 7 Shows a tranverse positron emission tomography image of two levels of baboon brain following i.v. injection of [N-methyl- 11 C]BTA-1.
  • FIG. 8 Shows post-mortem sections of human and transgenic mouse brain stained with a derivative of the present invention (BTA-1).
  • FIG. 9 Shows in vivo labeling of amyloid plaques and vascular amyloid stained by a derivative of the present invention (BTA-1) in living transgenic mice imaged with multiphoton microscopy.
  • the present invention exploits the ability of Thioflavin compounds and radiolabeled derivatives thereof to cross the blood brain barrier in vivo and bind to A ⁇ deposited in neuritic (but not diffuse) plaques, to A ⁇ deposited in cerebrovascular amyloid, and to the amyloid consisting of the protein deposited in NFT.
  • the present compounds are non-quaternary amine derivatives of Thioflavin S and T which are known to stain amyloid in tissue sections and bind to synthetic A ⁇ in vitro. Kelenyi J. Histochem. Cytochem. 15: 172 (1967); Burns et al. J. Path. Bact. 94:337 (1967); Guntern et al. Experientia 48: 8 (1992); LeVine Meth. Enzymol. 309: 274 (1999).
  • the thioflavin derivatives of the present invention have each of the following characteristics: (1) specific binding to synthetic A ⁇ in vitro and (2) ability to cross a non-compromised blood brain barrier in vivo.
  • lower alkyl is branched or straight chain C 1 -C 8 , preferably C 1 -C 6 and most preferably C 1 -C 4 (e.g., methyl, ethyl, propyl or butyl).
  • R 1 -R 14 is defined as “tri-alkyl tin”
  • the moiety is a tri-C 1 -C 8 alkyl Sn moiety, preferably tri-C 1 -C 6 alkyl Sn moiety, most preferably tri-C 1 -C 4 alkyl Sn moiety (e.g., methyl, ethyl, propyl or butyl).
  • the method of this invention determines the presence and location of amyloid deposits in an organ or body area, preferably brain, of a patient.
  • the present method comprises administration of a detectable quantity of a pharmaceutical composition containing an amyloid binding compound chosen from structures A-E or F-J, as defined above, called a “detectable compound,” or a pharmaceutically acceptable water-soluble salt thereof, to a patient.
  • a “detectable quantity” means that the amount of the detectable compound that is administered is sufficient to enable detection of binding of the compound to amyloid.
  • An “imaging effective quantity” means that the amount of the detectable compound that is administered is sufficient to enable imaging of binding of the compound to amyloid.
  • the invention employs amyloid probes which, in conjunction with non-invasive neuroimaging techniques such as magnetic resonance spectroscopy (MRS) or imaging (MRI), or gamma imaging such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), are used to quantify amyloid deposition in vivo.
  • non-invasive neuroimaging techniques such as magnetic resonance spectroscopy (MRS) or imaging (MRI), or gamma imaging such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • the radiation emitted from the organ or area being examined is measured and expressed either as total binding or as a ratio in which total binding in one tissue is normalized to (for example, divided by) the total binding in another tissue of the same subject during the same in vivo imaging procedure.
  • Total binding in vivo is defined as the entire signal detected in a tissue by an in vivo imaging technique without the need for correction by a second injection of an identical quantity of labeled compound along with a large excess of unlabeled, but otherwise chemically identical compound.
  • a “subject” is a mammal, preferably a human, and most preferably a human suspected of having dementia.
  • the type of detection instrument available is a major factor in selecting a given label.
  • radioactive isotopes and 19 F are particularly suitable for in vivo imaging in the methods of the present invention.
  • the type of instrument used will guide the selection of the radionuclide or stable isotope.
  • the radionuclide chosen must have a type of decay detectable by a given type of instrument.
  • Another consideration relates to the half-life of the radionuclide. The half-life should be long enough so that it is still detectable at the time of maximum uptake by the target, but short enough so that the host does not sustain deleterious radiation.
  • the radiolabeled compounds of the invention can be detected using gamma imaging wherein emitted gamma irradiation of the appropriate wavelength is detected.
  • Methods of gamma imaging include, but are not limited to, SPECT and PET.
  • the chosen radiolabel will lack a particulate emission, but will produce a large number of photons in a 140-200 keV range.
  • the radiolabel will be a positron-emitting radionuclide such as 19 F which will annihilate to form two 511 keV gamma rays which will be detected by the PET camera.
  • amyloid binding compounds/probes are made which are useful for in vivo imaging and quantification of amyloid deposition. These compounds are to be used in conjunction with non-invasive neuroimaging techniques such as magnetic resonance spectroscopy (MRS) or imaging (MRI), positron emission tomography (PET), and single-photon emission computed tomography (SPECT).
  • non-invasive neuroimaging techniques such as magnetic resonance spectroscopy (MRS) or imaging (MRI), positron emission tomography (PET), and single-photon emission computed tomography (SPECT).
  • MRS magnetic resonance spectroscopy
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • the thioflavin derivatives may be labeled with 19 F or 13 C for MRS/MRI by general organic chemistry techniques known to the art. See, e.g., March, J.
  • thioflavin derivatives also may be radiolabeled with 18 F, 11 C, 75 Br, or 76 Br for PET by techniques well known in the art and are described by Fowler, J. and Wolf, A. in POSITRON EMISSION TOMOGRAPHY AND AUTORADIOGRAPHY (Phelps, M., Mazziota, J., and Schelbert, H. eds.) 391-450 (Raven Press, NY 1986) the contents of which are hereby incorporated by reference.
  • the thioflavin derivatives also may be radiolabeled with 123 I for SPECT by any of several techniques known to the art. See, e.g., Kulkarni, Int. J. Rad. Appl. & Inst. (Part B) 18: 647 (1991), the contents of which are hereby incorporated by reference.
  • the thioflavin derivatives may be labeled with any suitable radioactive iodine isotope, such as, but not limited to 131 I, 125 I, or 123 I, by iodination of a diazotized amino derivative directly via a diazonium iodide, see Greenbaum, F. Am. J. Pharm.
  • the thioflavin derivatives also may be radiolabeled with known metal radiolabels, such as Technetium-99m ( 99m Tc). Modification of the substituents to introduce ligands that bind such metal ions can be effected without undue experimentation by one of ordinary skill in the radiolabeling art.
  • the metal radiolabeled thioflavin derivative can then be used to detect amyloid deposits. Preparing radiolabeled derivatives of Tc 99m is well known in the art.
  • the methods of the present invention may use isotopes detectable by nuclear magnetic resonance spectroscopy for purposes of in vivo imaging and spectroscopy.
  • Elements particularly useful in magnetic resonance spectroscopy include 19 F and 13 C.
  • Suitable radioisotopes for purposes of this invention include beta-emitters, gamma-emitters, positron-emitters, and x-ray emitters. These radioisotopes include 131 I, 123 I, 18 F, 11 C, 75 Br, and 76 Br.
  • Suitable stable isotopes for use in Magnetic Resonance Imaging (MRI) or Spectroscopy (MRS), according to this invention include 19 F and 13 C.
  • Suitable radioisotopes for in vitro quantification of amyloid in homogenates of biopsy or post-mortem tissue include 125 I, 14 C, and 3 H.
  • the preferred radiolabels are 11 C or 18 F for use in PET in vivo imaging, 123 I for use in SPECT imaging, 19 F for MRS/MRI, and 3 H or 14 C for in vitro studies.
  • any conventional method for visualizing diagnostic probes can be utilized in accordance with this invention.
  • the method may be used to diagnose AD in mild or clinically confusing cases. This technique would also allow longitudinal studies of amyloid deposition in human populations at high risk for amyloid deposition such as Down's syndrome, familial AD, and homozygotes for the apolipoprotein E4 allele. Corder et al., Science 261: 921 (1993).
  • a method that allows the temporal sequence of amyloid deposition to be followed can determine if deposition occurs long before dementia begins or if deposition is unrelated to dementia. This method can be used to monitor the effectiveness of therapies targeted at preventing amyloid deposition.
  • the dosage of the detectably labeled thioflavin derivative will vary depending on considerations such as age, condition, sex, and extent of disease in the patient, contraindications, if any, concomitant therapies and other variables, to be adjusted by a physician skilled in the art. Dosage can vary from 0.001 ⁇ g/kg to 10 ⁇ g/kg, preferably 0.01 ⁇ g/kg to 1.0 ⁇ g/kg.
  • Administration to the subject may be local or systemic and accomplished intravenously, intraarterially, intrathecally (via the spinal fluid) or the like. Administration may also be intradermal or intracavitary, depending upon the body site under examination. After a sufficient time has elapsed for the compound to bind with the amyloid, for example 30 minutes to 48 hours, the area of the subject under investigation is examined by routine imaging techniques such as MRS/MRI, SPECT, planar scintillation imaging, PET, and any emerging imaging techniques, as well. The exact protocol will necessarily vary depending upon factors specific to the patient, as noted above, and depending upon the body site under examination, method of administration and type of label used; the determination of specific procedures would be routine to the skilled artisan.
  • the amount (total or specific binding) of the bound radioactively labeled thioflavin derivative or analogue of the present invention is measured and compared (as a ratio) with the amount of labeled thioflavin derivative bound to the cerebellum of the patient. This ratio is then compared to the same ratio in age-matched normal brain.
  • compositions of the present invention are advantageously administered in the form of injectable compositions, but may also be formulated into well known drug delivery systems (e.g., oral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), intracisternal, intravaginal, intraperitoneal, local (powders, ointments or drops), or as a buccal or nasal spray).
  • a typical composition for such purpose comprises a pharmaceutically acceptable carrier.
  • the composition may contain about 10 mg of human serum albumin and from about 0.5 to 500 micrograms of the labeled thioflavin derivative per milliliter of phosphate buffer containing NaCl.
  • compositions include aqueous solutions, non-toxic excipients, including salts, preservatives, buffers and the like, as described, for instance, in REMINGTON'S PHARMACEUTICAL SCIENCES, 15th Ed. Easton: Mack Publishing Co. pp. 1405-1412 and 1461-1487 (1975) and THE NATIONAL FORMULARY XIV., 14th Ed. Washington: American Pharmaceutical Association (1975), the contents of which are hereby incorporated by reference.
  • non-aqueous solvents examples include propylene glycol, polyethylene glycol, vegetable oil and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, saline solutions, parenteral vehicles such as sodium chloride, Ringer's dextrose, etc.
  • Intravenous vehicles include fluid and nutrient replenishers.
  • Preservatives include antimicrobials, anti-oxidants, chelating agents and inert gases.
  • the pH and exact concentration of the various components of the pharmaceutical composition are adjusted according to routine skills in the art. See, Goodman and Gilman's THE PHARMACOLOGICAL BASIS FOR THERAPEUTICS (7th Ed.).
  • compositions of the present invention are those that, in addition to specifically binding amyloid in vivo and capable of crossing the blood brain barrier, are also non-toxic at appropriate dosage levels and have a satisfactory duration of effect.
  • a pharmaceutical composition comprising thioflavin amyloid binding compounds, is administered to subjects in whom amyloid or amyloid fibril formation are anticipated.
  • such subject is a human and includes, for instance, those who are at risk of developing cerebral amyloid, including the elderly, nondemented population and patients having amyloidosis associated diseases and Type 2 diabetes mellitus.
  • the term “preventing” is intended to include the amelioration of cell degeneration and toxicity associated with fibril formation.
  • amelioration is meant the treatment or prevention of more severe forms of cell degeneration and toxicity in patients already manifesting signs of toxicity, such as dementia.
  • the pharmaceutical composition comprises thioflavin amyloid binding compounds described above and a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier comprises serum albumin, thioflavin amyloid binding compounds and a phosphate buffer containing NaCl.
  • Other pharmaceutically acceptable carriers include aqueous solutions, non-toxic excipients, including salts, preservatives, buffers and the like, as described, for instance, in REMINGTON'S PHARMACEUTICAL SCIENCES, 15th Ed., Easton: Mack Publishing Co., pp. 1405-1412 and 1461-1487 (1975) and THE NATIONAL FORMULARY XIV., 14th Ed. Washington: American Pharmaceutical Association (1975), and the UNITED STATES PHARMACOPEIA XVIII. 18th Ed. Washington: American Pharmaceutical Association (1995), the contents of which are hereby incorporated by reference.
  • non-aqueous solvents examples include propylene glycol, polyethylene glycol, vegetable oil and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, saline solutions, parenteral vehicles such as sodium chloride, Ringer's dextrose, etc.
  • Intravenous vehicles include fluid and nutrient replenishers.
  • Preservatives include antimicrobial, anti-oxidants, chelating agents and inert gases. The pH and exact concentration of the various components the pharmaceutical composition are adjusted according to routine skills in the art. See, Goodman and Gilman's THE PHARMACOLOGICAL BASIS FOR THERAPEUTICS (7th Ed.).
  • the inventive pharmaceutical composition could be administered orally, in the form of a liquid or solid, or injected intravenously or intramuscularly, in the form of a suspension or solution.
  • pharmaceutically effective amount is meant an amount that prevents cell degeneration and toxicity associated with fibril formation. Such amount would necessarily vary depending upon the age, weight and condition of the patient and would be adjusted by those of ordinary skill in the art according to well-known protocols.
  • a dosage would be between 0.1 and 100 mg/kg per day, or divided into smaller dosages to be administered two to four times per day. Such a regimen would be continued on a daily basis for the life of the patient.
  • the pharmaceutical composition could be administered intramuscularly in doses of 0.1 to 100 mg/kg every one to six weeks.
  • the method involves incubating formalin-fixed tissue with a solution of a thioflavin amyloid binding compound chosen from structures A-E or F-J, described above.
  • the solution is 25-100% ethanol, (with the remainder being water) saturated with a thioflavin amyloid binding compound according to the invention.
  • the compound stains or labels the amyloid deposit in the tissue, and the stained or labeled deposit can be detected or visualized by any standard method.
  • detection means include microscopic techniques such as bright-field, fluorescence, laser-confocal and cross-polarization microscopy.
  • the method of quantifying the amount of amyloid in biopsy or post-mortem tissue involves incubating a labeled derivative of thioflavin according to the present invention, or a water-soluble, non-toxic salt thereof, with homogenate of biopsy or post-mortem tissue.
  • the tissue is obtained and homogenized by methods well known in the art.
  • the preferred label is a radiolabel, although other labels such as enzymes, chemiluminescent and immunofluorescent compounds are well known to skilled artisans.
  • the preferred radiolabel is 125 I, 14 C or 3 H, the preferred label substituent of an amyloid binding compound chosen from structures A-E or F-J is at least one of R 3 -R 14 .
  • Tissue containing amyloid deposits will bind to the labeled derivatives of the thioflavin amyloid binding compounds of the present invention.
  • the bound tissue is then separated from the unbound tissue by any mechanism known to the skilled artisan, such as filtering.
  • the bound tissue can then be quantified through any means known to the skilled artisan.
  • the units of tissue-bound radiolabeled thioflavin derivative are then converted to units of micrograms of amyloid per 100 mg of tissue by comparison to a standard curve generated by incubating known amounts of amyloid with the radiolabeled thioflavin derivative.
  • the method of distinguishing an Alzheimer's diseased brain from a normal brain involves obtaining tissue from (i) the cerebellum and (ii) another area of the same brain, other than the cerebellum, from normal subjects and from subjects suspected of having Alzheimer's disease. Such tissues are made into separate homogenates using methods well known to the skilled artisan, and then are incubated with a radiolabeled thioflavin amyloid binding compound. The amount of tissue which binds to the radiolabeled thioflavin amyloid binding compound is then calculated for each tissue type (e.g.
  • cerebellum, non-cerebellum, normal, abnormal cerebellum, non-cerebellum, normal, abnormal
  • the ratio for the binding of non-cerebellum to cerebellum tissue is calculated for tissue from normal and for tissue from patients suspected of having Alzheimer's disease. These ratios are then compared. If the ratio from the brain suspected of having Alzheimer's disease is above 90% of the ratios obtained from normal brains, the diagnosis of Alzheimer's disease is made.
  • the normal ratios can be obtained from previously obtained data, or alternatively, can be recalculated at the same time the suspected brain tissue is studied.
  • Amino Acid Sequnece for A ⁇ (1-40) is as follows: 1 2 3 4 5 6 7 8 9 10 11 12 Asp Ala Glu Phe Arg His Asp Ser Gly Tyr Glu Val 13 14 15 16 17 18 19 20 21 22 23 24 His His Gln Lys Leu Val Phe Phe Ala Glu Asp Val 25 26 27 28 29 30 31 32 33 34 35 36 Gly Ser Asn Lys Gly Ala Ile Ile Gly Leu Met Val 37 38 39 40 Gly Gly Val Val Val
  • [0174] [C-14]ThT was synthesized and used to determine relative lipophilicity by partitioning between octanol and phosphate-buffered saline. The log of the partition coefficient, logP oct , was found to be 0.57 for [C-14]ThT. It was determined that the quaternary amine renders ThT too polar for use as an effective brain imaging agent. Based on the results of lipophilic Congo red derivatives (phenols uncharged at physiologic pH, but potentially ionizable with a pK a of ⁇ 8.5) (Klunk et al.
  • WO09634853A1, WO09847969A1, WO09924394A2 the inventors removed the methyl group from the benzothiazole nitrogen for the ThT derivatives.
  • the removal of the methyl moiety eliminated the charged quaternary amine from the heterocycle portion of the molecule, leaving an aromatic amine which typically have pK b values ⁇ 5.5.
  • Shorthand nomenclature for the ThT derivatives is used wherein the basic backbone is designated BTA (for BenzoThiazole-Aniline).
  • BTA for BenzoThiazole-Aniline
  • Substituents on the benzothiazole ring are placed before the ‘B’ and the number of methyl groups on the aniline nitrogen is placed after the ‘A’ (see, e.g., FIG. 2).
  • ThT is a fluorescent dye that has been used as a histological stain for amyloid (Burns et al., “The specificity of the staining of amyloid deposits with thioflavine T” Journal of Pathology & Bacteriology 94:337-344;1967.). ThT weakly stains plaques (see, e.g., FIG. 3), tangles, neuropil threads and cerebrovascular amyloid (CVA) in AD brain.
  • CVA cerebrovascular amyloid
  • Preliminary tissue staining shows that both the primary amine 2-(4′-aminophenyl)-6-methyl-benzothiazole (6-Me-BTA-O) and the tertiary amine 2-(4′-dimethylaminophenyl)-6-methyl-benzothiazole (6-Me-BTA-2) also stain plaques and tangles in post-mortem AD brain (see, e.g., FIG. 3).
  • Experiments in which the concentrations of 6-Me-BTA-0 and 6-Me-BTA-2 were progressively decreased showed that staining by both 6-Me-BTA-0 and 6-Me-BTA-1 could still be detected with staining solutions containing only 10 nM of the BTA compound.
  • BTP 2-phenylbenzothiazole
  • ThT and CG have opposite charges at physiological pH, and it is unlikely that they share a common binding site. This is supported by the lack of competition of ThT for [ 3 H]CG binding to A ⁇ fibrils (see, e.g., FIG. 5).
  • ThT binding site lies somewhere between residues 12 and 24 of A ⁇ . It is likely that the positively charged ThT (a quaternary amine) will be attracted to negatively charged (acidic) residues on A ⁇ . Between amino acids 12 and 24, the only acidic residues are Glu-22 and Asp-23. While both of these are candidates, the existing model predicts that Glu-22 is involved very near the Lys-16 binding site for CG. The current “working” model localizes ThT binding to the area of Asp-23—on the opposite side of the fibril from the proposed CG site. Since the key feature of ThT (and CG) binding is the presence of a beta-sheet fibril, binding must require more than just a single amino acid residue.
  • ThT also interacts via hydrogen bonds to His-13 and Gln-15 of a separate, adjacent A ⁇ molecule comprising the beta-sheet fibril.
  • Assessing binding by tissue staining is useful, particularly for assessing specificity.
  • the compound BTP which is not very fluorescent, may not show staining either because it does not bind well enough, or because it is not fluorescent enough.
  • quantitative binding assays can be conducted spectrophotometrically (LeVine ibid). This assay depends on metachromatic spectral shift which occurs when ThT binds to the amyloid fibril. While this assay can be useful to individually screen highly fluorescent compounds that show this metachromatic shift, it has not been determined to be useful for competition assays.
  • test compounds e.g., CG
  • ThT-A ⁇ complex as well as ThT alone
  • Compounds that quench, but do not bind to the ThT site will falsely appear to bind. Therefore, it is preferable to use radiolabeled ThT in typical radioligand binding assays with aggregated A ⁇ . In this assay, inhibition of radiolabeled ThT binding to AD trapped on filters would represent true inhibition of ThT binding and does not require the test compound to be highly fluorescent.
  • the primuline derivatives are prepared based on Schubert's method (Schubert, M. Zurluiphilic der Dehydrothiotoluidin- and Primulin-sulfo Acid, Justus Liebigs Ann. Chem. 558, 10-33,1947) through condensation of 2-amino-5-methylthiophenol with 2-(p-nitrophenyl)-benzothiazole-6-carboxylic chloride and subsequent reduction of the nitro group with tin chloride in ethanol.
  • Substituted derivatives of primuline base are synthesized with the appropriate substituted p-nitrobenzoylchlorides and R 7 -R 10 substituted 2-aminothiophenol.
  • the other claimed primulin derivatives may be synthesized by substituting the appropriate substituted 3-mercapto-4-aminobenzoic acid derivative (e.g. 2-, 5-, or 6-methyl-3-mercapto-4-aminobenzoic acid), the appropriate 4-nitro-benzoyl chloride derivative (e.g. 2- or 3-methyl-4-nitro-benzoyl chloride) or the appropriate 2-amino-5-methylthiophenol derivative (e.g. 3,5-, 4,5-, or 5,6-dimethyl-2-aminothiophenol).
  • the appropriate substituted 3-mercapto-4-aminobenzoic acid derivative e.g. 2-, 5-, or 6-methyl-3-mercapto-4-aminobenzoic acid
  • 4-nitro-benzoyl chloride derivative e.g. 2- or 3-methyl-4-nitro-benzoyl chloride
  • 2-amino-5-methylthiophenol derivative e.g. 3,5-, 4,5-, or 5,6-dimethyl-2-aminothiophenol
  • trans-4-Nitrocinnamyl chloride 10 (1.77 g, 9.5 mmol, 1.2 eq.) in DMF (20 ml) was added dropwise to a solution of 2-aminothiophenol 9 (1.0 g, 8.0 mmol) in DMF(1 5 ml) at room temperature. The reaction mixture was stirred at room temperature for overnight. The reaction mixture was poured into a solution of 10% sodium carbonate (100 ml). The participate was collected by filtration under reduced pressure. Recrystallization from methanol gave 1.92 g (85.1%) of the product 11.
  • p-Anisidine 1 (1.0 g, 8.1 mmol) was dissolved in anhydrous pyridine (15 ml), 4-nitrobenzoyl chloride 2 (1.5 g, 8.1 mmol) was added. The reaction mixture was allowed to stand at room temperature for 16 hrs. The reaction mixture was poured into water and the precipitate was collected with filtrate under vacuum pressure and washed with 5% sodium bicarbonate(2 ⁇ 10 ml). The product 3 was used in the next step without further purification.
  • the other claimed 2-(4′-aminophenyl)-benzothiazole derivatives may be synthesized by substituting the appropriate substituted aniline derivative (e.g. 2-, 3-, or 4-methylaniline) and the appropriate 4-nitro-benzoyl chloride derivative (e.g. 2- or 3-methyl-4-nitro-benzoyl chloride).
  • the appropriate substituted aniline derivative e.g. 2-, 3-, or 4-methylaniline
  • the appropriate 4-nitro-benzoyl chloride derivative e.g. 2- or 3-methyl-4-nitro-benzoyl chloride
  • the other claimed 2-(4′-aminophenyl)-benzothiazole derivatives may be synthesized by substituting appropriate 4-nitro-benzoyl chloride derivative (e.g. 2- or 3-methyl-4-nitro-benzoyl chloride) or appropriate 4-dimethylamino-benzoic acid derivative (e.g. 2- or 3-methyl-4-dimethylamino-benzoic acid).
  • the other bis-2,2′-(4′-aminophenyl)-dibenzothiazole derivatives may be synthesized via the appropriate substituted benzidine dervative (e.g. 2,2′-, 3,3′-dimethylbenzidine) and the appropriate 4-nitro-benzoyl chloride derivative (e.g. 2- or 3-methyl-4-nitro-benzoyl chloride).
  • substituted benzidine dervative e.g. 2,2′-, 3,3′-dimethylbenzidine
  • 4-nitro-benzoyl chloride derivative e.g. 2- or 3-methyl-4-nitro-benzoyl chloride
  • FIG. 7 Transverse PET images at two levels of baboon brain following the i.v. injection of 3 mCi of [N-methyl- 11 C]BTA-1 are shown in FIG. 7.
  • Brain regions include: Ctx (cortex); Thl (thalamus); Occ (occipital cortex); and Cer (cerebellum). Note the uniform distribution of radioactivity throughout the brain, indicating lack of regional binding specificity in normal brain.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Medicinal Preparation (AREA)
  • Magnetic Resonance Imaging Apparatus (AREA)
  • Nuclear Medicine (AREA)
US09/935,767 2000-08-24 2001-08-24 Thioflavin derivatives for use in antemortem diagnosis of alzheimer's disease and vivo imaging and prevention of amyloid deposition Abandoned US20020133019A1 (en)

Priority Applications (11)

Application Number Priority Date Filing Date Title
US09/935,767 US20020133019A1 (en) 2000-08-24 2001-08-24 Thioflavin derivatives for use in antemortem diagnosis of alzheimer's disease and vivo imaging and prevention of amyloid deposition
US10/388,173 US7270800B2 (en) 2000-08-24 2003-03-14 Thioflavin derivatives for use in antemortem diagnosis of Alzheimer's disease and in vivo imaging and prevention of amyloid deposition
US10/859,600 US7351401B2 (en) 2000-08-24 2004-06-03 Thioflavin derivatives for use in the antemortem diagnosis of Alzheimers disease and in vivo imaging and prevention of amyloid deposition
US11/828,554 US7854920B2 (en) 2000-08-24 2007-07-26 Thioflavin derivatives for use in antemortem diagnosis of alzheimer's disease and in vivo imaging and prevention of amyloid deposition
US12/046,070 US20080154042A1 (en) 2000-08-24 2008-03-11 Thioflavin derivatives for use in the antemortem diagnosis of alzheimers disease and in vivo imaging and prevention of amyloid deposition
US12/971,886 US8404213B2 (en) 2000-08-24 2010-12-17 Thioflavin derivatives for use in antemortem diagnosis of Alzheimer's disease and in vivo imaging and prevention of amyloid deposition
US13/310,243 US20120095235A1 (en) 2000-08-24 2011-12-02 Thioflavin derivates for use in the antemortem diagnosis of alzheimer's disease and in vivo imaging and prevention of amyloid deposition
US13/779,063 US8911707B2 (en) 2000-08-24 2013-02-27 Thioflavin derivatives for use in antemortem diagnosis of alzheimer's disease and in vivo imaging and prevention of amyloid deposition
US14/571,082 US9808541B2 (en) 2000-08-24 2014-12-15 Thioflavin derivatives for use in antemortem diagnosis of Alzheimer's disease and in vivo imaging and prevention of amyloid deposition
US14/595,949 US9833458B2 (en) 2000-08-24 2015-01-13 Thioflavin derivatives for use in the antemortem diagnosis of Alzheimer's disease and in vivo imaging and prevention of amyloid deposition
US15/726,314 US10137210B2 (en) 2000-08-24 2017-10-05 Thioflavin derivatives for use in antemortem diagnosis of Alzheimer's disease and in vivo imaging and prevention of amyloid deposition

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US22760100P 2000-08-24 2000-08-24
US09/935,767 US20020133019A1 (en) 2000-08-24 2001-08-24 Thioflavin derivatives for use in antemortem diagnosis of alzheimer's disease and vivo imaging and prevention of amyloid deposition

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US10/388,173 Continuation-In-Part US7270800B2 (en) 2000-08-24 2003-03-14 Thioflavin derivatives for use in antemortem diagnosis of Alzheimer's disease and in vivo imaging and prevention of amyloid deposition
US10/859,600 Continuation US7351401B2 (en) 2000-08-24 2004-06-03 Thioflavin derivatives for use in the antemortem diagnosis of Alzheimers disease and in vivo imaging and prevention of amyloid deposition

Publications (1)

Publication Number Publication Date
US20020133019A1 true US20020133019A1 (en) 2002-09-19

Family

ID=22853739

Family Applications (5)

Application Number Title Priority Date Filing Date
US09/935,767 Abandoned US20020133019A1 (en) 2000-08-24 2001-08-24 Thioflavin derivatives for use in antemortem diagnosis of alzheimer's disease and vivo imaging and prevention of amyloid deposition
US10/859,600 Expired - Lifetime US7351401B2 (en) 2000-08-24 2004-06-03 Thioflavin derivatives for use in the antemortem diagnosis of Alzheimers disease and in vivo imaging and prevention of amyloid deposition
US12/046,070 Abandoned US20080154042A1 (en) 2000-08-24 2008-03-11 Thioflavin derivatives for use in the antemortem diagnosis of alzheimers disease and in vivo imaging and prevention of amyloid deposition
US13/310,243 Abandoned US20120095235A1 (en) 2000-08-24 2011-12-02 Thioflavin derivates for use in the antemortem diagnosis of alzheimer's disease and in vivo imaging and prevention of amyloid deposition
US14/595,949 Expired - Lifetime US9833458B2 (en) 2000-08-24 2015-01-13 Thioflavin derivatives for use in the antemortem diagnosis of Alzheimer's disease and in vivo imaging and prevention of amyloid deposition

Family Applications After (4)

Application Number Title Priority Date Filing Date
US10/859,600 Expired - Lifetime US7351401B2 (en) 2000-08-24 2004-06-03 Thioflavin derivatives for use in the antemortem diagnosis of Alzheimers disease and in vivo imaging and prevention of amyloid deposition
US12/046,070 Abandoned US20080154042A1 (en) 2000-08-24 2008-03-11 Thioflavin derivatives for use in the antemortem diagnosis of alzheimers disease and in vivo imaging and prevention of amyloid deposition
US13/310,243 Abandoned US20120095235A1 (en) 2000-08-24 2011-12-02 Thioflavin derivates for use in the antemortem diagnosis of alzheimer's disease and in vivo imaging and prevention of amyloid deposition
US14/595,949 Expired - Lifetime US9833458B2 (en) 2000-08-24 2015-01-13 Thioflavin derivatives for use in the antemortem diagnosis of Alzheimer's disease and in vivo imaging and prevention of amyloid deposition

Country Status (19)

Country Link
US (5) US20020133019A1 (ja)
EP (2) EP1334091B1 (ja)
JP (2) JP5022554B2 (ja)
CN (1) CN1285582C (ja)
AU (3) AU8670201A (ja)
BR (1) BRPI0113470B8 (ja)
CA (1) CA2419420C (ja)
CY (1) CY1113311T1 (ja)
DK (2) DK1334091T3 (ja)
ES (2) ES2395721T3 (ja)
HK (2) HK1058041A1 (ja)
HU (2) HU230375B1 (ja)
LT (1) LTC1334091I2 (ja)
NO (1) NO330176B1 (ja)
PL (1) PL215711B1 (ja)
PT (2) PT1334091E (ja)
RU (1) RU2324686C2 (ja)
SI (1) SI1334091T1 (ja)
WO (1) WO2002016333A2 (ja)

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040102435A1 (en) * 2000-12-22 2004-05-27 Bernard Barlaam Therapeutic compounds
US20040121960A1 (en) * 1999-11-05 2004-06-24 Claudio Soto-Jara Peptide analogs and mimetics suitable for in vivo use in the treatment of diseases associated with abnormal protein folding into amyloid, amyloid like deposits or beta sheet rich pathological precursor thereof
US20040152068A1 (en) * 2000-08-21 2004-08-05 Goldstein Lee E. Ocular diagnosis of Alzheimer's disease
US20060106074A1 (en) * 2001-11-28 2006-05-18 Peter Bernstein Er-b-selective ligands
US20070003552A1 (en) * 2002-07-09 2007-01-04 Gebbink Martijn F B Cross-beta structure comprising amyloid binding proteins and methods for detection of the cross-beta structure, for modulating cross-beta structures fibril formation and for modulating cross-beta structure-mediated toxicity and method for interfering with blood coagulation
US20070015133A1 (en) * 2005-07-13 2007-01-18 Umc Utrecht Holding B.V. Method for detecting and/or removing protein and/or peptide comprising a cross-beta structure from an aqueous solution comprising a protein
US20070015206A1 (en) * 2005-07-13 2007-01-18 Umc Utrecht Holding B.V. Method for detecting and/or removing protien comprising a cross-beta structure from a pharmaceutical composition
US20070122341A1 (en) * 2005-11-29 2007-05-31 Seoul National University Industry Foundation Benzylideneaniline derivatives and their radioisotope labeled compounds for binding and imaging of beta-amyloid plaques
WO2007064773A2 (en) * 2005-12-01 2007-06-07 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Isotopically-labeled benzothiazole compounds as imaging agents for amyloidogenic proteins
US20070154980A1 (en) * 2005-12-30 2007-07-05 Gasper Susan M Fluorescent dyes
US20070258887A1 (en) * 2006-05-08 2007-11-08 Tamagnan Gilles D Compounds and amyloid probes thereof for therapeutic and imaging uses
US20080118529A1 (en) * 2005-07-13 2008-05-22 Gebbink Martijn Frans Ben Gera Adjuvation Through Cross -Beta Structure
US20080241165A1 (en) * 2002-07-09 2008-10-02 Crossbeta Biosciences B.V. Cross-beta structure comprising amyloid-binding proteins and methods for detection of the cross-beta structure, for modulating cross-beta structures fiber formation and modulating cross-beta structure-mediated toxicity
US20080267948A1 (en) * 2005-07-13 2008-10-30 Martijn Frans Ben Gerard Gebbink Croos-B Structure Binding Compounds
US20090123373A1 (en) * 2007-11-05 2009-05-14 Yanming Wang Amyloid-imaging agents
US20090142377A1 (en) * 2007-11-08 2009-06-04 Crossbeta Biosciences B.V. Immunogenic compositions
US20090155254A1 (en) * 2006-02-16 2009-06-18 Martijn Frans Ben Gerard Gebbink Affinity Regions
US7653428B2 (en) 2000-08-21 2010-01-26 The Brigham And Women's Hospital, Inc. Methods for diagnosing a neurodegenerative condition
US7668586B2 (en) * 2000-11-02 2010-02-23 Cornell Research Foundation, Inc. In vivo multiphoton diagnostic detection and imaging of a neurodegenerative disease
US20100249408A1 (en) * 2007-10-30 2010-09-30 Nihon Medi-Physics Co., Ltd. Use of novel compound having affinity for amyloid, and process for production of the same
US20100249407A1 (en) * 2006-04-28 2010-09-30 Nihon Medi-Physics Co., Ltd. Novel Compound Having Affinity to Amyloid
US20100249418A1 (en) * 2007-10-24 2010-09-30 Nihon Medi-Physics Co., Ltd. Novel compound having affinity for amyloid
US20110008376A1 (en) * 2007-11-08 2011-01-13 Martijn Frans Ben Gerard Gebbink Immunogenic compositions capable of activating t-cells
US20110081428A1 (en) * 2009-09-16 2011-04-07 The Buck Institute For Age Research Use of thioflavin-like compounds to increase life span and/or health span
US20110250136A1 (en) * 2008-11-06 2011-10-13 Snu R&Db Foundation Fluorinated benzothiazole derivatives, preparation method thereof and imaging agent for diagnosing altzheimer's disease using the same
DE102010045797A1 (de) 2010-09-20 2012-03-22 Klinikum Darmstadt Gmbh Verbindungen für die Diagnostik neurodegenerativer Erkrankungen am Riechepithel
WO2012041292A2 (de) 2010-09-20 2012-04-05 Klinikum Darmstadt Gmbh Verbindungen für die diagnostik neurodegenerativer erkrankungen an der retina
US10675365B2 (en) 2016-09-29 2020-06-09 Korea Atomic Energy Research Institute Curcumin derivative, method for producing same, and photo-acoustic imaging agent comprising same for detecting beta-amyloid plaque

Families Citing this family (85)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2001239544A1 (en) * 2000-03-22 2001-10-03 Bf Research Institute, Inc. Image diagnosis probe based on substituted azobenzene or analogue thereof for disease attributable to amyloid accumulation and composition for image diagnosis containing the same
AU8670201A (en) * 2000-08-24 2002-03-04 Univ Pittsburgh Thioflavin derivatives for use in antemortem diagnosis of alzheimer's disease and in vivo imaging and prevention of amyloid deposition
US7270800B2 (en) 2000-08-24 2007-09-18 University Of Pittsburgh Thioflavin derivatives for use in antemortem diagnosis of Alzheimer's disease and in vivo imaging and prevention of amyloid deposition
GB0106953D0 (en) 2001-03-20 2001-05-09 Univ Aberdeen Neufofibrillary labels
US6774248B2 (en) 2001-12-18 2004-08-10 Wyeth Substituted 2-phenyl benzofurans as estrogenic agents
US7008958B2 (en) 2002-05-21 2006-03-07 Bristol-Myers Squibb Company 2-substituted 5-oxazolyl indole compounds useful as IMPDH inhibitors and pharmaceutical compositions comprising same
AU2003242233A1 (en) * 2002-06-12 2003-12-31 Bf Research Institute, Inc. Probe compound for image diagnosis of disease with amyloid accumulation, compound for staining age spots/diffuse age spots, and remedy for disease with amyloid accumulation
EP1547996A4 (en) * 2002-08-30 2006-08-02 Bf Res Inst Inc DIAGNOSTIC PROBES AND REMEDIES FOR DISEASES HAVING PRION PROTEIN ACCUMULATION AND METHOD OF MARKING
ES2312857T3 (es) 2002-12-19 2009-03-01 The Scripps Research Institute Composiciones y metodos para estabilizar la transtiretina e inhibir el mal replegamiento de la transtiretina.
GB0229686D0 (en) * 2002-12-20 2003-01-29 Amersham Plc Solid-phase fluorination of benzothiazoles
JP4875487B2 (ja) * 2003-03-14 2012-02-15 ユニバーシティー オブ ピッツバーグ − オブ ザ コモンウェルス システム オブ ハイヤー エデュケーション ベンゾチアゾール誘導体化合物、組成物および使用
CA2438032C (en) * 2003-03-14 2013-05-07 University Of Pittsburgh Benzothiazole derivative compounds, compositions and uses
GB0307855D0 (en) * 2003-04-04 2003-05-14 Novartis Ag Organic compounds
US20040223912A1 (en) * 2003-05-07 2004-11-11 Montalto Michael Christopher Compositions and methods for non-invasive imaging of soluble beta-amyloid
WO2004100998A2 (en) 2003-05-07 2004-11-25 General Electric Company Compositions and methods for non-invasive imaging of soluble beta-amyloid
WO2005016384A1 (ja) * 2003-08-13 2005-02-24 Bf Research Institute, Inc. アミロイド蓄積性疾患のプローブ、アミロイド染色剤、アミロイド蓄積性疾患の治療および予防薬、ならびに神経原線維変化の診断プローブおよび染色剤
AU2004265174A1 (en) * 2003-08-13 2005-02-24 Bf Research Institute, Inc. Probe for diseases in which amyloid accumulates, agents for staining amyloid, drugs for treatment and prophylaxis of diseases with accumulated amyloid, and probes for diagnosis of neurofibrillary tangles and agents for staining neurofibrillary tangles.
US8236282B2 (en) 2003-08-22 2012-08-07 University of Pittsburgh—of the Commonwealth System of Higher Education Benzothiazole derivative compounds, compositions and uses
WO2005042461A1 (ja) * 2003-10-30 2005-05-12 Dojindo Laboratories アミロイド親和性化合物
EP1719529A4 (en) * 2004-02-25 2008-05-21 Astellas Pharma Inc CONTRASTING FOR THROMBUS EDUCATION
JP5039541B2 (ja) 2004-04-27 2012-10-03 ワイス・エルエルシー プロゲステロン受容体調節剤の精製
GB0410448D0 (en) 2004-05-11 2004-06-16 Hammersmith Imanet Ltd Purification methods
WO2005112913A1 (en) 2004-05-20 2005-12-01 The Scripps Research Institute Transthyretin stabilization
AU2005270027A1 (en) * 2004-07-02 2006-02-09 University Of Pittsburgh - Of The Commonwealth System Of Higher Education A method of diagnosing prodromal forms of diseases associated with amyloid deposition
PL1771208T3 (pl) * 2004-07-02 2013-11-29 Univ Pittsburgh Commonwealth Sys Higher Education Zastosowanie radioznakowanych pochodnych tioflawiny w obrazowaniu amyloidu dla oceny terapii antyamyloidowej
US7868037B2 (en) 2004-07-14 2011-01-11 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US7781478B2 (en) 2004-07-14 2010-08-24 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US7772271B2 (en) 2004-07-14 2010-08-10 Ptc Therapeutics, Inc. Methods for treating hepatitis C
KR20070083484A (ko) 2004-07-14 2007-08-24 피티씨 테라퓨틱스, 인크. Ｃ형 간염 치료 방법
CA2573819A1 (en) * 2004-07-15 2006-02-23 The General Hospital Corporation Heterocyclic dye compounds for in vivo imaging and diagnosis of alzheimer's disease
WO2006019832A1 (en) 2004-07-22 2006-02-23 Ptc Therapeutics, Inc. Thienopyridines for treating hepatitis c
WO2007035405A2 (en) * 2005-09-16 2007-03-29 University Of Pittsburgh In-vivo and in-vitro method for detecting amyloid deposits having at least one amyloidogenic protein
WO2007063946A1 (ja) * 2005-11-30 2007-06-07 Fujifilm Ri Pharma Co., Ltd. アミロイドの凝集及び／又は沈着に起因する疾患の診断薬及び治療薬
WO2007075595A2 (en) * 2005-12-20 2007-07-05 Vertex Pharmacueticals Incorporated Biofilm assay
TW200736252A (en) 2006-01-27 2007-10-01 Astrazeneca Ab Novel heteroaryl substituted benzothiazoles
JP5376956B2 (ja) 2006-02-10 2013-12-25 スムミト コーポレーション ピーエルシー デュシェンヌ型筋ジストロフィーの治療
WO2007111179A1 (ja) * 2006-03-28 2007-10-04 Shiga University Of Medical Science 神経難病の画像診断薬
RU2008150377A (ru) 2006-05-19 2010-06-27 Нихон Меди-Физикс Ко., Лтд. (Jp) Новое соединение, обладающее сродством к амилоиду
TW200813035A (en) 2006-06-19 2008-03-16 Astrazeneca Ab Novel heteroaryl substituted benzoxazoles
CN101501033B (zh) 2006-06-21 2012-08-01 通用电气医疗有限公司 对淀粉状蛋白具有亲和性的化合物
EP2059491A1 (en) 2006-08-03 2009-05-20 Hammersmith Imanet Limited Method for the purification of radiolabelled compounds
ATE529425T1 (de) 2006-11-30 2011-11-15 Nihon Mediphysics Co Ltd Verbindungen mit affinität zu amyloid
CN101668560A (zh) * 2006-12-07 2010-03-10 宾夕法尼亚大学理事会 乙炔衍生物及它们在结合和显像淀粉样斑块中的应用
ES2414614T3 (es) * 2007-01-30 2013-07-22 Ge Healthcare Limited Herramientas para ayudar en el diagnóstico de enfermedades neurodegenerativas
JP5258583B2 (ja) 2007-02-13 2013-08-07 日本メジフィジックス株式会社 放射性画像診断剤の製造方法
TW200901998A (en) 2007-03-06 2009-01-16 Astrazeneca Ab Novel 2-heteroaryl substituted benzothiophenes and benzofuranes
CN101293878B (zh) * 2007-04-25 2010-12-15 中国科学院上海应用物理研究所 苯并噻唑苯胺类化合物及其制备方法和应用
TW200911237A (en) 2007-08-03 2009-03-16 Summit Corp Plc Drug combinations for the treatment of duchenne muscular dystrophy
CN101790387B (zh) 2007-08-30 2013-03-20 通用电气健康护理有限公司 放射性药物组合物
TW200918101A (en) 2007-10-26 2009-05-01 Nihon Mediphysics Co Ltd Novel compound having affinity for amyloid
AU2008319987A1 (en) 2007-10-30 2009-05-07 Nihon Medi-Physics Co., Ltd. Utilization of novel compounds with amyloid affinity and method of producing the same
CN102047061A (zh) * 2008-05-30 2011-05-04 福斯特韦勒能源股份公司 通过氧化燃料燃烧发电的方法和系统
WO2009155017A2 (en) 2008-05-30 2009-12-23 Merck & Co., Inc. Novel substituted azabenzoxazoles
US20110076230A1 (en) * 2008-05-30 2011-03-31 Barrow James C Novel Substituted Indoles
EP2307381B1 (en) * 2008-06-09 2021-01-13 Ludwig-Maximilians-Universität München New drugs for inhibiting aggregation of proteins involved in diseases linked to protein aggregation and/or neurodegenerative diseases
US20100099609A1 (en) * 2008-07-28 2010-04-22 Buck Institute For Age Research eAPP AND DERIVATIVES FOR TREATMENT OF ALZHEIMER'S DISEASE
EP2344877A4 (en) 2008-09-30 2014-09-10 Univ Case Western Reserve MOLECULAR PROBES FOR MYELIN IMAGING
US20100129290A1 (en) * 2008-11-26 2010-05-27 I.S.T. Corporation Smart contrast agent and detection method for detecting transition metal ions
CN101598703B (zh) * 2009-07-03 2012-08-22 中国人民解放军第三军医大学第一附属医院 dGTpase蛋白在制备用于鉴别诊断唐氏胎儿药物中的应用
FR2948685A1 (fr) * 2009-07-30 2011-02-04 Biomerieux Sa Nouveaux substrats
WO2012161116A1 (ja) 2011-05-20 2012-11-29 日本メジフィジックス株式会社 新規アミロイド親和性化合物
US9211350B2 (en) 2011-06-24 2015-12-15 Nihon Medi-Physics Co., Ltd. Compound with amyloid affinity
WO2013027694A1 (ja) * 2011-08-24 2013-02-28 国立大学法人京都大学 コンフォメーション病診断用分子イメージングプローブ
MX2014003043A (es) 2011-09-16 2015-02-05 Pfizer Formas solidas de un inhibidor de disociacion transtiretina.
CN102526765B (zh) * 2011-12-31 2014-07-30 郑州泰基鸿诺药物科技有限公司 一种Aβ斑块显像剂及其制备方法
KR20130111082A (ko) * 2012-03-30 2013-10-10 한미약품 주식회사 베타-아밀로이드 피브릴 형성 저해 효능을 갖는 아미노스티릴벤조퓨란 화합물 및 이를 함유하는 약학 조성물
EP2890700B1 (de) * 2012-08-28 2017-12-13 Eberhard Karls Universität Tübingen Medizinische Fakultät Halogenierte benzoxazine und ihre verwendung
DK2890700T3 (en) 2012-08-28 2018-03-12 Univ Tuebingen Medizinische Fakultaet HALOGENATED BENZOXAZINES AND THEIR USE
KR20190136125A (ko) 2012-12-21 2019-12-09 국립연구개발법인 양자과학기술연구개발기구 뇌 안에 축적된 타우 단백질을 이미징하기 위한 신규한 화합물
US9246108B2 (en) 2012-12-28 2016-01-26 Dow Global Technologies Llc Quinoline-benzoxazole derived compounds for electronic films and devices
EP2958596B1 (en) 2013-02-15 2019-12-04 Case Western Reserve University Psma ligands and uses thereof
WO2015044095A1 (en) 2013-09-26 2015-04-02 F. Hoffmann-La Roche Ag Imidazo[1,2-a]pyridin-7-amines as imaging tools
WO2015051188A1 (en) * 2013-10-02 2015-04-09 Washington University Heterocyclic molecules for biomedical imaging and therapeutic applications
EP4039255A1 (en) 2014-04-24 2022-08-10 Omoidesouzou Co. Ltd. Amyloid fiber formation limiter or inhibitor
CN104059028B (zh) * 2014-06-06 2020-10-16 北京智博高科生物技术有限公司 与Aβ斑块具有亲和力的含手性侧链取代的氟代2-芳基苯并杂环化合物、其制备方法及应用
JP6498412B2 (ja) * 2014-10-17 2019-04-10 国立大学法人群馬大学 新規チオフラビンｔ誘導体及びその利用
US9842938B2 (en) 2015-03-24 2017-12-12 Semiconductor Energy Laboratory Co., Ltd. Semiconductor device and display device including semiconductor device
WO2017156303A1 (en) 2016-03-09 2017-09-14 Case Western Reserve University Radioligands for myelin
MX2018010693A (es) * 2016-03-11 2019-03-28 Ac Immune Sa Compuestos biciclicos para diagnostico y terapia.
PT3781561T (pt) 2018-04-18 2024-06-18 Constellation Pharmaceuticals Inc Moduladores de enzimas modificadoras de metilo, composições e usos dos mesmos
US11167283B2 (en) 2018-05-04 2021-11-09 University Of South Carolina Dot blot box and use thereof
SG11202010946YA (en) 2018-05-09 2020-12-30 Aprinoia Therapeutics Inc Heteroaryl compounds and uses thereof
US11919912B2 (en) 2018-05-21 2024-03-05 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
TWI759962B (zh) 2019-11-13 2022-04-01 香港商新旭生技股份有限公司 用於降解tau蛋白聚集體的化合物及其用途
KR102426160B1 (ko) 2020-07-13 2022-07-29 (주)바이오액츠 알츠하이머 진단용 신규 형광화합물 및 이의 제조방법

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6034246A (en) * 1995-02-28 2000-03-07 Cancer Research Campaign Technology Limited 2-arylbenzazole compounds

Family Cites Families (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA241942A (en) 1924-08-05 Martinetto Vittorio Asynchronous machine
NL126227C (ja) * 1958-08-22
DE3148291A1 (de) 1981-12-05 1983-06-09 Basf Ag, 6700 Ludwigshafen Harnstoffderivate, verfahren zu ihrer herstellung und ihre verwendung zur bekaempfung unerwuenschten pflanzenwuchses
DE3307364A1 (de) * 1983-03-02 1984-09-06 Hoechst Ag, 6230 Frankfurt Zweikomponenten-diazontypiematerial
US4666829A (en) 1985-05-15 1987-05-19 University Of California Polypeptide marker for Alzheimer's disease and its use for diagnosis
CA1302403C (en) * 1987-04-08 1992-06-02 Steven C. Quay Amyloidosis and alzheimer's disease diagnostic assay and reagents therefor
US4933156A (en) * 1987-04-08 1990-06-12 Salutar, Inc. Amyloidosis and Alzheimer's disease diagnostic assay and reagents therefor
US5231000A (en) 1987-10-08 1993-07-27 The Mclean Hospital Antibodies to A4 amyloid peptide
CA1339014C (en) 1987-10-08 1997-03-25 Ronald E. Majocha Antibodies to a4 amyloid peptide
US5297562A (en) 1991-04-01 1994-03-29 President And Fellows Of Harvard College Method for detecting and treating Alzheimer's disease
US5434050A (en) 1991-08-13 1995-07-18 Regents Of The University Of Minnesota Labelled β-amyloid peptide and methods of screening for Alzheimer's disease
GB9317949D0 (en) * 1993-08-28 1993-10-13 Stevens Malcolm F G Benzothiazole compounds
US5935927A (en) 1994-02-03 1999-08-10 The Picower Institute For Medical Research Compositions and methods for stimulating amyloid removal in amyloidogenic diseases using advanced glycosylation endproducts
US6168776B1 (en) 1994-07-19 2001-01-02 University Of Pittsburgh Alkyl, alkenyl and alkynyl Chrysamine G derivatives for the antemortem diagnosis of Alzheimer's disease and in vivo imaging and prevention of amyloid deposition
US6417178B1 (en) * 1994-07-19 2002-07-09 University Of Pittsburgh Amyloid binding nitrogen-linked compounds for the antemortem diagnosis of alzheimer's disease, in vivo imaging and prevention of amyloid deposits
NZ307369A (en) 1995-05-01 1999-11-29 Univ Pittsburgh Azocompounds for the antemortem diagnosis of alzheimer's disease and in vivo imaging and prevention of amyloid deposition
WO1997026919A2 (en) * 1996-01-24 1997-07-31 Warner-Lambert Company Method of imaging amyloid deposits
JP2001510450A (ja) * 1996-10-23 2001-07-31 ザイモジェネティクス，インコーポレイテッド 骨欠損状態を処置するための組成物および方法
HUP0001383A3 (en) 1996-11-22 2001-11-28 Lilly Co Eli N-(aryl/heteroaryl) amino acid derivatives, pharmaceutical compositions comprising same and their use
AU736112B2 (en) * 1997-11-20 2001-07-26 Teijin Limited Biphenylamidine derivatives
WO2000002004A2 (en) 1998-06-30 2000-01-13 Kevin Mcclung Controlled-penetration projectile
GB9919673D0 (en) 1999-08-20 1999-10-20 Cancer Res Campaign Tech 2-Arlybenzazole compounds
AU8670201A (en) * 2000-08-24 2002-03-04 Univ Pittsburgh Thioflavin derivatives for use in antemortem diagnosis of alzheimer's disease and in vivo imaging and prevention of amyloid deposition
US7270800B2 (en) * 2000-08-24 2007-09-18 University Of Pittsburgh Thioflavin derivatives for use in antemortem diagnosis of Alzheimer's disease and in vivo imaging and prevention of amyloid deposition
WO2002051821A1 (en) 2000-12-22 2002-07-04 Astrazeneca Ab Therapeutic compounds
US6696039B2 (en) * 2001-04-23 2004-02-24 Trustees Of The University Of Pennsylvania Amyloid plaque aggregation inhibitors and diagnostic imaging agents
GB0229686D0 (en) 2002-12-20 2003-01-29 Amersham Plc Solid-phase fluorination of benzothiazoles
JP4875487B2 (ja) * 2003-03-14 2012-02-15 ユニバーシティー オブ ピッツバーグ − オブ ザ コモンウェルス システム オブ ハイヤー エデュケーション ベンゾチアゾール誘導体化合物、組成物および使用
US8236282B2 (en) * 2003-08-22 2012-08-07 University of Pittsburgh—of the Commonwealth System of Higher Education Benzothiazole derivative compounds, compositions and uses
PL1771208T3 (pl) * 2004-07-02 2013-11-29 Univ Pittsburgh Commonwealth Sys Higher Education Zastosowanie radioznakowanych pochodnych tioflawiny w obrazowaniu amyloidu dla oceny terapii antyamyloidowej
ES2379987T3 (es) * 2005-10-11 2012-05-07 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Compuestos de benzofurano marcados isotópicamente como radiotrazadores para proteínas amiloidógenas

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6034246A (en) * 1995-02-28 2000-03-07 Cancer Research Campaign Technology Limited 2-arylbenzazole compounds

Cited By (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060069058A1 (en) * 1999-11-05 2006-03-30 Axonyx, Inc. Beta-sheet breaker peptide analogs that inhibit beta-pleated sheet formation in amyloid beta-peptide
US20040121960A1 (en) * 1999-11-05 2004-06-24 Claudio Soto-Jara Peptide analogs and mimetics suitable for in vivo use in the treatment of diseases associated with abnormal protein folding into amyloid, amyloid like deposits or beta sheet rich pathological precursor thereof
US7653428B2 (en) 2000-08-21 2010-01-26 The Brigham And Women's Hospital, Inc. Methods for diagnosing a neurodegenerative condition
US20040152068A1 (en) * 2000-08-21 2004-08-05 Goldstein Lee E. Ocular diagnosis of Alzheimer's disease
US7297326B2 (en) * 2000-08-21 2007-11-20 The General Hospital Corporation Ocular diagnosis of Alzheimer's disease
US7668586B2 (en) * 2000-11-02 2010-02-23 Cornell Research Foundation, Inc. In vivo multiphoton diagnostic detection and imaging of a neurodegenerative disease
US7045539B2 (en) * 2000-12-22 2006-05-16 Astrazeneca Ab Therapeutic benzoxazole compounds
US20060111408A1 (en) * 2000-12-22 2006-05-25 Bernard Barlaam Therapeutic benzothiazole compounds
US20040102435A1 (en) * 2000-12-22 2004-05-27 Bernard Barlaam Therapeutic compounds
US20060106074A1 (en) * 2001-11-28 2006-05-18 Peter Bernstein Er-b-selective ligands
US20070003552A1 (en) * 2002-07-09 2007-01-04 Gebbink Martijn F B Cross-beta structure comprising amyloid binding proteins and methods for detection of the cross-beta structure, for modulating cross-beta structures fibril formation and for modulating cross-beta structure-mediated toxicity and method for interfering with blood coagulation
US8158585B2 (en) 2002-07-09 2012-04-17 Crossbeta Biosciences B.V. Cross-β structure comprising amyloid-binding proteins and methods for detection of the cross-β structure, for modulating cross-β structures fiber formation and modulating cross-β structure-mediated toxicity
US20080241165A1 (en) * 2002-07-09 2008-10-02 Crossbeta Biosciences B.V. Cross-beta structure comprising amyloid-binding proteins and methods for detection of the cross-beta structure, for modulating cross-beta structures fiber formation and modulating cross-beta structure-mediated toxicity
US20080267948A1 (en) * 2005-07-13 2008-10-30 Martijn Frans Ben Gerard Gebbink Croos-B Structure Binding Compounds
US20080118529A1 (en) * 2005-07-13 2008-05-22 Gebbink Martijn Frans Ben Gera Adjuvation Through Cross -Beta Structure
US8114832B2 (en) 2005-07-13 2012-02-14 Crossbeta Biosciences B.V. Method for detecting and/or removing a protein comprising a cross-beta structure from a pharmaceutical composition
US8067187B2 (en) 2005-07-13 2011-11-29 Crossbeta Biosciences B.V. Cross-β structure binding compounds
US20070015206A1 (en) * 2005-07-13 2007-01-18 Umc Utrecht Holding B.V. Method for detecting and/or removing protien comprising a cross-beta structure from a pharmaceutical composition
US20070015133A1 (en) * 2005-07-13 2007-01-18 Umc Utrecht Holding B.V. Method for detecting and/or removing protein and/or peptide comprising a cross-beta structure from an aqueous solution comprising a protein
US20070122341A1 (en) * 2005-11-29 2007-05-31 Seoul National University Industry Foundation Benzylideneaniline derivatives and their radioisotope labeled compounds for binding and imaging of beta-amyloid plaques
WO2007064773A3 (en) * 2005-12-01 2007-11-15 Univ Pittsburgh Isotopically-labeled benzothiazole compounds as imaging agents for amyloidogenic proteins
WO2007064773A2 (en) * 2005-12-01 2007-06-07 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Isotopically-labeled benzothiazole compounds as imaging agents for amyloidogenic proteins
US20090142269A1 (en) * 2005-12-01 2009-06-04 University Of Oittsburgh-Of The Commonwealth System Of Higher Education Isotoypically-labeled benzothiazole compounds as imaging agents for amyloidogenic proteins
US20070154980A1 (en) * 2005-12-30 2007-07-05 Gasper Susan M Fluorescent dyes
US7781187B2 (en) 2005-12-30 2010-08-24 Corning Incorporated Fluorescent dyes
US20090155254A1 (en) * 2006-02-16 2009-06-18 Martijn Frans Ben Gerard Gebbink Affinity Regions
US8022207B2 (en) 2006-04-28 2011-09-20 Nihon Medi-Physics Co., Ltd. Compound having affinity to amyloid
US20100249407A1 (en) * 2006-04-28 2010-09-30 Nihon Medi-Physics Co., Ltd. Novel Compound Having Affinity to Amyloid
US20100143251A1 (en) * 2006-05-08 2010-06-10 Tamagnan Gilles D Compounds and amyloid probes thereof for therapeutic and imaging uses
US20100150833A1 (en) * 2006-05-08 2010-06-17 Tamagnan Gilles D Compounds and amyloid probes thereof for therapeutic and imaging uses
US7700616B2 (en) 2006-05-08 2010-04-20 Molecular Neuroimaging, Llc. Compounds and amyloid probes thereof for therapeutic and imaging uses
US20070258887A1 (en) * 2006-05-08 2007-11-08 Tamagnan Gilles D Compounds and amyloid probes thereof for therapeutic and imaging uses
US20100143253A1 (en) * 2006-05-08 2010-06-10 Tamagnan Gilles D Compounds and amyloid probes thereof for therapeutic and imaging uses
US20100249418A1 (en) * 2007-10-24 2010-09-30 Nihon Medi-Physics Co., Ltd. Novel compound having affinity for amyloid
US20100249408A1 (en) * 2007-10-30 2010-09-30 Nihon Medi-Physics Co., Ltd. Use of novel compound having affinity for amyloid, and process for production of the same
US20090123373A1 (en) * 2007-11-05 2009-05-14 Yanming Wang Amyloid-imaging agents
US20110052564A1 (en) * 2007-11-08 2011-03-03 Martijn Frans Ben Gerard Gebbink Enhancement of immunogenicity of antigens
US20090142377A1 (en) * 2007-11-08 2009-06-04 Crossbeta Biosciences B.V. Immunogenic compositions
US20110008376A1 (en) * 2007-11-08 2011-01-13 Martijn Frans Ben Gerard Gebbink Immunogenic compositions capable of activating t-cells
US20110250136A1 (en) * 2008-11-06 2011-10-13 Snu R&Db Foundation Fluorinated benzothiazole derivatives, preparation method thereof and imaging agent for diagnosing altzheimer's disease using the same
US20110081428A1 (en) * 2009-09-16 2011-04-07 The Buck Institute For Age Research Use of thioflavin-like compounds to increase life span and/or health span
DE102010045797A1 (de) 2010-09-20 2012-03-22 Klinikum Darmstadt Gmbh Verbindungen für die Diagnostik neurodegenerativer Erkrankungen am Riechepithel
WO2012037928A2 (de) 2010-09-20 2012-03-29 Klinikum Darmstadt Gmbh Verbindungen für die diagnostik neurodegenerativer erkrankungen am riechepithel
WO2012041292A2 (de) 2010-09-20 2012-04-05 Klinikum Darmstadt Gmbh Verbindungen für die diagnostik neurodegenerativer erkrankungen an der retina
US10675365B2 (en) 2016-09-29 2020-06-09 Korea Atomic Energy Research Institute Curcumin derivative, method for producing same, and photo-acoustic imaging agent comprising same for detecting beta-amyloid plaque

Also Published As

Publication number Publication date
DK2264018T3 (en) 2015-05-11
EP1334091A2 (en) 2003-08-13
PT1334091E (pt) 2013-01-07
US20120095235A1 (en) 2012-04-19
AU2008202626B2 (en) 2010-02-04
HU230375B1 (hu) 2016-03-29
EP2264018A3 (en) 2012-04-25
HUP0302956A2 (hu) 2003-12-29
SI1334091T1 (sl) 2013-01-31
EP2264018A2 (en) 2010-12-22
WO2002016333A2 (en) 2002-02-28
AU2001286702B2 (en) 2008-03-13
PL360550A1 (en) 2004-09-06
ES2536449T3 (es) 2015-05-25
AU2008202626B9 (en) 2010-02-11
HK1146725A1 (en) 2011-07-08
CY1113311T1 (el) 2016-04-13
NO20030860D0 (no) 2003-02-24
JP5022554B2 (ja) 2012-09-12
RU2324686C2 (ru) 2008-05-20
HUP1500560A2 (en) 2003-12-29
NO20030860L (no) 2003-04-24
ES2395721T3 (es) 2013-02-14
US20150190400A1 (en) 2015-07-09
BR0113470A (pt) 2003-12-30
JP2004506723A (ja) 2004-03-04
CA2419420A1 (en) 2002-02-28
AU2008202626A1 (en) 2008-07-03
HK1058041A1 (en) 2004-04-30
WO2002016333A3 (en) 2002-05-30
HU230581B1 (hu) 2017-01-30
US9833458B2 (en) 2017-12-05
CA2419420C (en) 2011-08-02
EP1334091B1 (en) 2012-09-19
EP2264018B1 (en) 2015-02-11
PT2264018E (pt) 2015-06-03
JP2012102106A (ja) 2012-05-31
NO330176B1 (no) 2011-02-28
BRPI0113470B8 (pt) 2021-05-25
CN1285582C (zh) 2006-11-22
LTPA2015001I1 (lt) 2015-02-25
LTC1334091I2 (lt) 2018-05-25
DK1334091T3 (da) 2012-10-15
BRPI0113470B1 (pt) 2019-04-16
PL215711B1 (pl) 2014-01-31
AU8670201A (en) 2002-03-04
US20080154042A1 (en) 2008-06-26
US7351401B2 (en) 2008-04-01
CN1535268A (zh) 2004-10-06
HUP0302956A3 (en) 2006-05-29
US20050043377A1 (en) 2005-02-24

Similar Documents

Publication Publication Date Title
US9833458B2 (en) Thioflavin derivatives for use in the antemortem diagnosis of Alzheimer's disease and in vivo imaging and prevention of amyloid deposition
US10137210B2 (en) Thioflavin derivatives for use in antemortem diagnosis of Alzheimer's disease and in vivo imaging and prevention of amyloid deposition
AU2001286702A1 (en) Thioflavin derivatives and their use in diagnosis and theraphy of alzheimer's disease
AU2011200667B2 (en) Benzothiazole derivative compounds, compositions and uses
WO2004083195A1 (en) Benzothiazole derivative compounds, compositions and uses

Legal Events

Date Code Title Description
AS Assignment

Owner name: PITTSBURGH, UNIVERSITY OF, PENNSYLVANIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:KLUNK, WILLIAM E.;MATHIS, CHESTER A., JR.;WANG, YANMING;REEL/FRAME:012226/0828

Effective date: 20010914

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION