KR101336072B1 - Dual SPECT/MRI contrast agent and a process for the preparation thereof - Google Patents

Abstract

상기 리간드는 DOTA, DTPA, DO3A, NOTA, NODAGA, TETA, TE3A, TE2A, PCTA, 사이클렌(Cyclen), 또는 DFOM(Deferrioxamine) 이고,
상기 Gd는 가돌리늄이며, 상기 리간드에 배위결합되고,
상기 RGD는 Arg-Gly-Asp-Tyr-Lys를 포함하는 아미노산 서열이 환을 형성하는 시클릭 펩티드고, 라이신을 경유해 상기 리간드와 아미드 결합되어 있고,
상기 X는 I-123, I-124, I-125, 및 I-131에서 선택된 방사성 요오드이고, 상기 RGD의 티로신의 메타 위치에 공유결합되어 있다The present invention provides novel compounds of Formula 1, methods for their preparation, SPECT contrast agents comprising them, and SPECT / MRI dual contrast agents, which can be used as novel SPECT / MRI dual contrast agents:
[Chemical Formula 1]

Wherein the ligand is DOTA, DTPA, DO3A, NOTA, NODAGA, TETA, TE3A, TE2A, PCTA, Cyclen, or DFOM (Deferrioxamine)
Said Gd is gadolinium and is coordinated to said ligand,
The RGD is a cyclic peptide in which the amino acid sequence including Arg-Gly-Asp-Tyr-Lys forms a ring, and is amide bonded to the ligand via lysine,
X is a radioactive iodine selected from I-123, I-124, I-125, and I-131 and is covalently bound to the meta position of tyrosine of the RGD

Description

Dual SPECT / MRI contrast agent and method for manufacturing the same for diagnosis of cancer {Dual SPECT / MRI contrast agent and a preparation for the preparation}

The present invention relates to a novel compound that can be used as a novel single photon emission computed tomography / magnetic resonance imaging (SPECT / MRI) dual contrast agent, a preparation method thereof, an SPECT contrast agent comprising the same, and an SPECT / MRI dual contrast agent.

Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET), which are nuclear medicine imaging devices, are imaging devices for the distribution of radiopharmaceuticals injected into the body. The importance of nuclear medical imaging equipment is increasing because imaging biological changes can provide accurate information for early diagnosis of diseases and determination of treatment methods for diseases.

Magnetic Resonance Imaging (MRI) is a magnetic resonance imaging (MRI) technique that allows a human body to enter a large magnetic barrel producing a magnetic field and then generates high frequencies to resonate the protons in the body region to measure the difference in signal from each tissue. And is a technique of imaging. These MR images (MR images) have higher resolution and contrast compared to other imaging methods, and have the advantage of providing long-term images and 3D information in real time. Although the MR image can bioimage the unique tissue signal difference using various techniques, contrast agent can be used to change the magnetic relaxation time of the water molecule in the tissue to further increase the contrast of the tissue.

Examples of paramagnetic materials that can change the magnetic relaxation time of water molecules in the tissue include gadolinium (Gd ³⁺ ) and manganese (Mn ²⁺ ). However, since gadolinium and manganese elements themselves are toxic substances in the human body, for the purpose of counteracting the toxicity, Diethylene triamine penta aeetic acid (DTPA), DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10 -tetraacetic acid) or DO3A (1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid) and chelated with a ligand such as Gd-DTPA, Gd-DOTA, or Gd-DO3A It can be used as a complex. Since the toxicity of the gadolinium element is attributed to the fact that this element has many bonding sites in the living body to react with biomolecules, it is necessary to complex the gadolinium to the ligand to block the bonding sites at which gadolinium can react with the biomolecule To reduce toxicity. Such complexed metal chelates should maintain chemical stability in the human body. Chemical stability refers to how long a metal complex is not separated and maintained. If Gd-DTPA or the like is separated into gadolinium and ligand before being excreted in the body, this would have a fatal result. Such chemical stability is often expressed as a stability constant, which is a thermodynamic concept. In addition, the high magnetic relaxation rate in MR imaging is a factor that demonstrates the high efficiency of MRI contrast agent because contrast agents with high magnetic relaxation rate exhibit high contrast enhancement effects even with relatively low doses. That is, the MRI contrast agent is preferably thermodynamically stable with a high magnetic relaxation rate.

MRI has higher resolution and contrast than other imaging methods, but it is less sensitive than nuclear medical imaging devices. To overcome the shortcomings of MRI with low sensitivity (10 ^-5 mole / L), PET (Positron Emission Tomography) or SPECT (Single Photon Emission Computed) with higher sensitivity (10 ^-12 mole / L) than MRI Multiple imaging devices such as PET / MRI or SPECT / MRI combined with nuclear medicine imaging devices such as Tomography are being studied. In addition to the development of such a multi-image device, the development of a multi-contrast contrast agent is also actively progressing, a multi-mode contrast medium can improve the accuracy and sensitivity of the image. Multiple contrast agents can be used to acquire two or more images, such as magnetic resonance imaging, nuclear medicine imaging, magnetic resonance imaging and optical imaging, or nuclear medical imaging and optical imaging. It is a contrast agent with the ability to diagnose the disease more quickly and accurately and to allow for accurate recognition of the disease prior to entering the treatment phase. In this regard, research on multiple imaging contrast agents such as PET / MRI and SPECT / MRI has been reported, but it is still in the early stage of development.

Dr. Lee's research team at Stanford University developed a cancer diagnostic PET / MRI dual imaging contrast agent labeled with tumor-targeting peptide RGD and Cu-64, a radioisotope for PET imaging, on the surface of iron oxide nanoparticles that can be used as MRI contrast agents. Patent document 1).

Dr. Hwan-Jung Chung, Ph.D., Chonbuk National University, has coated the surface of iron oxide nanoparticles, which can be used as MRI contrast agents, with a phosphate group and an amine group to combine with target ligands, antibodies, and fluorescent probes. Contrast agent was developed (Patent Document 1) In addition, by combining Tc-99m on the surface of the iron oxide nanoparticles that can be used as MRI contrast agent, a dual contrast agent that can be used in MRI and SPECT was developed (Non Patent Literature 2). Peking University Fan Wang and Mingyuan Gao's team have developed dual contrast agents for use in MRI and γ-camera by combining iron oxide nanoparticles with I-125 (Non-Patent Document 3).

However, paramagnetic gadolinium chelates are usually used as contrast agents when taking T1-weighted images from MRI. The doses are micrograms or milligrams, and the radioisotopes used in nuclear medicine are about nanograms. That is, the nuclear medicine image is compared to the MRI 10 ⁶ to 10 ⁹ times, because of the high sensitivity simply MRI contrast media and contrast agents in a single molecular form that combines radioisotopes MR image of 10 ⁶ to 10 ⁹ min. Effect of 1 As low as, MRI and nuclear medical imaging cannot be effectively imaged, and if administered to a patient at an effective dose for MRI imaging, the patient is overexposed to radiation and the quality of the image is significantly degraded. For this reason, most of the conventionally developed dual contrast agents have iron oxide nanoparticles that are about 50 to 100 times larger than the magnetic properties of gadolinium chelate instead of gadolinium chelate (Patent Document 1). This is because nanoparticles can be variously modified by surface modification methods as well as the effect of showing various physical properties depending on the particle size. However, even if the dual contrast agent in the form of iron oxide nanoparticles has a high magnetic properties, it can be said that it is insufficient to overcome the sensitivity difference (10 ⁶ ~ 10 ⁹ ) between nuclear medical imaging equipment and magnetic resonance imaging equipment. In addition, the nanoparticle form is difficult to apply clinically because it is likely to be removed by macrophages present in the body and the long residence time is likely to cause toxicity in the body.

Thus, there is a need for the development of dual contrast agents that can act as sufficiently effective contrast agents in both MRI and nuclear medicine imaging devices, while minimizing toxicity.

On the other hand, DTPA, DOTA, or DO3A acting as a ligand for Gd has no specificity to cancer cells, and contrast agents in which Gd and the ligand are bound to each other lack selectivity for cancer cells, It is not effective as an effective contrast agent for diagnosis. In order to overcome this disadvantage, an MRI contrast agent of RGD- [ligand-> Gd] structure has been developed in which the ligand is bound to a peptide comprising an RGD (Arg-Gly-Asp) sequence selective for cancer cells (Patent Document 2). ). However, the patent document does not mention any dual contrast agent capable of obtaining both MRI and nuclear medicine images.

1. Korean Patent Publication 2010-0031885 2. Korean Patent Publication 2009-0096816

1. Lee et al., PET / MRI Dual-Modality Tumor Imaging Using Arginine-Glycine-Aspartic (RGD) -Conjugated Radiolabeled Iron Oxide Nanoparticles, J Nucl Med 2008; 49: 1371-1379 2. June et al., Superparamagnetic Iron Oxide Nanoparticles as a Dual Imaging Probe for Targeting Hepatocytes In Vivo. Magnetic Resonance in Medicine 2009, 62: 1440-1446 Fan Wang et al. A Novel Type of Dual-Modality Molecular Probe for MR and Nuclear Imaging of Tumor: Preparation, Characterization and in Vivo Application, Molecular pharmaceutics 2009, 6: 1074-1082

Accordingly, the present inventors have completed the present invention as a result of the study for the development of a dual contrast agent that can act effectively as a contrast agent for both MRI and nuclear medicine imaging devices without toxicity to the body, and can be effectively used for cancer diagnosis.

Accordingly, it is an object of the present invention that the compounds themselves can be used as SPECT contrast agents, or MRI and SPECT dual contrast agents while being effective in diagnosing cancer, as well as used as components of dual contrast compositions which are sufficiently effective and safe for both MRI and SPECT. It is to provide a compound.

Another object of the present invention is to provide a method for preparing the compound.

Another object of the present invention is to provide a SPECT contrast agent comprising the compound.

Another object of the present invention is to provide MRI and SPECT dual contrast agent comprising the compound.

In order to achieve the above object, one aspect of the present invention provides a compound of Formula 1:

[Formula 1]

The ligand is DOTA, DTPA, DO3A, NOTA, NODAGA, TETA, TE3A, TE2A, PCTA, Cyclen, or Deferrioxamine (DFOM),

Said Gd is gadolinium and is coordinated to said ligand,

The RGD is a cyclic peptide in which the amino acid sequence including Arg-Gly-Asp-Tyr-Lys forms a ring, and is amide bonded to the ligand via lysine,

X is a radioactive iodine selected from I-123, I-124, I-125, and I-131, and is covalently bound to the meta position of tyrosine of the RGD.

Another aspect of the present invention provides a method for preparing a compound of Formula 1, comprising reacting a compound of Formula 3 with a compound of Formula 4 to label radioactive iodine at the meta position of tyrosine of RGD:

(3)

The ligand, Gd, and RGD are as defined in claim 1;

[Chemical Formula 4]

MX

M is Na and X is I-123, I-124, I-125, or I-131.

Another aspect of the present invention provides a SPECT contrast agent comprising the compound of Formula 1.

Another aspect of the invention provides a MRI / SPECT dual contrast agent comprising the compound of formula (1).

Hereinafter, the present invention will be described in more detail.

All technical terms used in the present invention are used in the sense that they are generally understood by those of ordinary skill in the relevant field of the present invention unless otherwise defined. In addition, preferred methods or samples are described in this specification, but similar or equivalent ones are also included in the scope of the present invention. The contents of all publications referred to in this specification are incorporated herein by reference in their entirety.

The present inventors have described radioactive iodine (I) in an MR contrast agent comprising a ligand such as DOTA, DTPA or DO3A, a cyclic RGD (Arg-Gly-Asp) -containing peptide covalently bonded to the ligand, and a gadolinium complexed with the ligand. -123, I-124, I-125, or I-131) was found to be able to be used as SPECT contrast agent (Experimental Example 8) as well as SPECT / MRI dual contrast medium, which is also effective as MRI contrast agent. . In addition, in such a new SPECT / MRI double contrast compound (Formula 1), a compound in which the non-radioactive iodine, which is a cold form of the radioactive iodine instead of the compound (following formula 2) to the radioactive iodine SPECT / MRI double contrast compound (Formula 1 below) ) Can be used as an effective MRI / SPECT dual contrast agent.

Accordingly, one aspect of the present invention provides a compound of Formula 1:

[Formula 1]

The ligand is DOTA, DTPA, DO3A, NOTA, NODAGA, TETA, TE3A, TE2A, PCTA, Cyclen, or Deferrioxamine (DFOM),

Said Gd is gadolinium and is coordinated to said ligand,

The RGD is a cyclic peptide in which the amino acid sequence including Arg-Gly-Asp-Tyr-Lys forms a ring, and is amide bonded to the ligand via lysine,

X is a radioactive iodine selected from I-123, I-124, I-125, and I-131, and is covalently bound to the meta position of tyrosine of the RGD.

As used herein, the term "complex" refers to a group of atoms in which several other atoms, ions, molecules, or groups of atoms are directionally and three-dimensionally coordinated with respect to one or more atoms or ions to form a group of atoms. Say that. Here, a chelator or group of atoms coordinated with a central atom or ion is called a ligand.

As used herein, the term DTPA is Diethylene triamine penta aeetic acid, DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), and DO3A is 1,4,7,10-tetraazacyclododecane- 1,4,7-triacetic acid, NOTA is 1,4,7-triazacyclononane-1,4,7-triacetic acid, NODAGA is 1,4,7-Triazacyclononane, 1-glutaric acid-4,7-acetic acid, TETA is 1,4,8,11-tetraazacyclotetradecane-N, N ', N' ', N' ''-tetraacetic acid, TE3A is 1,4,8,11-tetraazacyclotetradecane-1,4,8-triacetic acid, TE2A is 1,4,8,11-Tetraazabicyclohexadecane-4,11-diacetic acid, PCTA is 3,6,9,15-tetraazabicyclo [9.3.1] pentadeca-1,11,13-triene-3,6,9 An abbreviation for, -triacetic acid is a metal-affinity ligand compound. The ligand acts as a metal affinity ligand to prevent the release of radioactive metal Gd in the body and to remove the radioactive material outside the body can reduce the cytotoxicity caused by the radioactive material chemical protection against radiation interference (Marouan Rami et al., Carbonic anhydrase inhibitors: Gd (III) complexes of DOTA- and TETA-sulfonamide conjugates targeting the tumor associated carbonic anhydrase isozymes IX and XII, New J. Chem., 2010, 34, 2139 -2144; Silvio Aime et al., NMR relaxometric studies of Gd (III) complexes with heptadentate macrocyclic ligands, Magnetic Resonance in Chemistry (1998) Volume: 36, Issue: S1, Pages: S200-S208).

The RGD is a cyclic RGD-containing peptide in which an amino acid sequence including Arg-Gly-Asp-Tyr-Lys forms a ring, and is in an amide bond with the ligand via lysine. Α _ν β ₃ integrins, which are not expressed in normal vascular endothelial cells but expressed during neovascularization of cancer cells, are characterized by binding to peptides having an RGD (Arg-Gly-Asp) sequence (Patent Document 2). Therefore, the RGD may be selectively bound to a receptor present in cancer cells due to the inclusion of Arg-Gly-Asp, thereby performing the function of targeting the compound of Formula 1 to cancer cells.

As used herein, "RGD-ligand" refers to a compound in which the terminal amino group of lysine of the cyclic RGD-containing peptide forms a covalent bond by an amide bond with a ligand.

As used herein, "ligand → Gd" refers to a complex formed by coordinating gadolinium to the ligand.

"는 상기 RGD-리간드에 가돌리늄이 배위결합하여 형성된 착물을 의미한다.In this specification,

"Means a complex formed by coordinating gadolinium to the RGD-ligand.

The compound of Formula 1 may be a compound of Formula 1a according to one embodiment:

[Formula 1a]

In formula (1a)

X is I-123, I-124, I-125, or I-131. Preferably, X is I-125.

Another aspect of the present invention provides a method of preparing a compound of Formula 1 or 1a comprising reacting a compound of Formula 3 with a compound of Formula 4 to label radioactive iodine at the meta position of tyrosine of RGD:

(3)

The ligand, Gd, and RGD are as defined in Formula 1 above;

[Chemical Formula 4]

MX

M is Na and X is I-123, I-124, I-125, or I-131.

The radioactive metal iodide compound of Formula 4 may vary depending on the kind of X (I-123, I-124, I-125, or I-131) of the compound of Formula 1 to be prepared. Compounds of formula 4 and specific reaction conditions that vary depending on the type of X may be appropriately selected by those of ordinary skill in the art of organic compounds based on the disclosure herein.

As the solvent for reacting the compound of Formula 3 and the compound of Formula 4, any solvent that does not inhibit the reaction may be used, and preferably a small amount of water may be used. In addition, the reaction may be promoted by adding an oxidizing agent. Such oxidants may be appropriately selected by those skilled in the art depending on the reactants, for example chloramine T, iodine, hydrogen peroxide, or a combination thereof may be used. By the reaction, radioactive iodine is labeled at the meta position of tyrosine, thereby forming a compound of Formula 1. The reaction can be carried out at room temperature, the reaction can be completed by reacting for about 2-6 minutes.

The product obtained by the reaction can be obtained by removing the impurities using any method known in the art to obtain the compound of formula 1 or 1a, preferably by HPLC can remove the impurities.

Compound of Formula 3 is

Reacting the ligand with the cyclic RGD containing peptide to prepare a compound of RGD-ligand wherein the lysine of the cyclic RGD containing peptide is bound to the ligand by amide bonds; And

It can be prepared by a method comprising the step of coordinating Gd to the ligand by reacting a Gd precursor to the compound of the RGD-ligand.

In preparing the compound of the RGD-ligand, any solvent that does not inhibit the reaction may be used as the reaction solvent, and preferably a small amount of water may be used. In addition, a catalyst may be added during the reaction to promote the reaction. Such catalysts may be appropriately selected by those skilled in the art depending on the reactants, for example EDC (1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide) or sulfo-NHS (N-hydroxysulfosuccinimide), HOBt (1-hydroxybenzotriazole) DCC (Dicyclohexylcarbodiimide) ), Diisopropylcarbodiimide (DIC), HBTu (O- (Benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate), or a combination thereof may be used. It is preferred to maintain the pH of the mixture of ligand and catalyst first with a weak acid, and then add the cyclic RGD containing peptide to maintain weak alkalinity during the reaction. The reaction can be carried out at room temperature and the reaction can be completed by reacting overnight. The resulting RGD-ligand can be obtained by removing the impurities using any method known in the art, and preferably the impurities can be removed by HPLC.

In the step of coordinating the Gd to the ligand, any solvent that does not inhibit the reaction may be used, and preferably water may be used as the reaction solvent. The Gd precursor is Gd (III) X ₃ , wherein X is F, Cl, Br, I, nitrate, acetylacetonate, or a compound that is an acetate, and the like, but is not limited thereto. Specific reaction conditions that depend on the type of Gd precursor may be appropriately selected by those skilled in the art based on the disclosures herein and techniques known in the art of organic compounds. The molar ratio of the RGD-ligand to the Gd precursor may be reacted at 1: 1 to 1: 6. The reaction can be completed by reacting at room temperature for about 24-48 hours. The RGD- [ligand-> Gd] can thus be obtained by removing the impurities using any method known in the art, preferably by HPLC.

The compound of Formula 1 or Formula 1a was found to be effective as a SPECT contrast agent, and also effective as an MRI contrast agent.

Therefore, in another aspect, the present invention provides a SPECT contrast agent comprising the compound of Formula 1 or Formula 1a.

In still another aspect, the present invention provides a SPECT / MRI dual contrast agent comprising the compound of Formula 1 or Formula 1a.

According to the following experimental example, the stability of the mouse was measured for the compound of Formula 1 or Formula 1a below, it was found that the compound is stable without degradation over 3 days. In addition, cytotoxicity of the compounds substituted with non-radioactive iodine instead of the radioactive iodine (compounds of the following Chemical Formula 2 or 2a) in the compounds of Formula 1 or Formula 1a and MR images in mice with tumors were obtained. Was found to be very low and MR images with increased signal at the tumor site of mice were obtained. In addition, as a result of experiments on the tumor selectivity of the compound of the formula (1) or (1a) substituted with non-radioactive iodine instead of radioactive iodine (compound of the formula (2) or 2a), it showed that the tumor selectivity is high . From these results, it can be seen that the compound of Formula 1 or Formula 1a also has low cytotoxicity, can be used as an MRI contrast agent, and has high tumor selectivity. In addition, as a result of obtaining a SPECT image of a mouse having a tumor with respect to the compound of Formula 1 or Formula 1a, a SPECT image having an increased signal at the tumor site of the mouse was obtained. From the results of the experiment, the compound of Formula 1 or 1a is effective as a SPECT contrast agent due to the presence of radioactive iodine in one compound, and also as an MRI contrast agent due to the presence of paramagnetic gadolinium. It can be seen that it can be useful for diagnosing cancer.

The SPECT contrast agent or MRI / SPECT dual contrast agent may be administered 0.1 to 30 mCi to adults based on the compound of Formula 1 or 1a of the active ingredient.

Although the compound of Formula 1 or 1a may be used as a SPECT / MRI dual contrast agent, a single molecule such as Formula 1 or 1a may have a nuclear sensitivity of 10 ⁶ to 10 ⁹ times higher than that of MRI. The type of contrast medium is low in MR images with an effect of 10 ⁶ to 10 ⁹ . Therefore, the compound of Formula 1 itself can be used effectively as a SPECT contrast agent, but it is difficult to contrast both MRI and SPECT sufficiently effectively, and when administered in an amount effective for low sensitivity MRI contrast, the radiation is excessively exposed to the patient and the quality of the image. Is also significantly reduced.

The compound of Formula 1 or 1a is an effective MRI / SPECT dual contrast agent by combining with a compound of Formula 2 or Formula 2a by replacing radioactive iodine in hot form with non-radioactive iodine in its cold form in the compound of Formula 1 or 1a Can be used as. That is, in the compound of Formula 1 or 1a, radioactive iodine (I-123, I-124, I-125, and I-131) is a non-radioactive iodine in the form of its cold form. When used in combination with a substituted compound (compound of Formula 2 or Formula 2a), it can be used as a more effective MRI / SPECT dual contrast agent. The compound of formula 2 or 2a does not contain radioactive iodine and thus has no effect as a SPECT contrast agent, but only as an MRI contrast agent. Since the compound of formula 1 or 1a can act as a SPECT contrast agent including radioactive iodine, the formula 1 or 1a The contrast agent combining the compound of and the compound of formula 2 or 2a can act as an effective contrast agent for both MRI and SPECT, and the radiation exposure is not excessive by using less compound of formula 1 or 1a than the compound of formula 2 or 2a. It can be effectively used for the imaging of both MRI and SPECT.

Accordingly, another aspect of the invention provides an MRI / SPECT dual contrast agent comprising a first agent comprising Formula 1 and a second agent comprising a compound of Formula 2:

[Formula 1]

The ligand is DOTA, DTPA, DO3A, NOTA, NODAGA, TETA, TE3A, TE2A, PCTA, Cyclen, or Deferrioxamine (DFOM),

Said Gd is gadolinium and is coordinated to said ligand,

The RGD is a cyclic peptide in which the amino acid sequence including Arg-Gly-Asp-Tyr-Lys forms a ring, and is amide bonded to the ligand via lysine,

X is a radioactive iodine selected from I-123, I-124, I-125, and I-131 and is covalently bound to the meta position of tyrosine of the RGD;

(2)

In Formula 2, the ligand, Gd, and RGD are as defined in Formula 1,

I is non-radioactive iodine, covalently attached to the meta position of tyrosine of RGD,

However, Chemical Formulas 1 and 2 have the same structure except for iodine.

As used herein, the term "hot form" refers to an element that emits radiation while having the same chemical properties as that of the non-radioactive element and having the same distribution when administered to a living body. On the contrary, an element that has the same chemical properties as that of the radioisotope and has the same distribution when administered to a living body and does not emit radiation is called a "cold form" for a "hot form". For non-radioactive iodine, radioactive iodine (I-123, I-124, I-125, and I-131) is the hot form, and radioactive iodine (I-123, I-124, I-125, and I-131). For 131, non-radioactive iodine (I) corresponds to cold form.

The double contrasting agent has the same structure of the compound of Formula 1 and Formula 2, except that iodine substituted in tyrosine of RGD has a relationship between a hot form and a cold form, so that the compounds of Formulas 1 and 2 have the same absorption in vivo, Pharmacokinetics of distribution, metabolism and excretion. The compound of formula 1 has activity as a SPECT contrast agent, the compound of formula 2 does not contain radioactive iodine, there is no SPECT contrast agent activity and can exhibit a remarkably excellent activity (high magnetic relaxation rate) as an MRI contrast agent. It was confirmed in Experimental Examples 4 and 6 that the compound of Formula 2 may exhibit MRI contrast agent activity. In addition, it was confirmed in Experiment 8 that the compound of Formula 1 can exhibit SPECT activity because it has radioactive iodine.

The dual contrast agent is preferably a molar ratio of the compound of formula 1, which is an SPECT contrast agent, to the compound of formula 2, which is an MRI contrast agent, in a range of 1: 10 ⁶ to 1: 10 ⁹ . MRI contrast agents are the sensitivity of both the approximately 10 ⁶ to 10 because ⁹ minutes, 10 a MRI contrast agent, a compound of formula (2) ⁶ to 10 ⁹ times more containing, by effect as the effect and SPECT contrast agent as MRI contrast agent, compared to SPECT contrast agent Can be obtained sufficiently. By controlling the content, it is possible to sufficiently increase the content of the compound of formula 2, which acts as a contrast medium of relatively low sensitivity MRI, while reducing the content of the compound of formula 1, which acts as a contrast agent for high sensitivity SPECT. In addition, MR imaging can also be used as an MRI / SPECT dual contrast agent, which can be effectively obtained while avoiding excessive radiation exposure to the living body.

The MRI / SPECT dual contrast agent comprising the first agent and the second agent may be administered at a dose of 0.1 to 30 mCi and 0.1 to 1 mmol / kg of the compound of Formula 1 as the active ingredient.

One embodiment of the dual contrast agent composition comprises a first agent comprising Formula 1a and a second agent comprising a compound of Formula 2a:

(2a)

However, Chemical Formulas 1a and 2a have the same structure except for iodine.

On the other hand, since the compound of Formula 1 and the compound of Formula 2 show the same distribution form in vivo, the contrast agent containing both the compound of Formula 1 and the compound of Formula 2 shows the contrast effect on MRI and SPECT at the same site It can be used as an effective dual contrast agent for MRI and SPECT. However, the compounds of Formulas 1 and 2 have selective specificity for the α _v β ₃ receptor present in cancer cells due to the RGD contained therein (Experimental Example 7), thus simultaneously administering the compounds of Formulas 1 and 2 If the compound of formula (2) provided at a significantly higher dose has the effect of preoccupying the receptor of cancer cells, the compound of formula (1) corresponding to the SPECT contrast agent has a result of significantly lower selectivity for cancer cells.

Accordingly, another aspect of the present invention is a method of acquiring SPECT and MRI dual images using the MRI / SPECT dual contrast composition,

Administering the first agent to a subject and obtaining a SPECT image;

Then, the present invention provides a method for acquiring SPECT and MRI dual images comprising administering the second agent to a subject and acquiring an MR image.

According to the method of acquiring the double image, a sufficient amount of available cancer cell receptor, which is not yet bound to the compound of Formula 1, even after the compound of Formula 1, which is administered in a relatively small amount, binds to the cancer cell receptor It remains so that the formula 2 to be administered afterwards can sufficiently bind to the cancer cells. If the administration order of the first agent and the second agent is reversed or simultaneously administered, the compound of Formula 2 administered in an excessive amount occupies all the cancer cell receptors so that blocking of the cancer cell receptors occurs and is subsequently administered. The compound of formula 1 will not be able to bind to cancer cell receptors. In the method of acquiring the SPECT / MRI dual image, the SPECT image should be obtained after the administration of the first agent and the MR image after the administration of the second agent.

In order to administer the compounds of Formula 1, Formula 2, Formula 1a, and Formula 2a as a contrast agent, the synthesized compounds may be purified, sterilized, and then used. Purification and sterilization may be any purification and sterilization method known in the art, for example, purified using high performance liquid chromatography (HPLC), Sep-Pak, etc., and then passed through a sterile filter It can be sterilized. As a sterile filter, a sterile filter having a pore size of 0.22 mm may be used.

The pharmaceutical composition of the SPECT contrast agent and the SPECT / MRI dual contrast agent according to the present invention may be formulated as an injection, and when formulated as an injection, it may include blood and isotonic non-toxic buffer as a diluent, for example pH 7.4. Phosphate buffer solution. The pharmaceutical composition may contain other diluents or additives in addition to the buffer solution. Excipients and excipients that can be added to such injectables are well known to those of ordinary skill in the art and can be found, for example, by reference to Dr. HP Fiedler "Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete "[Encyclopaedia of auxiliaries for pharmacy, cosmetics and related fields]

As described above, the compound of formula 1 according to the present invention can be used as a SPECT contrast agent specific to cancer cells and safe compared to conventional SPECT contrast agents. In addition, the compounds of formula 1 can be used as SPECT / MRI dual contrast agents by including both radioisotopes and paramagnetic elements.

In addition, by combining the compound of Formula 1, which is a hot form, with the compound of Formula 2, which is a cold form of the compound, a dual contrast composition can be constructed, and such a dual contrast composition has contrast effect on both MRI and SPECT at the same site. Since it can be shown, there is an advantage that more accurate diagnosis of the disease is possible. In addition, by adjusting the content and the order of administration of the compound of formula (1) and compound of formula (2), both MRI and SPECT images of cancer tissues can be obtained while it is preferable to avoid excessive exposure to radiation. Therefore, the compound of formula 1 according to the present invention can be very useful for monitoring the diagnosis and treatment of various diseases by providing high sensitivity information as well as accurate anatomical information.

1 is an HPLC image of RGD-DOTA prepared according to an embodiment of the present invention.
2 is a MALDI-TOF-MS image of the RGD-DOTA prepared according to an embodiment of the present invention.
3 is an HPLC image of RGD- [DOTA-> Gd] prepared according to an embodiment of the present invention,
4 is a MALDI-TOF-MS image of RGD- [DOTA-> Gd] prepared according to an embodiment of the present invention.
5 is a gamma tracer (HPLC) image of ¹²⁵ I-RGD- [DOTA-> Gd] prepared according to one embodiment of the present invention.
6 is a simplified scheme of a method for preparing ¹²⁵ I-RGD- [DOTA-> Gd] according to an embodiment of the present invention.
7 is an HPLC (UV 254 nm) image of I-RGD prepared according to one embodiment of the present invention,
8 is a MALDI-TOF-MS image of I-RGD prepared according to an embodiment of the present invention.
9 is an HPLC (UV 254 nm) image of I-RGD- [DOTA-> Gd] prepared according to one embodiment of the present invention.
10 is a MALDI-TOF-MS image of I-RGD- [DOTA-> Gd] prepared according to an embodiment of the present invention.
11 is a simplified scheme of a method for preparing I-RGD- [DOTA-> Gd] prepared according to one embodiment of the present invention.
12 is an HPLC image of a mixture of ¹²⁵ I-RGD- [DOTA-> Gd] (1a, red) and I-RGD- [DOTA-> Gd] (2a, blue) prepared according to one embodiment of the present invention. to be.
FIG. 13 is an HPLC image of the stability of mouse serum of I-RGD- [DOTA-> Gd] prepared according to an embodiment of the present invention over time. FIG.
FIG. 14 is an HPLC image of the stability of ¹²⁵ I-RGD- [DOTA-> Gd] in mouse serum prepared over time according to an embodiment of the present invention.
15 is a graph showing the results of measuring cell viability according to the concentration of I-RGD- [DOTA-> Gd] prepared according to an embodiment of the present invention according to the MTT assay.
FIG. 16 is a SPECT / CT image photographed by injection of 0.2 mCi of ¹²⁵ I-RGD- [DOTA-> Gd] prepared according to an embodiment of the present invention into a mouse having a tumor.
FIG. 17 is an MR image taken before and after injecting I-RGD- [DOTA-> Gd] prepared according to an embodiment of the present invention into a mouse having a tumor.
Figure 18 is a MR image taken before and after injection by injecting a cyclic RGDYK peptide to a mouse with tumor and then injected with I-RGD- [DOTA-> Gd] prepared according to an embodiment of the present invention.
Fig. 19 shows tumors of MR images upon administration of I-RGD- [DOTA-> Gd] prepared according to one embodiment of the present invention, with or without cyclic RGDYK peptide injection into mice with tumors; It is a graph showing the signal of the site over time.

Hereinafter, the present invention will be described in more detail with reference to the following Examples and Experimental Examples. However, these Examples and Experimental Examples are only for better understanding of the present invention, and the scope of the present invention is not limited by them in any sense.

Definition of abbreviations

EDC: 1-Ethyl-3- (3-dimethylaminopropyl) -carbodiimide

sulfo-NHS: N-Hydroxysulfosuccinimide

DCM: Dichloromethane

DMF: N, N-dimethylformamide

ACN: Acetonitrile

DIEA: Diisopropylethylamine

DOTA: 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid

GdCl ₃ 6H ₂ O: Gadolinium (III) chloride hexahydrate

DIC: diisopropylcarbodiimide

HOBt: N-hydroxybenzotriazole

HBTu: 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate

HPLC: High-performance liquid chromatograph

Example  1-1: RGD - Ligand  Produce

After dissolving 96.0 mg (192.0 μmol) of DOTA in 4.0 mL of distilled water, 18.4 mg (96.0 mmol) of EDC dissolved in 1 ml of distilled water was added and stirred. The pH of the said solution was adjusted to 5.0, adding NaOH 0.1M here. 16.8 mg (76.8 μmol) of Sulfo-NHS was added to the solution to adjust the pH to 5.5 and stirred at 4 ° C. for 30 minutes. After 30 minutes, 12.0 mg (19.2 μmol) of c (RGDYK) dissolved in 2.4 ml of distilled water was added to the solution. The pH of the solution was adjusted to 8.5 while NaOH 0.1 M was added thereto, followed by stirring overnight at 4 ° C. The prepared RGD-DOTA was separated by HPLC, using a VYDAC C-18 column (10.0 mm x 250 mm) to prepare an ACN solution of 0.1% TFA (A solution) and an aqueous solution of 0.1% TFA (B solution) of 0% A. The peak can be seen at RT 14 minutes by flowing at 1 ml / min rate for 35 minutes with 35% A composition at.

Instead of DOTA in the above preparation, DTPA, DO3A may be used.

FIG. 1 is an HPLC image of the prepared RGD-DOTA, and FIG. 2 is a MALDI-TOF-MS image of the prepared RGD-DOTA.

Example  1-2: RGD - [ Ligand -> Gd ]

After dissolving 95 mg (94.4 μmol) of DOTA-RGD prepared in 100 mL of distilled water, 175.5 mg (472 μmol) of GdCl ₃ · 6H ₂ O dissolved in 100 mL of distilled water was added thereto, and the resultant was stirred at room temperature for 36 hours. In this case, the M concentration (mol / L) ratio of DOTA-RGD and GdCl ₃ · 6H ₂ O was reacted at 1: 5, but the M concentration (mol / L) ratio could be changed to 1: 1 to 1: 6. have. The prepared Gd-DOTA-RGD was separated by HPLC, using 0.1% TFA ACN solution (A solution) and 0.1% TFA aqueous solution (B solution) using a VYDAC C-18 semi-preparative column (10.0 mm x 250 mm). If the flow rate is 5% A at 65% A composition for 32 minutes at a rate of 1 ml / min, the peak can be confirmed at RT 9.2 minutes. FIG. 3 is an HPLC image of the prepared RGD- [DOTA-> Gd], and FIG. 4 is a MALDI-TOF-MS image of the prepared RGD- [DOTA-> Gd].

Example  1-3: ¹²⁵ I- RGD - [ Ligand -> Gd Preparation of (Formula 1a)

Mix [125I] NaI 1.0 mCi / 0.015 mL with chloramin T (0.15 mg / 0.015 mL PBS, pH 7.0) and add RGD- [DOTA-> Gd] (0.05 mg / 0.05 mL PBS, pH 7.0) for 2 minutes. Reacted. Na ₂ S ₂ O ₅ (0.5 mg / 0.05 mL) was added and reacted for 2 minutes, followed by HPLC. ¹²⁵ I-RGD- [DOTA-> Gd] prepared was separated by HPLC (gamma-trace), using 0.1% TFA in ACN (A solution) and 0.1% using Altlantis dC-18 column (4.6 x 300 mm). TFA in water (B solution) was flowed at a rate of 3 ml / min for 30 minutes at a composition of 40% A at 5% A, and the peak was confirmed at RT 20 minutes (FIG. 5).

FIG. 5 is an HPLC image of ¹²⁵ I-RGD- [DOTA-> Gd] prepared. FIG.

A brief scheme of the preparation of ¹²⁵ I-RGD- [DOTA-> Gd] is shown in FIG. 6.

Example  2-1: I- RGD Manufacturing

Fmoc-Lys (Boc) -O-trityl resin was charged to a suitable reactor and washed with DCM and DMF. Coupling was performed by stirring the Fmoc-L-amino acid (4.5 mmol) and the HOBT / DIC (2 M) solution for about 4 hours under DMF solvent conditions. This process was repeated with the peptide sequence. The peptide sequence used at this time is Arg (R), Gly (G), Asp (D), Iodo-Tyr (Y), Lys (K). After binding of the final amino group, separation in resin was carried out using a trifluoroacetic acid cocktail solution. The resulting solution was filtered and then ether was added to recrystallize the linear (crude) and dried. Peptide (1.5 mM), HBTu (4.5 mM), HOBt (4.5 mM), DIEA (7.5 mM), DMF (75 ml), and DCM (300 ml) were added to the reactor and stirred for at least 12 hours. Then ether was added and the ether soluble fraction was extracted and purified by HPLC.

The prepared I-RGD was separated by HPLC (UV 254 nm), and 0.1% TFA in ACN (A solution) and 0.1% TFA in water (B solution) were extracted using Altlantis dC-18 column (4.6 x 300 mm). A peak at RT 15.5 min can be seen by flowing at 5% A at 40% A at a rate of 1 ml / min for 30 minutes (FIG. 7). It was found 745.5 in Maldi-TOF-MS (FIG. 8).

FIG. 7 is an HPLC image of the prepared I-RGD, and FIG. 8 is a MALDI-TOF-MS image of the prepared I-RGD.

Example  2-2: I- RGD - [ DOTA -> Gd ] (Formula 2a)

After dissolving I-RGD (1.5 mM) and DOTA (3.0 mM) prepared in Example 2-1 in 150 mL of DMSO, HOBt (1.8 mM) and DIC (1.8 mM) were added to the reactor and stirred for 48 hours. The resulting compound I- [RGD-> DOTA] was extracted by precipitation in ether. GdCl ₃ .6H ₂ O (15 mM) was mixed with the extracted I- [RGD-> DOTA] (15 mM) solution and stirred for 48 hours at 40 ° C. After the reaction was completed, the reaction solution was lyophilized. The resulting I-RGD- [DOTA-> Gd] was separated by HPLC (UV 254 nm) and an Altlantis dC-18 column (4.6 × 300 mm) was used. The peak can be seen at RT 19.8 minutes by flowing 0.1% TFA ACN solution (A solution) and 0.1% TFA aqueous solution (B solution) at 5% A at 40% A for 30 minutes at a rate of 1 ml / min. 9). It was identified as 1286.2 in Maldi-TOF-MS (FIG. 10).

9 is an HPLC image of the prepared I-RGD- [DOTA-> Gd], and FIG. 10 is a MALDI-TOF-MS image of the prepared I-RGD- [DOTA-> Gd].

A reaction scheme of the preparation method according to Example 2 is shown in FIG. 11.

Experimental Example  One : HPLC Confirmation of equivalence of Chemical Formulas 1a and 2a by

The compound of Formula 1a prepared in Example 1-3 and the compound of Formula 2a prepared in Example 2-2 are compounds of Formula 1a when iodine bound to tyrosine is in the form of radioisotopes, and non-radioactive isotopes. To a compound of Formula 2a. Formulas 1a and 2a have chemically equivalent structures, which can be verified by confirming that they are detected at the same time in HPLC. Thus, for a mixture of ¹²⁵ I-RGD- [DOTA-> Gd] and I-RGD- [DOTA-> Gd], 5% of the 0.1% TFA ACN solution (A solution) and 0.1% TFA aqueous solution (B solution) HPLC images were obtained while flowing at A at a rate of 1 ml / min for 30 minutes at 40% A composition. The result is shown in FIG.

12 is an HPLC image of a mixture of ¹²⁵ I-RGD- [DOTA-> Gd] (1a, red) and I-RGD- [DOTA-> Gd] (2a, blue).

Experimental Example  2: i- RGD - [ DOTA -> Gd ]of in - vitro  Serum Stability ( serum stability ) Measure

Serum stability of mice of compound I-RGD- [DOTA-> Gd] of formula 2a prepared in Example 2-2 was measured. I-RGD- [DOTA-> Gd] (10 mM, 0.05 mL) was mixed with mouse serum (0.95 mL) and incubated at 37 ° C. A small amount was removed in the time zone to be measured (0 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 24 hours, 4 days, 7 days) and precipitated by adding ethanol. After centrifugation (13200 rpm, 10 minutes), the supernatant was taken out, filtered and subjected to HPLC. If I-RGD- [DOTA-> Gd] were degraded in serum, the RT and area at the time of measurement relative to the base time (0 min, RT 13 min) would vary. HPLC conditions were performed using Altlantis dC-18 column (3 x 150 mm) in a 0.1% TFA ACN solution (A solution) and 0.1% TFA aqueous solution (B solution) at 5% A to 40% A for 30 minutes. Flow was at ml / min. The stability results of I-RGD- [DOTA-> Gd] in mouse serum by time zone are shown in FIG. 13.

Figure 13 shows the results of measuring the stability in mouse serum of I-RGD- [DOTA-> Gd] by HPLC over time. These results indicate that I-RGD- [DOTA-> Gd] is stable for 7 days in mouse serum.

Experimental Example  3: ¹²⁵ I- RGD - [ DOTA -> Gd ]of in - vitro  Serum Stability ( serum stability ) Measure

The stability in mouse serum of ¹²⁵ I-RGD- [DOTA-> Gd] prepared in Examples 1-3 was measured. ¹²⁵ I-RGD- [DOTA-> Gd] (0.1 mCi, 0.01 mL) was mixed in mouse serum (0.5 mL) and incubated at 37 ° C. HPLC was performed by removing a small amount in the time zone to be measured (0 minutes, minutes, 1 hour, 4 hours, 16 hours, 3 days). If I-RGD- [DOTA-> Gd] were degraded in serum, the RT and area at the time of measurement relative to the base time (0 min, RT 20 min) would vary. HPLC conditions were performed using an Altlantis dC-18 column (4.6 x 300 mm) in an ACN solution of 0.1% TFA (Solution A) and 0.1% aqueous solution of TFA (Solution B) for 30 minutes at 5% A to 40% A. Flow was at ml / min. The stability results of ¹²⁵ I-RGD- [DOTA-> Gd] in mouse serum by time zone are shown in FIG. 14.

Figure 14 shows the results of measuring the stability in mouse serum of ¹²⁵ I-RGD- [DOTA-> Gd] over time by HPLC. These results indicate that ¹²⁵ I-RGD- [DOTA-> Gd] is stable for 3 days in mouse serum.

Experimental Example  4: I- RGD - [ DOTA -> Gd ] Self-relaxation rate ( Relaxivity ) Measure

The magnetic relaxation rate of I-RGD- [DOTA-> Gd] prepared in Example 2-2 was measured. Relaxation time was measured on a 3T (128 MHz) MRI machine. Inversion-recovery pulse train was used to measure T1 relaxation time and Carr-Purcell-Meiboon-Gill (CPMG) pulse train was used for T2 relaxation time. Relaxation rates (R1, R2) were calculated as the inverse of the relaxation time per mM. Dotarem ^® was used as a control.

The results are shown in Table 1 below.

According to Table 1, I-RGD- [DOTA-> Gd] has about twice as much self-relaxation rate as Dotarem ^® , so it can be said to be an MRI contrast agent that can signal more effectively.

Complex R1 (mM ^-1 s ^-1 ) R2 (mM ^-1 s ^-1 ) Dotarem ^® 3.4 ± 0.1 3.9 ± 0.1 1a 6.2 ± 0.1 6.4 ± 0.1

Experimental Example  5: I- RGD - [ DOTA -> Gd Cytotoxicity measurement

In order to confirm cytotoxicity, MTT (Tetrazolium-based colorimetric) screening method was used. MTT screening is a method of mitochondria that reduces yellow water-soluble MTT tetrazolium by dehydrogenase to blue purple water-insoluble MTT formazan (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyl-tetrazolium bromide). Is to use the ability. When MTT tetrazolium is treated in living cells 2400918, MTT tetrazolium is reduced by mitochondrial reductase to form MTT formazan. In other words, if MTT tetrazolium is treated after a compound is treated for a certain period of time to induce cell death, MTT formazan is formed at low concentrations without cytotoxicity, and MTT formazan at high concentrations with cytotoxicity. It is not formed. Cell viability can be determined by measuring the formation of MTT formazan by concentration gradient of these compounds. Nothing was added to the cells as a control, and the formation of MTT formazan in the control was measured to determine cell viability at 100%. Dotarem as a positive control ^? Was used. As a result, the cell viability measurement results according to the measured concentration of I-RGD- [DOTA-> Gd] are shown in FIG. 15.

15 is a graph showing the results of measuring cell viability according to the concentration of I-RGD- [DOTA-> Gd] according to the MTT assay.

When cells were added with various concentrations of I-RGD- [DOTA-> Gd] (0.0005-500 μM), they showed over 80% cell viability and showed similar cell viability as Dotarem ^® . These results indicate that I-RGD- [DOTA-> Gd] is very low in cytotoxicity and thus useful for use as a contrast agent.

Experimental Example  6: ¹²⁵ I- RGD - [ DOTA -> Gd ] SPECT  Image acquisition

SPECT images were taken on a multiple PET / SPECT / CT system (INVEON, Simens Medical Solutions). SPECT / CT images were obtained by injecting 0.2 mCi of ¹²⁵ I-RGD- [DOTA-> Gd] through the tail vein of tumor-bearing mice (ICR, 35 g), and the results are shown in FIG. 16.

16 shows SPECT / CT images of mice with tumors injected with 0.2 mCi of ¹²⁵ I-RGD- [DOTA-> Gd].

According to Figure 16, after the administration of ¹²⁵ I-RGD- [DOTA-> Gd] it is possible to observe the increased signal (lightening color) at the tumor site.

Experimental Example  7: i- RGD - [ DOTA -> Gd Using] MR  Image acquisition

To confirm the in vivo contrast effect of I-RGD- [DOTA-> Gd] prepared in Example 2-2, T1 weighted images were obtained from tumor-bearing mice (ICR, 35 g).

MR images were taken by T1-weighted imaging on a 3T MRI (Magnetom Trio Tim, Siemens, Erlangen, Germany). 0.1 mmol / kg of I-RGD- [DOTA-> Gd] was injected through the tail vein of anesthetized mice, and images were taken before and after the injection. The results are shown in FIG. 17.

FIG. 17 shows MR images taken before and after injection of I-RGD- [DOTA-> Gd] into mice with tumors.

As can be seen in FIG. 17, an increased signal (lightening of color) was observed at the tumor site after injection than before I-RGD- [DOTA-> Gd].

Experimental Example  8: I- RGD - [ DOTA -> Gd Tumor selectivity

Experiments were performed to confirm the selective specificity of I-RGD- [DOTA-> Gd] prepared in Example 2-2 for receptors expressed in tumor cells. First, cyclic RGDYK peptide (10 mg) was injected through the tail vein of anesthetized mice for receptor blocking. After 30 minutes, I-RGD- [DOTA-> Gd] (0.1 mmol / kg) was injected to obtain MR images in the same manner as in Example 7. The results are shown in FIG.

FIG. 18 shows MR images taken before and after injection of cyclic RGDYK peptide and then injection of I-RGD- [DOTA-> Gd] into mice with tumors.

According to FIG. 18, after blocking the receptor, no increased signal was observed in the tumor (dotted line). These results show that I-RGD- [DOTA-> Gd] has a selective specificity for receptors expressed in tumor cells.

In addition, in the MR images obtained in Experimental Examples 7 and 8, the results of comparing the change of the signal of the tumor region with time are shown in FIG. 19.

19 is a graph showing the signal of the tumor region of the MR image over time when I-RGD- [DOTA-> Gd] administration is performed with or without cyclic RGDYK peptide in mice with tumors. to be.

According to the result of FIG. 19, it can be seen that the signal at the tumor site where the receptor is blocked is lower than the signal at the tumor site where the receptor is not blocked.

Claims (11)

A compound of formula
[Chemical Formula 1]

Wherein the ligand is DOTA, DTPA, DO3A, NOTA, NODAGA, TETA, TE3A, TE2A, PCTA, Cyclen, or DFOM (Deferrioxamine)
Said Gd is gadolinium and is coordinated to said ligand,
The RGD is a cyclic peptide in which the amino acid sequence including Arg-Gly-Asp-Tyr-Lys forms a ring, and is amide bonded to the ligand via lysine,
X is a radioactive iodine selected from I-123, I-124, I-125, and I-131, and is covalently bound to the meta position of tyrosine of the RGD. The compound of claim 1 having the structure of formula 1a:
[Formula 1a]

In Formula 1,
X is I-123, I-124, I-125, or I-131. The compound of claim 2, wherein X is I-125. A process for preparing a compound according to any one of claims 1 to 3 comprising reacting a compound of Formula 3 with a compound of Formula 4 to label radioactive iodine at the meta position of tyrosine of RGD:
(3)

The ligand, Gd, and RGD are as defined in claim 1;
[Chemical Formula 4]
MX
M is Na,
X is I-123, I-124, I-125, or I-131. The compound of claim 4, wherein
Reacting the ligand with the cyclic RGD peptide sequence to prepare a compound of RGD-ligand wherein the lysine of the cyclic RGD is bound to the ligand by amide bonds; And
And coordinating Gd to the ligand by reacting a Gd precursor to the compound of RGD-ligand. The method of claim 5, wherein the Gd precursor is Gd (III) X ₃ , wherein X is F, Cl, Br, I, nitrate, acetylacetonate, or acetate. The method of claim 4, wherein the RGD is Arg-Gly-Asp-Tyr-Lys, the ligand is DOTA, and the compound of Formula 4 is Na ¹²⁵ I. SPECT contrast agent comprising a compound according to any one of claims 1 to 3. The SPECT contrast agent according to claim 8, which is used for diagnosing cancer. SPECT / MRI dual contrast agent comprising a compound according to any one of claims 1 to 3. 10. The SPECT / MRI dual contrast agent according to claim 9, which is used for diagnosing cancer.

Images