RGD dimer compounds, their preparation methods, and use

Abstract

The present invention relates to an RGD dimer compound having a structure represented by formula (I) or formula (I-1), and a method for preparing and using the same, which are related to the fields of nuclear medicine and molecular imaging. The present invention also provides a radionuclide-labeled compound having the RGD dimer compound represented by formula (I-1) as a ligand, a pharmaceutical composition comprising or consisting of the RGD dimer compound, and a kit comprising or consisting of the RGD dimer compound or pharmaceutical composition. The present invention also provides a method for detecting integrin α v The present invention provides a use of an RGD dimer compound or a pharmaceutical composition in the diagnosis or treatment of a disease characterized by overexpression of integrin αβ3. The RGD dimer compound and radionuclide-labeled compound of the present invention have high tumor uptake, long retention time, and inhibit the activity of integrin αβ3. v It is expected that this method will be useful for the diagnosis or treatment of diseases characterized by overexpression of β3. JPEG2025533999000070.jpg99170JPEG2025533999000071.jpg96170

Description

Technical Field

[0001] The present invention relates to the field of nuclear medicine and molecular imaging, and specifically to RGD dimer compounds, their preparation methods, and uses.

Background Art

[0002] Integrin α v β3 is a heterodimer receptor located on the cell surface, which is hardly expressed in normal vascular endothelial cells and epithelial cells, but is highly expressed on the cell surfaces of various solid tumors such as lung cancer, osteosarcoma, neuroblastoma, breast cancer, prostate cancer, bladder cancer, glioblastoma, and invasive melanoma. It is also highly expressed on the membranes of neovascular endothelial cells in all tumor tissues, suggesting that integrin α v β3 plays an important role in the processes of tumor growth, invasion, and metastasis. Polypeptides containing the arginine-glycine-aspartic acid (RGD) sequence can specifically bind to integrin α v β3. RGD peptides labeled with various radionuclides have been successful in imaging studies of various tumor-bearing animal models. Clinically, 18 18F-Galacto-RGD is the first non-invasive integrin α v β-targeted tumor imaging agent to enter clinical trials and has been used in the PET diagnosis of tumor patients. It showed good biological distribution and specific target recognition in clinical trials of glioblastoma.

[0003] However, existing radionuclide-labeled RGD cyclic peptides have a short blood half-life and rapid metabolic clearance, so they cannot maintain a therapeutic level at the tumor site. To achieve the purpose of treatment, higher doses or frequent repeated administrations are required, increasing the possibility of harmful side effects. Although polyethylene glycol modification slows down the clearance rate of RGD cyclic peptides, it may cause immunogenicity and reduce bioavailability.

[0004] As described above, conventional radionuclide-labeled RGD cyclic peptides have limitations, such as low uptake by tumors and short retention times, making it impossible to achieve therapeutic objectives. Using high doses and frequent doses of the drug to achieve therapeutic objectives increases the risk of side effects, making widespread clinical use difficult. [Overview of the project] [Problems that the invention aims to solve]

[0005] Based on the above background, in order to solve the problem of low tumor uptake and short retention time of radionuclide-labeled RGD peptides, the main objective of the present invention is to enable effective binding to serum albumin via a cleaved Evans blue structure, allowing albumin to be used as a delivery carrier for the RGD dimer peptide, thereby extending the half-life in peripheral blood and improving tumor uptake, concentration, and retention time, by cleaved Evans blue (tEB) and integrin α v We will develop a conjugate of the β3-specific ligand RGD dimer peptide (2RGD).

[0006] Another objective of the present invention is to research and develop radionuclide-labeled compounds based on the aforementioned conjugate structure.

[0007] A further object of the present invention is to provide a method for preparing the conjugate and a method for preparing the radionuclide-labeled compound.

[0008] A further object of the present invention is integrin α v The present invention provides the use of the conjugate or the radionuclide-labeled compound in the diagnosis or treatment of diseases characterized by β3 overexpression. [Means for solving the problem]

[0009] The above-mentioned objectives of the present invention are achieved by the following technical solutions. In a first aspect, the present invention provides an RGD dimer compound modified with a cleavable Evans blue and having a structure represented by the following formula (I) or (I-1). JPEG0007844752000001.jpg101170JPEG0007844752000002.jpg103170(Wherein R1 and R2 are independently selected from OH or H, M and P are the same or different and independently JPEG0007844752000003.jpg21170where, when M and P are -(CH2) n -, n is an integer from 0 to 30, and each -CH2- is independently substituted or unsubstituted with -O-, -NH-, -(CO)-, -NH(CO)- or -(CO)-NH-, provided that two adjacent -CH2- groups are not substituted, Z is JPEG0007844752000004.jpg28170JPEG0007844752000005.jpg25170Q and U are present or absent and independently JPEG0007844752000006.jpg21170or -(CH2) n -, and when Q and U are -(CH2) n -, n is an integer from 0 to 30, and each -CH2- is independently substituted or unsubstituted with -O-, -NH-, -(CO)-, -NH(CO)- or -(CO)-NH-, provided that two adjacent -CH2- groups are not substituted, Q' and U' are present or absent, and the structure of either Q' or U' is connected to W. When Q' or U' is present and connected to W, Q' and U' are independently JPEG0007844752000007.jpg27170JPEG0007844752000008.jpg25170When Q' or U' is present and not connected to W, Q' and U' are independently JPEG0007844752000009.jpg20170 or -(CH2) n - Selected from, Q' and U' are -(CH2) n If -, then n is an integer between 0 and 30, and each -CH2- is either substituted or unsubstituted by -O-, -NH-, -(CO)-, -NH(CO)- or -(CO)-NH-, and the substitution condition is that no two adjacent -CH2- groups are substituted. W is a group capable of chelating radionuclides and is one of the following structures selected from: 1,4,7,10-tetraazacyclododecane-N,N',N,N'-tetraacetic acid (DOTA), ethylenediaminetetraacetic acid (EDTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), triethylenetetramine (TETA), iminodiacetic acid, diethylenetriamine-N,N,N',N',N'-pentaacetic acid (DTPA)bis-(carboxymethylimidazole)glycine, or 6-hydrazinopyridine-3-carboxylic acid (HYNIC).

[0010] In a preferred embodiment of the present invention, the compound having the structure represented by formula (I-1) of the first embodiment may be any of the following formulas (II-1) to (II-16). JPEG0007844752000010.jpg100170JPEG0007844752000011.jpg99170JPEG0007844752000012.jpg97170JPEG0007844752000013.jpg97170 JPEG0007844752000014.jpg106170JPEG0007844752000015.jpg112170JPEG0007844752000016.jpg110170JPEG0007844752000017.jpg1131 70JPEG0007844752000018.jpg107170JPEG0007844752000019.jpg103170JPEG0007844752000020.jpg90170JPEG0007844752000021.jpg921 70JPEG0007844752000022.jpg94170JPEG0007844752000023.jpg94170JPEG0007844752000024.jpg90170JPEG0007844752000025.jpg83170

[0011] A first aspect of the present invention also provides a radionuclide-labeled compound obtained by using any of the compounds represented by formula (I-1) as a ligand and chelating a radioactive isotope to a group W capable of chelating the radionuclide. Preferred radioactive isotopes include those that emit alpha rays, beta rays, gamma rays, Auger electrons, and X-rays. The radioactive isotopes include: 18 F, 51 Cr, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 89 Zr, 111 In, 99m Tc, 186 Re, 188 Re, 139 La, 140 La, 175 Yb, 153 Sm, 166 Ho, 86 Y, 90 Y, 149 PM,165 Dy, 169 Er, 177 Lu, 47 Sc, 142 Pr, 159 Gd, 212 Bi, 213 Bi, 72 As, 72 Se, 97 Ru, 109 Pd, 105 Rh, 101m Rh, 119 Sb, 128 Ba, 123 I, 124 I, 131 I, 197 Hg, 211 At, 151 EU, 153 EU, 169 EU, 201 Tl, 203 Pb, 212 Pb, 198 Au, 225 Ac, 227 Th, or 199 Any of Ag is more preferable, and a more preferred radioactive isotope is 18 F, 64 Cu, 68 Ga, 89 Zr, 90 Y, 111 In, 99m Tc, 177 Lu, 188 Re, or 225 It is Ac.

[0012] The present invention also provides pharmaceutically acceptable tautomers, racemates, hydrates, solvates, or salts of all the compounds described in the first embodiment.

[0013] In a second aspect, the present invention provides a method for preparing an RGD dimer compound represented by formula (I) as described in the first aspect. Step (1) involves cleavage-type Evans blue undergoing an amide condensation reaction with amino-protected glutamic acid, lysine, or cysteine ​​carboxyl to obtain amino-protected intermediate compound A, Step (2) involves reacting c(RGDfK) or c(RGDyK) with tert-butyloxycarbonyl-tetrapolyethylene glycol-succinimidyl acrylate to remove the tert-butyloxycarbonyl (Boc) protection, and then reacting it with fluorenyl methoxycarbonyl (Fmoc) protected glutamic acid diactivate to prepare the RGD dimer peptide. The method includes step (3), in which intermediate compound A obtained in (1) and the RGD dimer peptide obtained in (2) are subjected to an amide condensation reaction, and then Boc protection is removed using p-toluenesulfonic acid to obtain the RGD dimer compound represented by formula (I).

[0014] The present invention further provides a method for producing the RGD dimer compound represented by formula (I-1) as described in the first embodiment, comprising connecting the amino of the RGD dimer compound represented by formula (I) obtained in step (3) above to a group capable of chelating a radionuclide to obtain the RGD dimer compound represented by formula (I-1).

[0015] Furthermore, the present invention also provides a method for preparing a radionuclide-labeled compound according to the first embodiment, comprising labeling an RGD dimer compound represented by formula (I-1) with a radionuclide element by a conventional wet method or freeze-drying method to obtain the radionuclide-labeled compound of the present invention.

[0016] In a third aspect, the present invention provides a pharmaceutical composition comprising, or comprising: i) an RGD dimer compound or radionuclide-labeled compound as described in any one of the first aspects; and ii) at least one pharmaceutically acceptable carrier and / or excipient.

[0017] In a fourth aspect, the present invention relates to integrin α in animals or humans. v The present invention provides the use of an RGD dimer compound according to the first embodiment, a radionuclide-labeled compound according to the first embodiment, or a pharmaceutical composition according to the third embodiment in the preparation of a drug for diagnosing or treating a disease characterized by β3 overexpression.

[0018] The aforementioned integrin α vDiseases characterized by β3 overexpression are preferably selected from lung cancer, glioma, glioma, breast cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, head and neck cancer, ovarian cancer, hepatocellular carcinoma, esophageal cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cell carcinoma, bladder cancer, bile duct cancer, clear cell renal cancer, neuroendocrine tumors, carcinogenic osteomalacia, sarcoma, CUP (cancer of unknown primary origin), thymic carcinoma, astrocytoma, cervical cancer, or prostate cancer.

[0019] In a fifth aspect, the present invention provides a kit comprising an RGD dimer compound, a radionuclide-labeled compound, or a pharmaceutical composition according to any of the first aspects of the present invention. [Effects of the Invention]

[0020] Compared to the conventional technology, the beneficial effect of the present invention is that the RGD dimer compound structure can improve tumor uptake and retention time, and integrin α v It is expected to be applied to the diagnosis or treatment of diseases characterized by β3 overexpression. [Brief explanation of the drawing]

[0021] [Figure 1] This is the mass spectrum of compound H in Example 1 of the present invention. [Figure 2] This figure shows the 68Ga-labeled HPLC quality control results for compound H in Example 1 of the present invention. [Figure 3] This is an in vitro stability analysis of compound H labeled with 68Ga in Example 1 of the present invention. [Figure 4] This figure shows the results of in vivo MicroPET imaging of the 68Ga-labeled complex of compound H in Example 1 of the present invention in U87 tumor-bearing mice. [Modes for carrying out the invention]

[0022] The technical solutions of the present invention are further illustrated and described below through specific embodiments in conjunction with the drawings.

[0023] Example 1: Preparation of 2RGD-EB (compound (II-1)) Preparation of compound c(RGDfK)-PEG4: Fmoc-PEG4-CH2CH2COOH (compound i) (1.46 g, 3.0 mmol) was dissolved in DMF, then DCC (0.68 g, 3.3 mmol) and HOSu (0.38 g, 3.3 mmol) were added, and the mixture was reacted at room temperature for 6 hours. The mixture was filtered, and TEA (0.90 g, 9.0 mmol) was added to the filtrate, then c(RGDfK) (compound ii) (2.23 g, 3.6 mmol) was added, and the mixture was reacted at room temperature for 3 hours. The reaction mixture was evaporated by rotation, then dissolved in 25% DEA / THF, and the mixture was reacted at room temperature for 4 hours. The mixture was concentrated until only a small amount of solution remained, and added to 10 times the volume of ethyl ether to precipitate a large amount of solid. The mixture was filtered to obtain the crude product c(RGDfK)-PEG4, which was purified by reverse-phase preparative liquid chromatography to obtain the purified product c(RGDfK)-PEG4. The eluents used are: Solution A is ultrapure water containing 1 vol‰ of trifluoroacetic acid, and Solution B is acetonitrile.

[0024] Synthesis of compound 2(RGDfK)PEG4-Glu Boc-Glu-OH (0.4 g, 2.0 mmol) was dissolved in DMF, then DCC (0.45 g, 2.2 mmol) and HOSu (0.25 g, 2.2 mmol) were added, and the mixture was reacted at room temperature for 6 hours. The mixture was filtered, and TEA (0.60 g, 6.0 mmol) was added to the filtrate, then c(RGDfK)-PEG4 (2.61 g, 2.4 mmol) was added, and the mixture was reacted at room temperature for 3 hours. The reaction mixture was evaporated by rotation, dissolved in TFA, and reacted at room temperature for 10 minutes. A large amount of solid was added to 10 times the volume of ethyl ether, precipitated, filtered, and crude product 2(RGDfK)PEG4-Glu was obtained. The crude product was purified by reverse-phase preparative liquid chromatography to obtain purified product 2(RGDfK)PEG4-Glu. As eluents, solution A was ultrapure water containing 1 vol‰ of trifluoroacetic acid, and solution B was acetonitrile. Next, the pH of the purified product 2(RGDfK)PEG4-Glu was adjusted to neutral with TEA, and then subjected to reverse-phase preparative liquid chromatography and freeze-dried to obtain the finished product 2(RGDfK)PEG4-Glu. Solution A was ultrapure water and solution B was acetonitrile as the eluent.

[0025] Preparation of compound A: Under room temperature conditions, o-tolidine (50.00 g, 235.53 mmol) was added to 450 ml of dichloromethane, stirred and dissolved, and then 50 ml of a dichloromethane solution of di-tert-butyl dicarbonate (51.40 g, 235.53 mmol) was added dropwise, and the reaction was allowed to proceed at room temperature for 42 hours. The mixture was filtered, and the filtrate was washed three times in 500 ml portions with 0.1 mol / L hydrochloric acid solution. The organic phase was washed with 500 ml of water, dried over anhydrous sodium sulfate, and the organic phase was rotated and evaporated under reduced pressure. After rotational evaporation, the mixture was redissolved in 500 ml of ethyl acetate, 60 ml of 4 mol / L HCl / EA solution was added, followed by 1 L of methyl tert-butyl ether. The temperature was cooled to 0-10°C to precipitate crystals, filtered, and baked at 45°C to obtain compound A (47.32 g, yield 64.31%).

[0026] Preparation of compound B: Under room temperature conditions, compound A (50.00 g, 143.42 mmol), DIPEA (46.37 g, 358.55 mmol), Fmoc-Glu(OtBu)-OH (67.12 g, 157.77 mmol), and HATU (60.00 g, 157.77 mmol) were sequentially added to 400 ml of acetonitrile, dissolved, and reacted at room temperature for 18 hours. After the reaction was complete, the reaction mixture was evaporated under reduced pressure by rotation, redissolved in 500 ml of dichloromethane, washed twice with 500 ml of saturated sodium bicarbonate solution and then 500 ml of pure water, the organic phase was evaporated under reduced pressure by rotation, and then purified by silica gel column chromatography (dichloromethane:ethyl acetate = 20:1). The product eluent was collected, evaporated under reduced pressure by rotation, slurryed with 1 L of methyl tert-butyl ether, filtered, and baked at 45°C to obtain compound B (103.49 g, yield 89.82%).

[0027] Preparation of compound C: Under room temperature conditions, compound B (56.00 g, 77.84 mmol) was added to 560 ml of dichloromethane, stirred to dissolve, then 112 ml of trifluoroacetic acid was added, and the reaction was carried out with stirring at 30°C for 2 hours. After the reaction was complete, the reaction mixture was added to 2.24 L of methyl tert-butyl ether, the solid was precipitated, filtered, and baked at 45°C to obtain compound C (49.12 g, yield 97.46%).

[0028] Preparation of compound D: Under room temperature conditions, compound C (27.64 g, 49.04 mmol) was added to a mixture of 750 ml of acetonitrile and 200 ml of purified water, stirred to dissolve, cooled to -5 to 0°C in an ice bath, 81.6 ml of 2 mol / L hydrochloric acid was added, then sodium nitrite aqueous solution (3.38 g, 49.04 mmol, 50 ml water) was added, and the mixture was stirred for 30 minutes to react. The above diazonium salt solution was slowly added dropwise to an aqueous solution (200 ml) of 1-amino-8-naphthol-2,4-disulfonic acid monosodium salt (16.74 g, 49.04 mmol) and sodium bicarbonate (24.72 g, 294.24 mmol), with the temperature controlled to 0 to 5°C during the addition process. After the dropwise addition was complete, the reaction was allowed to proceed by incubating at 0-5°C for 2 hours. The reaction mixture was then evaporated under reduced pressure using rotational evaporation, and purified by preparative liquid chromatography to obtain compound D (19.91 g, yield 45.28%).

[0029] Preparation of compound F: Under room temperature conditions, compound D (0.5576 g, 0.624 mmol) and HATU (0.2419 g, 0.636 mmol) were added to 50 ml of DMF and stirred at room temperature for 30 min. 2(RGDfK)PEG4-Glu (1.1874 g, 0.655 mmol) was added and the mixture was stirred at room temperature for 4 hours. After the reaction was complete, 11 ml of piperidine was added to the reaction flask and the mixture was stirred for a further 4.5 hours. After the reaction was complete, the mixture was evaporated under reduced pressure and purified by preparative liquid chromatography to obtain compound F (0.80 g, 2-step yield 51.97%).

[0030] Preparation of compound H: Under room temperature conditions, compound F (0.3662 g, 0.148 mmol), DIPEA (0.2304 g, 1.78 mmol), and DOTA-TRIS-TBU-ESTERNHS (0.2982 g, 0.42 mmol) were added to 7.3 ml of DMF and reacted at 30°C for 40 hours. After the reaction was complete, the reaction mixture was evaporated under reduced pressure to obtain 0.7332 g of crude compound G. Crude compound G was added to 7 ml of trifluoroacetic acid, stirred to dissolve, and reacted at 30°C for 3 hours. After the reaction was complete, the reaction mixture was added to 40 ml of methyl tert-butyl ether, filtered by suction, and the solid was dried under reduced pressure to obtain 0.5494 g of crude compound H. Crude compound H was purified by preparative liquid chromatography to obtain compound H (0.1426 g, 2-step yield 31.89%). Figure 1 shows the mass spectrum of compound H. [M+K+H+H] 3+ / 3 = 964.

[0031] The synthesis scheme for the above steps is as follows: JPEG0007844752000026.jpg160170JPEG0007844752000027.jpg220170JPEG0007844752000028.jpg161170

[0032] Examples 2 to 16 The structures of the compounds in Examples 2 to 16 are shown by formulas (II-2) to (II-16), respectively. The preparation methods for these compounds were all based on the preparation in Example 1, with some raw materials changed. For example, c(RGDfK) was changed to c(RGDyK), N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-glutamic acid was changed to N-Boc-N'-Fmoc-L-lysine, and tert-butyloxycarbonyl-tetrapolyethylene glycol-succinimidyl acrylate was changed to bis(2,5-dioxopyrrolidine-1-yl)3,3'-(ethane-1,2-diylbis(oxy))dipropanoate to obtain the corresponding structures shown below. JPEG0007844752000029.jpg99170JPEG0007844752000030.jpg99170JPEG0007844752000031.jpg99170JPEG0007844752000032.jp g109170JPEG0007844752000033.jpg108170JPEG0007844752000034.jpg109170JPEG0007844752000035.jpg113170JPEG000784475 2000036.jpg102170JPEG0007844752000037.jpg103170JPEG0007844752000038.jpg88170JPEG0007844752000039.jpg92170JPEG0 007844752000040.jpg94170JPEG0007844752000041.jpg96170JPEG0007844752000042.jpg87170JPEG0007844752000043.jpg81170

[0033] Example 17. Preparation of radioactive Ga-68 labeled 2RGD-EB complex Wet method: A centrifuge tube containing 0.5 mL of the acetic acid-acetate salt solution (1.0 g / L) of compound H prepared in Example 1 was used to collect approximately 18.5 to 1850 megabecquerels (MBq). 68 GaCl3 hydrochloric acid solution (eluted from a germanium gallium generator) was added, and the reaction was carried out at 37°C for 20 minutes. A C18 separation column was prepared, and the sample was first slowly eluted with 10 mL of anhydrous ethanol, and then with 10 mL of water. The labeling solution was diluted with 10 mL of water and then passed through the separation column. First, the unlabeled sample was obtained. 68 The Ga ions were removed with 10 mL of water, and then eluted with 0.3 mL of 10 mM HCl ethanol solution. 68 Ga-labeled 2RGD-EB complex was obtained. This eluate was diluted with physiological saline and subjected to sterile filtration. 68 An injectable solution of Ga-labeled 2RGD-EB complex was obtained.

[0034] Freeze-drying method: Approximately 18.5 to 1850 megabecquerels (MBq) of compound H are placed in a freeze-drying case. 68GaCl3 hydrochloric acid solution (eluted from a germanium gallium generator) was added and mixed uniformly, then the reaction was carried out at 37°C for 20 minutes. A C18 separation column was prepared, and the sample was first slowly eluted with 10 mL of anhydrous ethanol, and then with 10 mL of water. The labeling solution was diluted with 10 mL of water and then passed through the separation column. First, the unlabeled sample was tested. 68 Ga ions were removed with 10 mL of water, and then eluted with 0.3 mL of 10 mM HCl ethanol solution to obtain an eluate of the complex. This eluate was diluted with physiological saline and filtered sterile. 68 An injectable solution of Ga-labeled 2RGD-EB complex was obtained.

[0035] Analysis of experimental examples and results of applications 1. HPLC analysis and identification The HPLC system is as follows: SHIMADZULC-20A; C18 column (YMC, 3 μm, 4.6 × 150 mm) was used for analysis. Detection wavelength: 254 nm, flow rate: 1 mL / min, elution gradient: 0-3 min: maintain constant 10% acetonitrile, 90% water (50 mM ammonium acetate); 3-16 min: increase to 90% acetonitrile, 10% water (50 mM ammonium acetate); 16-18 min: maintain 90% acetonitrile, 10% water (50 mM ammonium acetate); 18-20 min: decrease to 10% acetonitrile, 90% water (50 mM ammonium acetate); 20-22 min: maintain 10% acetonitrile, 90% water (50 mM ammonium acetate). The labeling system for 2RGD-EB (compound H) prepared in Example 1 is shown in Figure 2.

[0036] Prepared in Example 17 68 20 μL of Ga-2RGD-EB (3.7 MBq activity / 20 μL) solution was transferred to a centrifuge tube containing 100 μL of physiological saline or PBS (pH=7.4), and incubated at 37°C for 0.5 h, 1 h, 2 h, and 4 h to obtain co-incubation solutions. 20 μL of the co-incubation solution was taken, passed through a 0.22 μm needle filter, and its radiochemical purity was analyzed by HPLC. The test results are shown in Figure 3. After incubation in PBS and physiological saline, 68Ga-2RGD-EB showed no obvious decomposition, and the radiochemical purity was higher than 98%, which indicates that 68 Ga-2RGD-EB has excellent stability.

[0037] 2. MicroPET imaging of 68 Ga-labeled 2RGD-EB complex in U87 tumor-bearing mice For Ga-2RGD-EB prepared according to the method of Example 17, 68 7.4 MBq of 68 Ga-2RGD-EB was injected into the tail vein of U87 tumor-bearing mice. Then, MicroPET imaging was performed under isoflurane anesthesia at 30, 120, and 240 min after administration. The results are shown in Figure 4. The right side of Figure 4 shows, from left to right, five groups of blood, liver, kidney, tumor, and muscle, indicating the uptake of the drug into different tissues or organs of the mice at different times after injection. The corresponding times from left to right for each group were 0.5 h, 2 h, and 4 h, respectively. The results showed that the uptake into the tumor increased with time at the tested time points.

[0038] As described above, the present invention has developed a 2RGD-EB structure that can improve the uptake and retention time in tumors, and is expected to be applied to the diagnosis or treatment of diseases characterized by overexpression of integrin α v β3.

[0039] Although the present invention has been described in detail above by general description, specific embodiments and tests, it is obvious to those skilled in the art that some changes or improvements can be made based on the present invention. Therefore, all changes or improvements made without departing from the spirit of the present invention belong to the scope of protection required by the present invention.

Claims

1. An RGD dimer compound characterized by being a compound whose structure is represented by formula (II-1), or a pharmaceutically acceptable tautomer, racemate, hydrate, solvate, or salt thereof.

2. A radionuclide-labeled compound, A radionuclide-labeled compound characterized by being obtained by using the compound of formula (II-1) described in claim 1 or a pharmaceutically acceptable tautomer, racemate, hydrate, solvate, or salt thereof as a ligand, and chelating a radioactive isotope to the 1,4,7,10-tetraazacyclododecane-N,N',N,N'-tetraacetic acid (DOTA) skeleton in the compound of formula (II-1).

3. The radioactive isotope is an isotope that emits alpha rays, an isotope that emits beta rays, an isotope that emits gamma rays, an isotope that emits Auger electrons, or an isotope that emits X-rays, as described in claim 2.

4. The radioactive isotope is ２１２ , １９９ , １９８ , ２２５ , ２２７ , ２０３ F, ５１ Cr, ６４ Cu, ６７ Cu, ６７ Ga, ６８ Ga, ８９ Zr, １１１ In, ９９ｍ Tc, １８６ Re, １８８ Re, １３９ La, １４０ La, １７５ Yb, １５３ Sm, １６６ Ho, ８６ Y, ９０ Y, １４９ Pm, １６５ Dy, １６９ Er, １７７ Lu, ４７ Sc, １４２ Pr, １５９ Gd, ２１２ Bi, ２１３ Bi, ７２ As, ７２ Se, ９７ Ru, １０９ Pd, １０５ Rh, １０１ｍ Rh, １１９ Sb, １２８ Ba, １２３ I, １２４ I, １３１ I, １９７ Hg, ２１１ At, １５１ Eu, １５３ Eu, １６９ Eu, ２０１ Tl, ２０３ Pb, ２１２ Pb, １９８ Au, ２２５ Ac, ２２７ Th, or １９９ Ag, and is characterized by the radioactive nuclide-labeled compound according to claim 2.

5. i) an RGD dimer compound according to claim 1, and ii) at least one pharmaceutically acceptable carrier and / or excipient, comprising or comprising these, a pharmaceutical composition.

6. i) a radionuclide-labeled compound according to claim 2, and ii) at least one pharmaceutically acceptable carrier and / or excipient, comprising or comprising these, a pharmaceutical composition.

7. Integrin α for animals or humans ｖ β ３ Use of the RGD dimer compound according to claim 1 in the preparation of a drug for diagnosing or treating a disease characterized by overexpression of .

8. Integrin α for animals or humans ｖ β ３ Use of the radionuclide-labeled compound according to claim 2 in the preparation of a drug for diagnosing or treating a disease characterized by overexpression of .

9. Integrin α for animals or humans ｖ β ３ Use of the pharmaceutical composition according to claim 6 in the preparation of a drug for diagnosing or treating a disease characterized by the overexpression of .

10. The aforementioned integrin α ｖ β ３ The use according to claim 8, characterized in that the disease characterized by overexpression of is lung cancer, glioma, glioma, breast cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, head and neck cancer, ovarian cancer, hepatocellular carcinoma, esophageal cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cell carcinoma, bladder cancer, bile duct cancer, clear cell renal cancer, neuroendocrine tumor, carcinogenic osteomalacia, sarcoma, CUP (cancer of unknown primary origin), thymic carcinoma, astrocytoma, cervical cancer, or prostate cancer.

11. The aforementioned integrin α ｖ β ３ The use according to claim 9, characterized in that the disease characterized by overexpression of is lung cancer, glioma, glioma, breast cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, head and neck cancer, ovarian cancer, hepatocellular carcinoma, esophageal cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cell carcinoma, bladder cancer, bile duct cancer, clear cell renal cancer, neuroendocrine tumor, carcinogenic osteomalacia, sarcoma, CUP (cancer of unknown primary origin), thymic carcinoma, astrocytoma, cervical cancer, or prostate cancer.

12. A kit characterized by comprising the RGD dimer compound described in claim 1.

13. A kit characterized by comprising the radionuclide-labeled compound described in claim 2.

14. A kit characterized by comprising the pharmaceutical composition described in claim 6.

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