RGD dimer compounds and methods for their preparation 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 in particular to RGD dimer compounds and methods for their preparation and use. [Background technology]

[0002] Integrin α v β3 is a heterodimeric receptor located on the cell surface. It is hardly expressed on normal vascular endothelial cells or epithelial cells, but is highly expressed on the cell surface of various solid tumors, including lung cancer, osteosarcoma, neuroblastoma, breast cancer, prostate cancer, bladder cancer, glioblastoma, and invasive melanoma, and is also highly expressed on the membrane of neovascular endothelial cells in all tumor tissues. Integrin α v These findings suggest that β3 plays an important role in tumor growth, invasion, and metastasis. Polypeptides containing the arginine-glycine-aspartic acid (RGD) sequence interact with integrin α v RGD peptides labeled with various radionuclides have been successfully used in imaging studies of various tumor-bearing animal models. 18 F-Galacto-RGD is the first non-invasive integrin α to enter clinical trials v It has become a β3-targeted tumor imaging agent and has been used for PET diagnosis in tumor patients, and has shown good biological distribution and specific target recognition in clinical trials for glioblastoma.

[0003] However, existing radionuclide-labeled RGD cyclic peptides have short blood half-lives and rapid metabolic clearance, making it impossible to maintain therapeutic levels at tumor sites. Higher doses or frequent repeated administration are required to achieve therapeutic goals, increasing the potential for adverse side effects. Polyethylene glycol modification slows the clearance rate of RGD cyclic peptides, but can also cause immunogenicity and reduce bioavailability.

[0004] As described above, the radionuclide-labeled RGD cyclic peptides in the prior art have limitations such as low tumor uptake and short retention time, which makes it impossible to achieve the therapeutic goal. If the drug is used at a high dose and frequently to achieve the therapeutic goal, there is a risk of increased side effects, making it difficult to widely use in clinical practice. Summary of the Invention [Problem to be solved by the invention]

[0005] Based on the above background, in order to solve the problems of radionuclide-labeled RGD peptides, such as low tumor uptake and short retention time, the main objective of this invention is to develop a cleaved Evans Blue (tEB)-integrin α complex that can effectively bind to serum albumin via the truncated Evans Blue structure, allowing albumin to be used as a delivery carrier for RGD dimer peptides, thereby extending their half-life in peripheral blood and improving tumor uptake, concentration, and retention time. v Develop a conjugate of the β3-specific ligand RGD dimer peptide (2RGD).

[0006] Another object of the present invention is to research and develop radionuclide-labeled compounds based on said conjugate structures.

[0007] It is a further object of the present invention to provide methods for preparing said conjugates and methods for preparing said radionuclide-labeled compounds.

[0008] A further object of the present invention is to provide a method for the preparation of integrin α v Use of the conjugate or the radionuclide-labeled compound in the diagnosis or treatment of a disease characterized by overexpression of β3 is provided. [Means for solving the problem]

[0009] The above object of the present invention is achieved by the following technical solutions. In a first aspect, the present invention provides an RGD dimer compound, which is an RGD dimer structure modified with truncated Evans Blue, and has a structure represented by the following formula (I) or (I-1): JPEG2025533999000002.jpg101170JPEG2025533999000003.jpg103170(where, R1 and R2 are independently selected from OH or H; M and P are the same or different and independently represent: JPEG2025533999000004.jpg21170, M and P are -(CH2) n -, n is an integer from 0 to 30, and each -CH2- is independently substituted with -O-, -NH-, -(CO)-, -NH(CO)-, or -(CO)-NH-, or is unsubstituted, provided that two adjacent -CH2- groups are unsubstituted; Z is JPEG2025533999000005.jpg28170JPEG2025533999000006.jpg25170Q and U may be present or absent, independently JPEG2025533999000007.jpg21170 or -(CH2) n -, and Q and U are selected from -(CH2) n -, n is an integer from 0 to 30, and each -CH2- is independently substituted with -O-, -NH-, -(CO)-, -NH(CO)-, or -(CO)-NH-, or is unsubstituted, provided that two adjacent -CH2- groups are unsubstituted; Q' and U' are either 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 JPEG2025533999000008.jpg27170JPEG2025533999000009.jpg25170If Q' or U' exist and are not connected to W, then Q' and U' are independently JPEG2025533999000010.jpg20170 or -(CH2) n -, and Q' and U' are selected from -(CH2) n -, n is an integer from 0 to 30, and each -CH2- is independently substituted with -O-, -NH-, -(CO)-, -NH(CO)-, or -(CO)-NH-, or is unsubstituted, provided that two adjacent -CH2- groups are unsubstituted; W is a group capable of chelating a radionuclide and is one of the 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 aspect may be any of the compounds represented by the following formulas (II-1) to (II-16). JPEG2025533999000011.jpg100170JPEG2025533999000012.jpg99170JPEG2025533999000013.jpg97170JPEG2025533999000014.jpg97170 JPEG2025533999000015.jpg106170JPEG2025533999000016.jpg112170JPEG2025533999000017.jpg110170JPEG2025533999000018.jpg1131 70JPEG2025533999000019.jpg107170JPEG2025533999000020.jpg103170JPEG2025533999000021.jpg90170JPEG2025533999000022.jpg921 70JPEG2025533999000023.jpg94170JPEG2025533999000024.jpg94170JPEG2025533999000025.jpg90170JPEG2025533999000026.jpg83170

[0011] The 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 radioisotope to the group W capable of chelating the radionuclide. Preferred radioisotopes include isotopes that emit α-rays, isotopes that emit β-rays, isotopes that emit γ-rays, isotopes that emit Auger electrons, and isotopes that emit X-rays. Examples of the radioisotopes 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 More preferably, any of Ag, and even more preferably, the radioisotope 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 compounds described in the first aspect.

[0013] In a second aspect, the present invention provides a method for preparing an RGD dimer compound of formula (I) according to the first aspect, Step (1) of amide condensation of the truncated Evans Blue with the carboxyl of an amino-protected glutamic acid, lysine, or cysteine ​​to obtain an amino-protected intermediate compound A; Step (2) of reacting c(RGDfK) or c(RGDyK) with tert-butyloxycarbonyl-tetrapolyethyleneglycol-succinimidyl acrylate, removing the tert-butyloxycarbonyl (Boc) protection, and then reacting with fluorenylmethoxycarbonyl (Fmoc)-protected glutamic acid diactive ester to prepare an RGD dimer peptide; and step (3) of subjecting the intermediate compound A obtained in step (1) and the RGD dimer peptide obtained in step (2) to an amide condensation reaction, followed by removing the Boc protection 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 of formula (I-1) according to the first aspect, which comprises connecting the amino of the RGD dimer compound of formula (I) obtained in step (3) above to a group capable of chelating a radionuclide to obtain the RGD dimer compound of formula (I-1).

[0015] Furthermore, the present invention also provides a method for preparing the radionuclide-labeled compound according to the first aspect, which comprises labeling the RGD dimer compound represented by formula (I-1) with a radionuclide 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 consisting of i) an RGD dimer compound or radionuclide-labeled compound according to any one of the first aspect, and ii) at least one pharmaceutically acceptable carrier and / or excipient.

[0017] In a fourth aspect, the present invention provides a method for detecting integrin α in an animal or human subject. v There is provided the use of an RGD dimer compound of the first aspect, a radionuclide-labeled compound of the first aspect, or a pharmaceutical composition of the third aspect in the preparation of a medicament for diagnosing or treating a disease characterized by overexpression of β3.

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

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

[0020] Compared with the prior art, the beneficial effect of the present invention is that the RGD dimer compound structure can improve tumor uptake and retention time, and inhibit integrin α v It is expected that this method will be applied to the diagnosis or treatment of diseases characterized by overexpression of β3. [Brief explanation of the drawings]

[0021] [Figure 1] 1 is a mass spectrum of compound H in Example 1 of the present invention. [Figure 2] FIG. 1 shows the results of 68Ga-labeled HPLC quality control of Compound H in Example 1 of the present invention. [Figure 3] 68Ga-labeled in vitro stability analysis of Compound H in Example 1 of the present invention. [Figure 4] FIG. 1 shows the results of MicroPET imaging in vivo of a U87 tumor-bearing mouse using a 68Ga-labeled conjugate of Compound H in Example 1 of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0022] The technical solutions of the present invention are further illustrated and explained below through specific embodiments in combination 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, 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 rotary evaporated, and then dissolved in 25% DEA / THF and reacted at room temperature for 4 hours. The mixture was concentrated until a small amount of solution remained, and added to 10 volumes of ethyl ether. A large amount of solid precipitated and filtered to obtain crude c(RGDfK)-PEG4. The crude c(RGDfK)-PEG4 was purified by reverse-phase preparative liquid chromatography to obtain purified c(RGDfK)-PEG4. As the eluent, liquid A is ultrapure water containing 1% by volume of trifluoroacetic acid, and liquid B is acetonitrile.

[0024] Synthesis of compound 2 (RGDfK)PEG4-Glu Boc-Glu-OH (0.4 g, 2.0 mmol) was dissolved in DMF, followed by DCC (0.45 g, 2.2 mmol) and HOSu (0.25 g, 2.2 mmol). The mixture was incubated at room temperature for 6 hours, filtered, and the filtrate was added with TEA (0.60 g, 6.0 mmol), followed by c(RGDfK)-PEG4 (2.61 g, 2.4 mmol). The mixture was then evaporated by rotary evaporation, dissolved in TFA, incubated at room temperature for 10 minutes, and added to 10 volumes of ethyl ether to precipitate a large amount of solid. The crude product 2(RGDfK)PEG4-Glu was obtained by filtration and purified by reverse-phase preparative liquid chromatography (RPLC). Solution A was ultrapure water containing 1 volume of trifluoroacetic acid, and solution B was acetonitrile. The purified product 2(RGDfK)PEG4-Glu was then adjusted to neutral pH with TEA, subjected to reverse-phase preparative liquid chromatography, and lyophilized to obtain the final product 2(RGDfK)PEG4-Glu. The eluents were ultrapure water (Solution A) and acetonitrile (Solution B).

[0025] Preparation of Compound A: At room temperature, o-tolidine (50.00 g, 235.53 mmol) was added to 450 mL of dichloromethane and stirred to dissolve. A solution of di-tert-butyl dicarbonate (51.40 g, 235.53 mmol) in 50 mL of dichloromethane was added dropwise and allowed to react for 42 h at room temperature. The filtrate was filtered, washed three times with 500 mL of 0.1 mol / L hydrochloric acid solution, and the organic phase was washed with 500 mL of water. It was then dried over anhydrous sodium sulfate and rotary evaporated under reduced pressure. After rotary evaporation, the residue was redissolved in 500 mL of ethyl acetate, added with 60 mL of 4 mol / L HCl / EA solution, and then added with 1 L of methyl tert-butyl ether. The mixture was cooled to 0-10 °C to precipitate crystals, which were then filtered and baked at 45 °C to obtain Compound A (47.32 g, 64.31% yield).

[0026] Preparation of Compound B: 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 added sequentially to 400 ml of acetonitrile at room temperature, dissolved, and reacted at room temperature for 18 hours. After the reaction was completed, the reaction solution was rotary evaporated under reduced pressure, redissolved in 500 ml of dichloromethane, and washed twice with 500 ml of saturated sodium bicarbonate solution and 500 ml of pure water, respectively. The organic phase was rotary evaporated under reduced pressure and then purified by silica gel column chromatography (dichloromethane:ethyl acetate=20:1). The product eluate was collected and rotary evaporated under reduced pressure, then slurried in 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: At room temperature, compound B (56.00 g, 77.84 mmol) was added to 560 ml of dichloromethane and stirred to dissolve, after which 112 ml of trifluoroacetic acid was added and the reaction was carried out with stirring for 2 hours at 30° C. After completion of the reaction, the reaction solution was added to 2.24 L of methyl tert-butyl ether to precipitate a solid, which was filtered and baked at 45° C. to obtain compound C (49.12 g, yield 97.46%).

[0028] Preparation of Compound D: Compound C (27.64 g, 49.04 mmol) was added to a mixture of 750 mL of acetonitrile and 200 mL of purified water at room temperature, stirred to dissolve, and cooled to -5 to 0 °C in an ice bath. 81.6 mL of 2 mol / L hydrochloric acid was added, followed by aqueous sodium nitrite (3.38 g, 49.04 mmol, 50 mL of water), and the mixture was stirred for 30 minutes. The 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). The temperature was controlled at 0 to 5 °C during the addition. After the dropwise addition was completed, the mixture was allowed to react at 0 to 5°C for 2 hours, and the reaction solution was rotary evaporated under reduced pressure and then purified by preparative liquid chromatography to obtain compound D (19.91 g, yield 45.28%).

[0029] Preparation of Compound F: 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 h. After the reaction was complete, 11 mL of piperidine was added to the reaction flask and the mixture was stirred for an additional 4.5 h. After the reaction was complete, the mixture was rotary evaporated under reduced pressure and purified by preparative liquid chromatography to obtain compound F (0.80 g, 51.97% yield for the second stage).

[0030] Preparation of Compound H: 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 at room temperature and incubated at 30 °C for 40 h. After completion of the reaction, the reaction solution was rotary evaporated under reduced pressure to give 0.7332 g of crude compound G. The crude compound G was added to 7 mL of trifluoroacetic acid, dissolved by stirring, and reacted at 30 °C for 3 h. After completion of the reaction, the reaction solution was added to 40 mL of methyl tert-butyl ether, filtered with suction, and the solid was dried under reduced pressure to give 0.5494 g of crude compound H. The crude compound H was purified by preparative liquid chromatography to give compound H (0.1426 g, 31.89% yield for the second stage). Figure 1 shows the mass spectrum of compound H. [M+K+H+H] 3+ / 3=964.

[0031] The synthetic scheme for the above steps is as follows: JPEG2025533999000027.jpg160170JPEG2025533999000028.jpg220170JPEG2025533999000029.jpg161170

[0032] Examples 2 to 16 The structures of the compounds of Examples 2 to 16 are represented by formula (II-2) to formula (II-16), respectively. These preparation methods are all based on the preparation of Example 1, with some raw materials being 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-tetrapolyethyleneglycol-succinimidyl acrylate was changed to bis(2,5-dioxopyrrolidin-1-yl)3,3'-(ethane-1,2-diylbis(oxy))dipropanoate, to obtain the following corresponding structures. JPEG2025533999000030.jpg99170JPEG2025533999000031.jpg99170JPEG2025533999000032.jpg99170JPEG2025533999000033.jp g109170JPEG2025533999000034.jpg108170JPEG2025533999000035.jpg109170JPEG2025533999000036.jpg113170JPEG202553399 9000037.jpg102170JPEG2025533999000038.jpg103170JPEG2025533999000039.jpg88170JPEG2025533999000040.jpg92170JPEG2 025533999000041.jpg94170JPEG2025533999000042.jpg96170JPEG2025533999000043.jpg87170JPEG2025533999000044.jpg81170

[0033] Example 17. Preparation of radioactive Ga-68 labeled 2RGD-EB conjugate Wet method: 0.5 mL of the acetic acid-acetate solution (1.0 g / L) of Compound H prepared in Example 1 was placed in a centrifuge tube, and approximately 18.5 to 1850 megabecquerels (MBq) of 68 A GaCl3 hydrochloric acid solution (eluted from a germanium gallium generator) was added and reacted at 37°C for 20 minutes. A C18 separation column was prepared and first slowly eluted with 10 mL of absolute ethanol, then with 10 mL of water. The labeling solution was diluted with 10 mL of water and then applied to the separation column. First, unlabeled 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 The eluate was diluted with saline and sterile filtered to obtain Ga-labeled 2RGD-EB complex. 68 An injection of Ga-labeled 2RGD-EB complex was obtained.

[0034] Freeze-drying method: A freeze-drying case containing compound H is filled with approximately 18.5 to 1850 megabecquerels (MBq). 68GaCl3 hydrochloric acid solution (eluted from a germanium gallium generator) was added, mixed uniformly, and then reacted at 37°C for 20 minutes. A C18 separation column was prepared, and first, eluted slowly with 10 mL of absolute ethanol, and then with 10 mL of water. The labeling solution was diluted with 10 mL of water and then applied to the separation column. First, unlabeled 68 The 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 saline and sterile filtered to obtain the complex. 68 An injection of Ga-labeled 2RGD-EB complex was obtained.

[0035] Analysis and application results of experimental examples 1. HPLC Analysis and Identification The HPLC system used was the following: SHIMADZULC-20A; C18 column (YMC, 3 μm, 4.6 × 150 mm). Detection wavelength: 254 nm; flow rate: 1 mL / min; elution gradient: 0-3 min: 10% acetonitrile, 90% water (50 mM ammonium acetate) maintained constant; 3-16 min: increased to 90% acetonitrile, 10% water (50 mM ammonium acetate); 16-18 min: maintained at 90% acetonitrile, 10% water (50 mM ammonium acetate); 18-20 min: decreased to 10% acetonitrile, 90% water (50 mM ammonium acetate); 20-22 min: maintained at 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 saline or PBS (pH=7.4) and incubated at 37°C for 0.5, 1, 2, and 4 hours to obtain a co-incubation solution. 20 μL of the co-incubation solution was collected, passed through a 0.22 μm needle filter, and analyzed for radiochemical purity by HPLC. The test results are shown in Figure 3. After incubation in PBS and saline, 68Ga-2RGD-EB showed no obvious decomposition and the radiochemical purity was higher than 98%, which indicates that the Ga-2RGD-EB produced in this invention 68 This indicates that Ga-2RGD-EB has excellent stability.

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

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

[0039] Although the present invention has been described in detail above by means of general descriptions, specific embodiments and tests, it is obvious to those skilled in the art that any 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 claimed by the present invention.

Claims

1. An RGD dimer compound having a structure represented by formula (I) or formula (I-1): (where, R １ and R ２ is independently selected from OH or H; M and P are the same or different and independently represent: or -(CH ２ ) ｎ -, and M and P are selected from -(CH ２ ) ｎ -, n is an integer from 0 to 30, and each -CH ２ - is independently substituted with -O-, -NH-, -(CO)-, -NH(CO)- or -(CO)-NH-, or is unsubstituted, and the substitution condition is two adjacent -CH ２ - group is unsubstituted, Z is Q and U are present or absent and independently represent: or -(CH ２ ) ｎ -, and Q and U are selected from -(CH ２ ) ｎ -, n is an integer from 0 to 30, and each -CH ２ - is independently substituted with -O-, -NH-, -(CO)-, -NH(CO)- or -(CO)-NH-, or is unsubstituted, and the substitution condition is two adjacent -CH ２ - group is unsubstituted, Q' and U' are either 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 If Q' or U' are present and not connected to W, then Q' and U' are independently or -(CH ２ ) ｎ -, and Q' and U' are selected from -(CH ２ ) ｎ -, n is an integer from 0 to 30, and each -CH ２ - is independently substituted with -O-, -NH-, -(CO)-, -NH(CO)- or -(CO)-NH-, or is unsubstituted, and the substitution condition is two adjacent -CH ２ - group is unsubstituted, W is a group capable of chelating a radionuclide and is one of 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).

2. The RGD dimer compound according to claim 1, characterized in that the structure of the RGD dimer compound represented by formula (I-1) is any one of the structures represented by the following formulas (II-1) to (II-16):

3. A radionuclide-labeled compound comprising: A radionuclide-labeled compound, characterized in that it is obtained by using the compound of formula (I-1) according to any one of claims 1 and 2 as a ligand and chelating a radioisotope to the group W capable of chelating the radionuclide.

4. 4. The radionuclide-labeled compound according to claim 3, wherein the radioisotope is an α-ray emitting isotope, a β-ray emitting isotope, a γ-ray emitting isotope, an Auger electron emitting isotope, or an X-ray emitting isotope.

5. The radioisotope is 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 4. The radionuclide-labeled compound of claim 3, wherein the radionuclide-labeled compound is any one of: Ag.

6. The radioisotope is １８ F. ６４ Cu, ６８ Ga, ８９ Zr, ９０ Y. １１１ In, ９９ｍ Tc, １７７ Lu, １８８ Re, or ２２５ 4. The radionuclide-labeled compound of claim 3, wherein the compound is Ac.

7. 1. A pharmaceutical composition comprising or consisting of: i) an RGD dimer compound according to claim 1 or 2, or a radionuclide-labeled compound according to claim 3; and ii) at least one pharmaceutically acceptable carrier and / or excipient.

8. Integrin alpha in animal or human subjects ｖ β ３ 10. Use of the RGD dimer compound of any one of claims 1 to 2, the radionuclide-labeled compound of any one of claims 3 to 6, or the pharmaceutical composition of claim 7 in the preparation of a medicament for diagnosing or treating a disease characterized by overexpression of

9. The integrin α ｖ β ３ 9. The use according to claim 8, wherein the disease characterized by overexpression of is lung cancer, glioma, neuroglioma, breast cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, head and neck cancer, ovarian cancer, hepatocellular carcinoma, esophageal cancer, hypopharyngeal cancer, nasopharyngeal carcinoma, laryngeal cancer, myeloma cells, bladder cancer, bile duct cancer, clear cell renal carcinoma, neuroendocrine tumors, oncogenetic osteomalacia, sarcoma, CUP (cancer of unknown primary), thymic carcinoma, astrocytoma, cervical cancer, or prostate cancer.

10. A kit comprising or consisting of the RGD dimer compound according to any one of claims 1 to 2, the radionuclide-labeled compound according to any one of claims 3 to 6, or the pharmaceutical composition according to claim 7.

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