Compounds targeting SSTR2, and methods for their preparation and use - Patents.com

Abstract

The present invention relates to a compound that targets SSTR2, as well as its preparation method and use, which relate to the fields of nuclear medicine and molecular imaging. The structure of the compound that targets SSTR2 is shown in the following formula (I), and the structure of the compound that can be labeled with a radionuclide and targets SSTR2 is shown in the following formula (II). The present invention further provides a radionuclide-labeled compound that targets SSTR2, obtained by labeling the compound represented by formula (II) with a radionuclide. The present invention provides methods for preparing the compounds represented by formula (I) and formula (II), and their use in preparing drugs for diagnosing and / or treating diseases characterized by SSTR2 overexpression. [Formula 1] JPEG2025540268000012.jpg90170

Description

[Technical Field]

[0001] The present invention relates to the fields of nuclear medicine and molecular imaging, and in particular to compounds that target SSTR2, as well as methods for their preparation and use. [Background technology]

[0002] Somatostatin receptors (SSTRs) are glycoproteins and G protein-coupled receptors with five subtypes, SSTR1-SSTR5. SSTRs affect intracellular cAMP levels by regulating the activity of adenylate cyclase (AC), thereby transducing exogenous signals into the cell. SSTRs are involved in regulating the secretion of multiple hormones and are associated with processes such as tumor growth and proliferation. Researchers have found high SSTR expression in various tumor tissues, with somatostatin receptor 2 (SSTR2) being the most highly expressed. SSTR2 can participate in many cell signaling pathways in living organisms, including GPCR downstream signaling and the adenylate cyclase inhibitor pathway. By changing its structure, it activates downstream signaling molecules, thereby regulating many physiological and pathological response processes in the body. SSTR2 is frequently highly expressed in various tumor cells, especially neuroendocrine tumors. Given its widespread expression and important role in tumors, SSTR2 has become an important target for tumor imaging and therapy.

[0003] In recent years, peptide receptor radionuclide therapy (PRRT) has attracted widespread attention. Radionuclide-labeled peptide ligands specifically bind to receptors that are highly expressed in tumor cells, transporting the chelated radionuclide into the cells or adsorbing it to the cell surface, causing damage to tumor cells through alpha or beta rays emitted by the decay of the radionuclide. 177Lu-DOTA-TATE (Lu-DOTA-TATE), the first PRRT targeting somatostatin receptor 2, was approved by the FDA in 2018 and is used to treat unresectable or metastatic neuroendocrine tumors in the United States and several European countries. However, its rapid clearance from the blood (mainly through the kidneys) significantly reduces the dose reaching the tumor tissue and increases nephrotoxicity.

[0004] Previous studies have shown that long-acting somatostatin analogs 177 Lu-EB-TATE has been disclosed. This is an azo dye (shortened EB) with high affinity for albumin introduced into the side chain of Lutathera, which reversibly binds to albumin in vivo and extends the blood half-life to 9.47 hours, approximately four times longer than Lutathera. 177 Lu-EB-TATE utilizes a maleimide-thiol coupling method to form a thiosuccinimide bond, which offers advantages such as high selectivity, fast reaction rate, and mild reaction conditions. However, the thiosuccinimide bond is easily removed by reverse Michael reaction or thiol exchange under physiological conditions or in the presence of free thiols, resulting in reduced in vivo stability. It is well known in the art that rupture of the succinimide bond results in separation of the targeting moiety from the nuclide chelating moiety, resulting in incomplete targeting of the nuclide. Long-circulating PRRT drugs, in particular, require higher in vivo stability to ensure complete binding to highly expressed receptors at tumor sites due to their long blood circulation time. Therefore, to meet the needs of nuclide therapy and imaging, it is necessary to improve the coupling of EB-TATE, increase its in vivo stability, and increase its tumor uptake. Summary of the Invention [Problem to be solved by the invention]

[0005] In view of the above background, in order to solve the problem of poor in vivo stability of peptide receptor radionuclide therapeutics, the main objective of the present invention is to develop a novel radionuclide-labeled compound targeting SSTR2, which has improved in vivo stability and increased tumor uptake by coupling the EB moiety and TATE moiety through an amide bond.

[0006] Another object of the present invention is to provide a process for the preparation of said novel compounds by a simple and efficient synthetic route.

[0007] A further object of the present invention is to provide the use of said compounds in the diagnosis or treatment of diseases characterized by SSTR2 overexpression. [Means for solving the problem]

[0008] The above object of the present invention is achieved by the following technical solutions.

[0009] In a first aspect, the present invention provides a compound capable of targeting SSTR2, having a structure represented by formula (I), which comprises both an SSTR2-binding ligand and a truncated Evans Blue in its structure (i.e., truncated EB), and wherein the SSTR2-binding ligand and the truncated Evans Blue are linked via a flexible connecting arm comprising an amide bond. [ka]

[0010] In a second aspect, the present invention provides a compound that can be labeled with a radionuclide that targets SSTR2, the compound comprising an SSTR2-binding ligand, a truncated Evans Blue, a flexible connecting arm, and a radionuclide chelating structure all in its structure, the structure of the compound being represented by the following formula (II): [ka]

[0011] In a third aspect, the present invention provides a radionuclide-labeled compound that targets SSTR2, which is a compound according to the second aspect of the invention having the structure of formula (II) labeled with a radionuclide.

[0012] In this aspect of the invention, the radionuclide may be an alpha-emitting isotope, a beta-emitting isotope, a gamma-emitting isotope, an Auger electron-emitting isotope, or an X-ray-emitting isotope, for example. 51 Cr, 67 Ga, 68 Ga, 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, 64 Cu, 67 Cu, 198 Au, 225 Ac, 227 Th, 89 Zr, or 199The radionuclide may be any one selected from Ag, but more preferably 177 Lu, 225 Ac, 68 Ga, 64 Cu, 89 Zr, 90 Y, 99m Tc, 188 Re, or 111 In.

[0013] In a fourth aspect, the present invention provides a method for preparing a radionuclide-labeled compound targeting SSTR2 according to the third aspect, the preparation method according to the present invention comprising the following steps (1) and (2):

[0014] (1) 10.05 g of 2-CTC resin was used as a starting material. After swelling, 10.78 g of Fmoc-O-tert-butyl-L-threonine and 11.17 g of N,N-diisopropylethylamine were added. After the reaction, the resin was first rinsed with dichloromethane, then reacted with dichloromethane, methanol, and N,N-diisopropylethylamine to cap the ends, washed with dichloromethane, methanol, and N,N-dimethylformamide in that order, and then washed with 20% piperidine in N,N-dimethylformamide. The Fmoc group was removed by adding 100 mL of amide solution, and the mixture was washed. 6.84 g of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, 0.23 g of 1-hydroxybenzotriazole (HOBT), 10.55 g of Fmoc-S-trityl-L-cysteine, and 2.37 g of N,N-diisopropylethylamine were added. After the reaction was completed, the mixture was filtered with suction, washed with dichloromethane, methanol, and N,N-dimethylformamide in that order, and then 20 mL of dimethylformamide was added. The Fmoc group was removed by adding 100 mL of a 100% piperidine N,N-dimethylformamide solution, and the mixture was washed with 6.84 g of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, 0.18 g of 1-hydroxybenzotriazole, 7.17 g of Fmoc-O-tert-butyl-L-threonine, and 2.37 g of N,N-diisopropylethylamine. After the reaction was completed, the mixture was filtered with suction and purified by dichloromethane, methanol, and N,N-dimethylformamide. The mixture was washed with 2,000 ml of 20% piperidine in N,N-dimethylformamide, and then 100 ml of a 20% solution of piperidine in N,N-dimethylformamide was added to remove the Fmoc group. After washing, the mixture was added with 6.84 g of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, 0.18 g of 1-hydroxybenzotriazole, 8.45 g of Nε-(tert-butyloxycarbonyl)-Nα-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-lysine, and 2.0 g of N,N-diisopropylethylamine.After the reaction was completed, the mixture was filtered with suction, washed with dichloromethane, methanol, and N,N-dimethylformamide in that order, and then 100 mL of 20% piperidine N,N-dimethylformamide solution was added to remove the Fmoc group. After washing, 6.84 g of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, 0.12 g of 1-hydroxybenzotriazole, 1-[(1,1-dimethylethoxy)carbonyl]-N-[(9H-fluorene-9-methoxy)carbonyl]-D-tryptophan was obtained. 9.48 g of ethanol and 2.37 g of N,N-diisopropylethylamine were added, and after the reaction was completed, the mixture was filtered by suction, washed with dichloromethane, methanol, and N,N-dimethylformamide in that order, and then 100 mL of 20% piperidine N,N-dimethylformamide solution was added to remove the Fmoc group. After washing, 6.84 g of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, 0.18 g of 1-hydroxybenzotriazole, 8.28 g of Fmoc-O-tert-butyl-L-tyrosine were added. After the reaction was completed, the mixture was filtered with suction, washed with dichloromethane, methanol, and N,N-dimethylformamide in that order, and then 100 mL of 20% piperidine N,N-dimethylformamide solution was added to remove the Fmoc group. After washing, 6.84 g of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, 0.23 g of 1-hydroxybenzotriazole, 10.55 g of Fmoc-S-trityl-L-cysteine, and N,N- 2.37 g of diisopropylethylamine was added, and after the reaction was complete, the mixture was filtered under suction and washed successively with dichloromethane, methanol, and N,N-dimethylformamide. 100 mL of 20% piperidine N,N-dimethylformamide solution was added to remove the Fmoc group, and after washing, 6.84 g of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, 0.14 g of 1-hydroxybenzotriazole, 6.97 g of Fmoc-D-phenylalanine, and 2.0 g of N,N-diisopropylethylamine were added.After the reaction is complete, the mixture is filtered with suction, washed with dichloromethane, methanol, and N,N-dimethylformamide in that order, and 200 mL of N,N-dimethylformamide is added. Next, a mixture of 8.44 g of iodine, 10 mL of methanol, and 10 mL of N,N-dimethylformamide is added to remove the Trt protection and cyclize the product. After removing the Fmoc protection with 100 mL of 20% piperidine N,N-dimethylformamide solution, the product is washed and added with 60 mL of N,N-dimethylformamide and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyl-N, ... 3.42 g of methyluronium hexafluorophosphate, 1.16 g of N,N-diisopropylethylamine, and 7.43 g of (S)-5-((4'-amino-3,3'-dimethyl-[1,1'-diphenyl]-4-yl)carbonyl)-1-(9H-fluoren-9-yl)-3,11-dioxy-2,14,17 trioxo-4,10-diazaeicosan-20-oic acid were added, and after the reaction was completed, the mixture was filtered with suction, washed with dichloromethane, methanol, and N,N-dimethylformamide in that order, and then with 20% piperidine N,N-dimethylformamide solution. The Fmoc group was removed by adding 100 mL of N,N-dimethylformamide solution, and 8.44 g of 2,2',2''-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate tri-tert-butyl were added after washing. After the reaction was completed, the mixture was filtered by suction. The resin was then cleaved with 200 mL of a 20% solution of hexafluoroisopropanol in dichloromethane. The solvent was then evaporated by rotary evaporation, followed by acetonitrile, water, and 2 M HCl solution. Add 4.5 mL of the product, add 25 mL of N,N-dimethylformamide, dissolve, cool, add 0.75 g of an aqueous solution of sodium nitrite, and add 3.38 g of 1-amino-8-naphthol-2,4-disulfonic acid monosodium salt and 11.34 g of an aqueous solution of sodium bicarbonate at low temperature. After the reaction is complete, the solvent is evaporated by rotary evaporation, and the intermediate is obtained by purification through preparative separation. The obtained intermediate is then added to a 95% aqueous solution of trifluoroacetic acid for deprotection, and purified through preparative liquid phase separation to obtain the desired product, i.e., the compound having the structure represented by formula (II) described in the second aspect of the present invention.

[0015] (2) The radionuclide-labelable compound and radionuclide-containing compound obtained in step (1) are reacted by a wet labeling method or a freeze-drying labeling method to prepare a radionuclide-labeled compound targeting SSTR2 according to the third aspect of the present invention.

[0016] In a fifth aspect, the present invention provides a pharmaceutical composition comprising a radionuclide-labelable compound that targets SSTR2 as described in the second aspect of the invention, or a radionuclide-labeled compound that targets SSTR2 as described in the third aspect of the invention, or a pharmaceutically acceptable hydrate, solvate, or salt thereof.

[0017] In a sixth aspect, the present invention further provides the use of a radionuclide-labellable compound targeted to SSTR2 according to the second aspect of the invention, a radionuclide-labelled compound targeted to SSTR2 according to the third aspect of the invention, or a pharmaceutical composition according to the fifth aspect, in the preparation of a medicament for diagnosing or treating a disease characterised by SSTR2 overexpression in an animal or human individual.

[0018] In the use according to the present invention, said diseases characterized by SSTR2 overexpression include, but are not limited to, neuroendocrine tumors, gastrointestinal tumors, lung cancer, hepatocellular carcinoma, nasopharyngeal carcinoma, breast cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, head and neck cancer, ovarian cancer, esophageal cancer, hypopharyngeal cancer, laryngeal cancer, myeloma cells, bladder cancer, cholangiocarcinoma, clear cell renal cell carcinoma, oncogeneic osteomalacia, sarcoma, CUP (cancer of unknown primary), thymic carcinoma, glioma, glioma, astrocytoma, cervical cancer, or prostate cancer. [Effects of the Invention]

[0019] The compounds targeting SSTR2 according to the present invention have higher in vivo stability and a relatively long blood circulation time compared to conventional techniques, and can therefore exhibit excellent metabolic kinetics, high tumor uptake, and tumor retention time, and are expected to be applied to the diagnosis or treatment of diseases characterized by overexpression of SSTR2.

[0020] Furthermore, the method for preparing the compound targeting SSTR2 according to the present invention employs a combination of solid-phase synthesis and liquid-phase synthesis, which has a simple reaction pathway, simple operation, short synthesis cycle, high yield, and is suitable for industrial scale-up production. [Brief explanation of the drawings]

[0021] [Figure 1] FIG. 1 is a liquid phase diagram of TATE-EB-01 in Example 1 of the present invention. [Figure 2] 1 is a mass spectrum of TATE-EB-01 in Example 1 of the present invention. [Figure 3] Figure 1 shows the results of cellular uptake of the 177Lu-labeled TATE-EB-01 conjugate of the present invention, where A shows the results of a cellular uptake experiment of 177Lu-TATE-EB-01 in AR42J tumor cells and the results of cellular uptake when blocked with TATE-EB-01, and B shows the results of a competitive binding experiment of TATE-EB-01 and DOTA-TATE in AR42J tumor cells. [Figure 4] 1 shows MicroPET imaging results at various times after injection of 68Ga-labeled TATE-EB-01 conjugate according to the present invention, and statistics of tumor and vital organ uptake results. [Figure 5] 1 shows statistics of MicroPET imaging results and tumor and vital organ uptake results at various times after injection of 68Ga-labeled EB-TATE. [Figure 6] 6A-6C are statistics of MicroPET imaging results and tumor and vital organ uptake results at various times after injection of 68Ga-DOTA-TATE. [Figure 7] MicroPET imaging results of an inhibition experiment in which unlabeled TATE-EB-01 and 68Ga-DOTA-TATE were co-injected into AR42J tumor mice are shown. [Figure 8] 1 shows statistics of SPECT imaging results and tumor and vital organ uptake results at various times after injection of 177Lu-labeled TATE-EB-01 conjugate. [Figure 9] 1 shows statistics of SPECT imaging results and tumor and vital organ uptake results at various times after injection of 177Lu-EB-TATE. [Figure 10] 1 shows the biodistribution of 177Lu-TATE-EB-01 of the present invention in major organs and tumor tissues of AR42J tumor-bearing mice at 1, 4, 24, 48, 72, and 96 hours after injection. [Figure 11] 1 shows the biodistribution of 177Lu-EB-TATE in major organs and tumor tissues of AR42J tumor-bearing mice at 1, 4, 24, 48, and 96 hours after injection. [Figure 12] 1 shows the biodistribution of 177Lu-DOTA-TATE in major organs and tumor tissues of AR42J tumor-bearing mice at 1, 4, 24, and 48 hours after injection. [Figure 13] Figure 1 shows the in vitro and in vivo stability of the 68Ga-labeled TATE-EB-01 conjugate of the present invention, where (A) shows the stability of 68Ga-TATE-EB-01 after 2 hours of incubation in saline and glutathione solution, respectively, and after 2 hours of in vivo urinary metabolism in mice, as determined by HPLC analysis; (B) shows the stability of 68Ga-EB-TATE after 2 hours of incubation in saline and glutathione solution, respectively, and after 2 hours of in vivo urinary metabolism in mice, as determined by HPLC analysis. DETAILED DESCRIPTION OF THE INVENTION

[0022] Hereinafter, the technical solutions of the present invention will be explained and described step by step through specific embodiments and with reference to the drawings.

[0023] The codes and structures of the main compounds according to this example are as follows:

[0024] [Table 1]

[0025] Example 1 Preparation of Compound II

[0026] Synthesis of intermediate 21 according to the Fmoc solid-phase synthesis strategy: 10.05 g of 2-CTC resin was used as the starting material. After swelling, 10.78 g of Fmoc-O-tert-butyl-L-threonine (Fmoc-Thr(tBu)-OH) and 11.17 g of N,N-diisopropylethylamine were added. After reaction, intermediate 1 was obtained. The resin was rinsed with dichloromethane, and then reacted with dichloromethane, methanol, and N,N-diisopropylethylamine to cap the ends. The reaction mixture was washed with dichloromethane, methanol, and N,N-dimethylformamide in this order. 100 mL of 20% piperidine in N,N-dimethylformamide was added to remove the Fmoc group, and intermediate 2 was obtained. After washing, 6.84 g of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, 0.23 g of 1-hydroxybenzotriazole (HOBT), 10.55 g of Fmoc-S-trityl-L-cysteine, and 2.37 g of N,N-diisopropylethylamine were added, and after the reaction was completed, the mixture was filtered by suction to obtain intermediate 3. The mixture was washed successively with dichloromethane, methanol, and N,N-dimethylformamide, and further, 100 mL of 20% piperidine N,N-dimethylformamide solution was added to remove the Fmoc group to obtain intermediate 4. After washing, 6.84 g of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, 0.18 g of 1-hydroxybenzotriazole, 7.17 g of Fmoc-O-tert-butyl-L-threonine, and 2.37 g of N,N-diisopropylethylamine were added, and after the reaction was completed, the mixture was filtered by suction to obtain intermediate 5. The mixture was washed successively with dichloromethane, methanol, and N,N-dimethylformamide, and further, 100 mL of 20% piperidine N,N-dimethylformamide solution was added to remove the Fmoc group, to obtain intermediate 6.After washing, 6.84 g of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, 0.18 g of 1-hydroxybenzotriazole, 8.45 g of Nε-(tert-butyloxycarbonyl)-Nα-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-lysine, and 2.37 g of N,N-diisopropylethylamine were added, and after the reaction was completed, the mixture was filtered by suction to obtain intermediate 7. The mixture was washed successively with dichloromethane, methanol, and N,N-dimethylformamide, and further, 100 mL of 20% piperidine N,N-dimethylformamide solution was added to remove the Fmoc group, to obtain intermediate 8. After washing, 6.84 g of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, 0.12 g of 1-hydroxybenzotriazole, 9.48 g of 1-[(1,1-dimethylethoxy)carbonyl]-N-[(9H-fluorene-9-methoxy)carbonyl]-D-tryptophan, and 2.37 g of N,N-diisopropylethylamine were added, and after the reaction was completed, the mixture was filtered by suction to obtain intermediate 9. The mixture was washed successively with dichloromethane, methanol, and N,N-dimethylformamide, and further, 100 mL of 20% piperidine-N,N-dimethylformamide solution was added to remove the Fmoc group, yielding intermediate 10. After washing, 6.84 g of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, 0.18 g of 1-hydroxybenzotriazole, 8.28 g of Fmoc-O-tert-butyl-L-tyrosine, and 2.37 g of N,N-diisopropylethylamine were added, and after the reaction was completed, the mixture was filtered by suction to obtain intermediate 11. The mixture was washed successively with dichloromethane, methanol, and N,N-dimethylformamide, and further, 100 mL of 20% piperidine N,N-dimethylformamide solution was added to remove the Fmoc group to obtain intermediate 12.After washing, 6.84 g of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, 0.23 g of 1-hydroxybenzotriazole, 10.55 g of Fmoc-S-trityl-L-cysteine, and 2.37 g of N,N-diisopropylethylamine were added, and after the reaction was completed, the mixture was filtered by suction to obtain intermediate 13. The mixture was washed successively with dichloromethane, methanol, and N,N-dimethylformamide, and further, 100 mL of 20% piperidine N,N-dimethylformamide solution was added to remove the Fmoc group to obtain intermediate 14. After washing, 6.84 g of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, 0.14 g of 1-hydroxybenzotriazole, 6.97 g of Fmoc-D-phenylalanine, and 2.37 g of N,N-diisopropylethylamine were added. After the reaction was completed, the mixture was filtered under suction to obtain intermediate 15. The mixture was washed successively with dichloromethane, methanol, and N,N-dimethylformamide, and 200 mL of N,N-dimethylformamide was added. Next, a mixture of 8.44 g of iodine, 10 mL of methanol, and 10 mL of N,N-dimethylformamide was added to remove the Trt protection and cyclize the product to obtain intermediate 16. Fmoc protection was then removed using 100 mL of a 20% piperidine solution in N,N-dimethylformamide to obtain intermediate 17. After washing, 60 mL of N,N-dimethylformamide, 3.42 g of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1.16 g of N,N-diisopropylethylamine, and 7.43 g of (S)-5-((4'-amino-3,3'-dimethyl-[1,1'-diphenyl]-4-yl)carbonyl)-1-(9H-fluoren-9-yl)-3,11-dioxy-2,14,17-trioxo-4,10-diazaeicosan-20-oic acid were added, and after the reaction was completed, the mixture was filtered with suction to obtain intermediate 18. The mixture was washed successively with dichloromethane, methanol, and N,N-dimethylformamide, and then 100 mL of 20% piperidine-N,N-dimethylformamide solution was added to remove the Fmoc group, yielding intermediate 19.After washing, 60 mL of N,N-dimethylformamide solution and 8.44 g of tri-tert-butyl 2,2',2''-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate were added, and after the reaction was completed, the mixture was filtered under suction to obtain intermediate 20. Next, the resin was cleaved with 200 mL of a 20% solution of hexafluoroisopropanol in dichloromethane to obtain intermediate 20' (i.e., intermediate 20 cut from the resin). After rotary evaporation of the solvent, acetonitrile, water, and 4.5 mL of 2 M HCl solution were added, followed by the addition of 25 mL of N,N-dimethylformamide to dissolve the mixture. The temperature was lowered, and 0.75 g of aqueous sodium nitrite solution was added. At low temperature, 3.38 g of 1-amino-8-naphthol-2,4-disulfonic acid monosodium salt and 11.34 g of aqueous sodium bicarbonate solution were added. After the reaction was completed, the solvent was rotary evaporated, and the mixture was purified by preparative separation to obtain intermediate 21. The resulting intermediate 21 was then added to 200 mL of 95% aqueous trifluoroacetic acid solution for deprotection, and purified by preparative liquid phase separation to obtain the desired product, TATE-EB-01 (i.e., the compound of Formula II described in the present invention). Figure 1 shows the liquid phase diagram of TATE-EB-01 in this example. Figure 2 shows the mass spectrum of TATE-EB-01 in this example. The theoretical molecular weight [M+K-3H] was calculated. 2- / 2=1155.89235, actual molecular weight [M+K-3H] 2- / 2=1155.88451.

[0027] The synthetic route for the above steps is as follows: [ka] JPEG2025540268000006.jpg129170JPEG2025540268000007.jpg81170JPEG2025540268000008.jpg141170JPEG2025540268000009.jpg98170

[0028] Example 2 Radioactive Ga-68 labeled TATE-EB-01 complex ( 68Preparation of Ga-TATE-EB-01

[0029] Wet: Approximately 18.5 to 1850 megabecquerels (MBq) 68 The GaCl3 hydrochloric acid solution (rinsed from the germanium gallium generator) was added to a centrifuge tube containing 0.5 mL of the acetic acid-acetate salt solution (1.0 g / L) of the compound TATE-EB-01 prepared in Example 1, and the mixture was reacted at 95°C for 20 minutes. 18 The separation column was prepared by first slowly rinsing with 10 mL of absolute ethanol and then with 10 mL of water. After diluting the labeling solution with 10 mL of water, it was injected into the separation column. 68 The Ga ions were removed, and then the sample was rinsed with 0.3 mL of a 10 mM HCl ethanol solution. 68 The rinsing solution was diluted with saline and sterile filtered to obtain the Ga-labeled complex. 68 Injection solution of Ga-labeled TATE-EB-01 complex ( 68 Ga-TATE-EB-01) was obtained.

[0030] Freeze-drying method: Approximately 18.5 to 1850 megabecquerels (MBq) 68 The GaCl3 hydrochloric acid solution (rinsed from the germanium gallium generator) was added to the freeze-drying case containing the compound TATE-EB-01, mixed uniformly, and then reacted at 95°C for 20 minutes. A C18 separation column was prepared and first slowly rinsed with 10 mL of absolute ethanol, then rinsed with 10 mL of water. The labeling solution was diluted with 10 mL of water, and then injected into the separation column. First, the unlabeled solution was diluted with 10 mL of water. 68 The Ga ions were removed, and then the complex was rinsed with 0.3 mL of 10 mM HCl in ethanol to obtain a rinse solution. This rinse solution was diluted with saline and sterile filtered to obtain a rinsing solution. 68 Injection solution of Ga-labeled TATE-EB-01 complex ( 68 Ga-TATE-EB-01) was obtained.

[0031] Example 3 Radioactive Lu- 177 Labeled TATE-EB-01 complex ( 177Preparation of Lu-TATE-EB-01

[0032] Preparation of pH 5.5 buffer solution: 57.6 mg of acetic acid, 189 mg of gentisic acid, and 525 mg of sodium acetate trihydrate were weighed and dissolved in 48 ml of pure water, and the pH was adjusted to 5.5 with sodium hydroxide solution. 200 μg of compound TATE-EB-01 prepared in Example 1 was thoroughly dissolved in 200 μL of buffer solution (pH 5.5), and then 5 ml of buffer solution (pH 5.5) and approximately 150 mCi of 177 A solution of LuCl3 in hydrochloric acid was added. The mixture was shaken evenly and heated at 80°C for 20 minutes. After the reaction was completed, it was cooled to room temperature. The reaction solution was diluted with saline, sterile filtered, and diluted with 10 mCi / mL of HCl. 177 Injection solution of Lu-labeled TATE-EB-01 complex ( 177 Lu-TATE-EB-01) was obtained.

[0033] Experimental Example 1: Cellular uptake experiment

[0034] In cell uptake experiments, 2 × 10 5 AR42J tumor cells were seeded in 24-well plates and allowed to adhere overnight, after which the cells were treated with 37 kBq of ATP prepared in Example 3. 177 The cells were incubated with Lu-TATE-EB-01 in 0.5 mL of culture medium at 37°C for 0.16, 0.5, 2, 4, and 24 hours. In blocking experiments, unlabeled TATE-EB-01 (50 μg / mL) was added as an inhibitor to confirm its target specificity. In competitive binding experiments, AR42J tumor cells were incubated with various concentrations (10 -5 ~10 -12 M) unlabeled TATE-EB-01 (i.e., a compound of formula II according to the present invention), or DOTA-TATE and 177 Lu-DOTA-TATE (i.e., 177 The cells were incubated with Lu-labeled DOTA-TATE for 1 hour. The supernatant was then removed, and the AR42J tumor cells were washed twice with ice-cold PBS and lysed with 1 M NaOH solution. The cell lysates were collected and their radioactivity was measured using a gamma counter. 177The cellular uptake of Lu-TATE-EB-01 gradually increased over time, reaching a maximum value of 36.96 ± 1.60% at 24 hours. The addition of unlabeled TATE-EB-01 as an inhibitor reduced the cellular uptake to 3.37 ± 0.17%, demonstrating the relatively high binding specificity of these compounds to SSTR2 (see Figure 3A). Furthermore, the IC of TATE-EB-01 was significantly higher than that of TATE-EB-01. 50 The IC value was 20.39 nM, and the IC value for DOTA-TATE 50 The value was 11.48 nM, indicating that both TATE-EB-01 and DOTA-TATE have similar affinities for the SSTR2 receptor (see Figure 3B), which means that the modification strategy had little effect on the binding affinity of the SSTR2 receptor.

[0035] Experimental Example 2: In vivo analysis of tumor-bearing mice 68 MicroPET imaging of Ga-labeled TATE-EB-01 complex

[0036] According to the method of Example 2 68 Ga-TATE-EB-01 was prepared and administered to the tail vein of randomly assigned AR42J tumor-bearing mice at a dose of 7.4 MBq each. 68 Ga-TATE-EB-01, 68 Ga-EB-TATE (i.e., 68 Ga-labeled EB-TATE) and 68 Ga-DOTA-TATE (i.e., 68 The mice were then anesthetized 0-240 min after injection and placed in a PET / CT scanner for MicroPET imaging. 68 Ga-DOTA-TATE was injected into AR42J tumor-bearing mice simultaneously, followed by PET scans. The results are shown in Figures 4, 5, 6, and 7. Part A in Figures 4 to 6 indicates the 68 Ga-TATE-EB-01, 68 Ga-EB-TATE, and 68PET imaging images taken 0.5, 2, and 4 hours after Ga-DOTA-TATE was injected into AR42J tumor-bearing mice. Part B in Figures 4 to 6 shows the tumor-bearing tumors in the mice. 68 Ga-TATE-EB-01, 68 Ga-EB-TATE, and 68 6A-6C are bar graphs showing quantitative analysis of uptake values ​​in major organs and tissues after intravenous injection of Ga-DOTA-TATE (quantitative analysis was performed on three mice per group). As can be seen in part A of Figures 4-6, tumors were clearly visible at the time of collection and imaging. As can be seen in part B of Figures 4-6, 68 The uptake of Ga-TATE-EB-01 into the tumor reached 16.08±1.26%ID / g at 2 hours after injection and 22.42±1.28%ID / g at 4 hours after injection, which was significantly higher than the uptake in normal tissues (see Figure 4). 68 The signal of Ga-EB-TATE is 68 The tumor uptake values ​​at 2 and 4 hours post-injection were significantly lower than that of Ga-TATE-EB-01, with values ​​of 8.67±1.46%ID / g and 12.25±1.52%ID / g, respectively (see Figure 5). 68 For Ga-DOTA-TATE, tumor uptake was 7.33±1.91%ID / g and 6.67±1.94%ID / g at 2 and 4 hours after injection, respectively (see Figure 6). To evaluate targeting specificity, unlabeled TATE-EB-01 and 68 Inhibition experiments were performed by co-injecting Ga-DOTA-TATE into AR42J tumor-bearing mice. The results showed that unlabeled TATE-EB-01 could significantly inhibit tumor uptake (see parts A and B in Figure 7). The corresponding quantitative results of tumor drug uptake are shown in parts C and D in Figure 7. Compared with the PET imaging without inhibition described above, the tumor uptake values ​​in the TATE-EB-01 inhibition group were significantly lower.

[0037] Experimental Example 3 In vivo in tumor-bearing mice 177SPECT imaging of Lu-labeled TATE-EB-01 complex

[0038] According to the method of Experimental Example 3, 177 Lu-labeled TATE-EB-01 was prepared and administered at a dose of 37 MBq into the tail vein of randomly assigned AR42J tumor-bearing mice. 177 Lu-TATE-EB-01 and 177 Lu-EB-TATE (i.e., 177 Lu-labeled EB-TATE was injected. SPECT imaging was then performed 1 to 96 hours after administration under isoflurane anesthesia. The results are shown in Figures 8 and 9. Part a) of Figures 8 and 9 shows the results of SPECT imaging. 177 Lu-TATE-EB-01 and 177 Maximum density projection images of SPECT imaging of AR42J tumor-bearing mice at various times after injection of Lu-EB-TATE. At each time point of acquisition and imaging, two groups of tumors were clearly visible. 177 The SPECT imaging effect of Lu-TATE-EB-01-injected mice was better at each time point. Part b) of Figure 8 and Figure 9 shows the SPECT imaging results of various organs or tissues (blood, liver, kidney, tumor, and muscle) at various time points after intravenous injection into mice. 177 Lu-TATE-EB-01 and 177 The uptake of Lu-EB-TATE is shown. The three uptake values ​​for each group correspond to 1, 4, 12, 24, 48, 72, and 96 hours after injection, from left to right. The distribution of the two drugs in the blood, liver, kidney, and muscle at the same time points was relatively similar, but the distribution in the tumor was significantly different. 177 Lu-TATE-EB-01 uptake was significantly higher at all time points. 177 It was found that the levels were significantly higher than those of Lu-EB-TATE. 177 Lu-TATE-EB-01 and 177 The target / non-target ratio at various time points after intravenous injection of Lu-EB-TATE is shown. 177The ratio of tumor to normal organs at each time point in the Lu-TATE-EB-01 group was also 177 The results showed that the EB-TATE group had significantly higher blood glucose levels than the Lu-EB-TATE group. 177 The tumor-to-muscle ratio of Lu-TATE-EB-01 was over 120, 177 The tumor-to-muscle ratio in the Lu-EB-TATE group was less than 50. Therefore, whether in terms of absolute tumor uptake or target / non-target ratio, 177 Lu-TATE-EB-01 is 177 The compound targeting SSTR2 and its radionuclide marker described in the present invention exhibit excellent metabolic kinetics, high tumor uptake, and tumor retention time, and are expected to be useful in the diagnosis or treatment of diseases characterized by overexpression of SSTR2.

[0039] Experimental Example 4 Biodistribution

[0040] In a biodistribution study, AR42J tumor-bearing mice were treated with the 177 Lu-TATE-EB-01, 177 Lu-EB-TATE, or 177 Lu-DOTA-TATE (i.e., 177 1.48 MBq of Lu-labeled DOTA-TATE was intravenously injected into each mouse, and the mouse was dissected at various time points to collect and weigh the target organs and tumor tissues. Radioactivity was detected using a gamma counter, and the biodistribution results were calculated as the percentage of injected dose per gram of tissue (%ID / g). The results are shown in Figure 10. 177 For Lu-TATE-EB-01, tumor uptake gradually increased over time, reaching a peak at 72 hours after injection, with an uptake value of 158.32 ± 20.04%ID / g. The tumor uptake value remained high at 112.44 ± 20.57%ID / g even 96 hours after injection, far exceeding the uptake values ​​in other organs, including the kidney (15.15 ± 6.20%ID / g), as shown in Figure 11.177 The tumor uptake value of LuEB-TATE (37.28 ± 9.50%ID / g at 96 h) was 177 It was observed that the value was much lower than that of Lu-TATE-EB-01. 177 Lu-DOTA-TATE showed the lowest tumor uptake, with only 9.19±2.16% ID / g at 48 hours after injection, and continued to decrease from 4 hours after injection. These results support the present invention. 177 It shows that Lu-TATE-EB-01 has the highest tumor uptake and best biodistribution compared with the other two markers.

[0041] Experimental Example 5 Stability test

[0042] To investigate the reason for the difference in distribution of radiolabeled TATE-EB-01 and EB-TATE in the animals, 68 Ga-TATE-EB-01 and 68 Ga-EB-TATE was incubated in vitro in saline and glutathione solutions for 2 hours, respectively, and analyzed using radioactive high-performance liquid chromatography. 68 Ga-TATE-EB-01 and 68 Ga-EB-TATE was injected into BALB / c nude mice, and urine samples were collected after 2 hours and analyzed by radioactive high performance liquid chromatography. As shown in Figure 13, even after being left in the glutathione solution and urine for 2 hours, 68 Ga-TATE-EB-01 maintained almost the same shape as the original drug substance, and its radiochemical purity remained above 99%. However, the 68 The 2-hour stability of Ga-EB-TATE was poor, with multiple by-product peaks being generated and the radiochemical purity of the main peak being significantly reduced. 68 Ga-EB-TATE has been shown to be less stable in vitro in the reducing environment of glutathione and in vivo, with by-products being generated as quickly as 2 hours after injection, which may indirectly explain the poor pharmacokinetics of the probe in vivo.

[0043] Although the present invention has been described in detail above using general descriptions, specific embodiments, and tests, it is obvious to those skilled in the art that some modifications or improvements can be made based on the present invention. Therefore, any such modifications or improvements made without departing from the spirit of the present invention should fall within the scope of the claims of the present invention.

Claims

1. A compound that targets SSTR2, A compound comprising both an SSTR2-binding ligand and a truncated Evans Blue in its structure, wherein the SSTR2-binding ligand and the truncated Evans Blue are linked via a flexible connecting arm comprising an amide bond, and wherein the compound has a structure represented by formula (I): 【Chemistry 1】

2. A compound that can be labeled with a radionuclide that targets SSTR2, A compound comprising an SSTR2 binding ligand, a truncated Evans blue, a flexible connecting arm and a nuclide chelating structure all in its structure, the structure of the compound being represented by the following formula (II): 【Chemistry 2】

3. The method for preparing a compound that can be labeled with a radionuclide targeting SSTR2 according to claim 2, wherein a diazotization reaction precursor is synthesized using an Fmoc solid phase synthesis strategy, and finally, a target product is obtained by a one-step diazotization reaction, specifically comprising: 10.05 g of 2-CTC resin was used as a starting material, and after swelling, 10.78 g of Fmoc-O-tert-butyl-L-threonine and 11.17 g of N,N-diisopropylethylamine were added. After the reaction, the resin was first rinsed with dichloromethane, then reacted with dichloromethane, methanol, and N,N-diisopropylethylamine to cap the ends, washed with dichloromethane, methanol, and N,N-dimethylformamide in that order, and further added 100 mL of a 20% N,N-dimethylformamide solution of piperidine to remove the Fmoc group. After removing and washing, 6.84 g of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, 0.23 g of 1-hydroxybenzotriazole, 10.55 g of Fmoc-S-trityl-L-cysteine, and 2.37 g of N,N-diisopropylethylamine were added, and after the reaction was completed, the mixture was filtered by suction, washed with dichloromethane, methanol, and N,N-dimethylformamide in this order, and further 100 mL of a 20% piperidine N,N-dimethylformamide solution was added to remove the Fmoc group. After washing, 6.84 g of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, 0.18 g of 1-hydroxybenzotriazole, 7.17 g of Fmoc-O-tert-butyl-L-threonine, and 2.37 g of N,N-diisopropylethylamine were added, and after the reaction was completed, the mixture was filtered by suction and washed with dichloromethane, methanol, and N,N-dimethylformamide in this order, and further 100 mL of a 20% piperidine N,N-dimethylformamide solution was added to remove the Fmoc group. After washing, 6.84 g of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, 0.18 g of 1-hydroxybenzotriazole, 8.45 g of Nε-(tert-butyloxycarbonyl)-Nα-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-lysine, and 2.37 g of N,N-diisopropylethylamine were added, and after the reaction was completed, the mixture was filtered by suction, washed with dichloromethane, methanol, and N,N-dimethylformamide in this order, and further washed with 20% piperidine N,100 mL of N-dimethylformamide solution was added to remove the Fmoc group, and after washing, 6.84 g of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, 0.12 g of 1-hydroxybenzotriazole, 9.48 g of 1-[(1,1-dimethylethoxy)carbonyl]-N-[(9H-fluorene-9-methoxy)carbonyl]-D-tryptophan, and 2.37 g of N,N-diisopropylethylamine were added. After the reaction was completed, the mixture was filtered with suction and washed with dichloromethane, methanol, and N , and N-dimethylformamide in that order, and then 100 mL of a 20% piperidine N,N-dimethylformamide solution was added to remove the Fmoc group. After washing, 6.84 g of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, 0.18 g of 1-hydroxybenzotriazole, 8.28 g of Fmoc-O-tert-butyl-L-tyrosine, and 2.37 g of N,N-diisopropylethylamine were added. After the reaction was completed, the mixture was filtered with suction and eluted with dichloromethane, methanol, and N,N-diisopropylethylamine. The reaction mixture was washed with 1,1,3,3-tetramethyluronium hexafluorophosphate, 0.23 g of 1-hydroxybenzotriazole, 10.55 g of Fmoc-S-trityl-L-cysteine, and 2.37 g of N,N-diisopropylethylamine in this order, and then washed with 100 mL of 20% piperidine in N,N-dimethylformamide to remove the Fmoc group. After washing, 6.84 g of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, 0.23 g of 1-hydroxybenzotriazole, 10.55 g of Fmoc-S-trityl-L-cysteine, and 2.37 g of N,N-diisopropylethylamine were added. After the reaction was completed, the mixture was filtered with suction and extracted with dichloromethane, methanol, and N,N-dimethylformamide. The reaction mixture was washed with 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, 0.14 g of 1-hydroxybenzotriazole, 6.97 g of Fmoc-D-phenylalanine, and 2.37 g of N,N-diisopropylethylamine in this order, and then 100 mL of a 20% piperidine N,N-dimethylformamide solution was added to remove the Fmoc group. After washing, 6.84 g of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, 0.14 g of 1-hydroxybenzotriazole, 6.97 g of Fmoc-D-phenylalanine, and 2.37 g of N,N-diisopropylethylamine were added. After the reaction was completed, the mixture was filtered with suction, washed with dichloromethane, methanol, and N,N-dimethylformamide in this order, and then N,200 mL of N-dimethylformamide was added, followed by the addition of a mixture of 8.44 g of iodine, 10 mL of methanol, and 10 mL of N,N-dimethylformamide to remove the Trt protection and cyclize the product. After removing the Fmoc protection with 100 mL of 20% piperidine in N,N-dimethylformamide, the product was washed and added with 60 mL of N,N-dimethylformamide, 3.42 g of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, and N,N-diisopropylethyl ether. 1.16 g of diaminomethane and 7.43 g of (S)-5-((4'-amino-3,3'-dimethyl-[1,1'-diphenyl]-4-yl)carbonyl)-1-(9H-fluoren-9-yl)-3,11-dioxy-2,14,17-trioxo-4,10-diazaeicosan-20-oic acid were added, and after the reaction was completed, the mixture was filtered by suction, washed with dichloromethane, methanol, and N,N-dimethylformamide in this order, and then 100 mL of 20% piperidine N,N-dimethylformamide solution was added to remove the Fmoc group, and the mixture was washed. Then, 60 mL of N,N-dimethylformamide solution and 8.44 g of 2,2',2''-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate tri-tert-butyl were added, and after the reaction was completed, the mixture was filtered by suction. The resin was then cut with 200 mL of a 20% solution of hexafluoroisopropanol in dichloromethane, and the solvent was evaporated by rotary evaporation. Then, the mixture was washed with acetonitrile, water, and 2 M HCl solution. 5 mL of the reaction mixture, 25 mL of N,N-dimethylformamide is added to dissolve the reaction mixture, the temperature is lowered, 0.75 g of an aqueous solution of sodium nitrite is added, and the reaction mixture is added at a low temperature to 3.38 g of 1-amino-8-naphthol-2,4-disulfonic acid monosodium salt and 11.34 g of an aqueous solution of sodium bicarbonate. After the reaction is completed, the solvent is evaporated by rotary evaporation, and the reaction mixture is purified by preparative separation to obtain an intermediate. The obtained intermediate is then added to a 95% aqueous solution of trifluoroacetic acid for deprotection, and the desired product is obtained by purifying the intermediate by preparative liquid phase separation.

4. A radionuclide-labeled compound targeting SSTR2, characterized in that it is obtained by labeling a compound having the structure of formula (II) according to claim 2 with a radionuclide.

5. 5. The SSTR2-targeted radionuclide-labeled compound of claim 4, wherein the radionuclide is selected from an alpha-emitting isotope, a beta-emitting isotope, a gamma-emitting isotope, an Auger electron-emitting isotope, or an X-ray-emitting isotope.

6. The radionuclide is 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 5. The radionuclide-labeled compound targeting SSTR2 according to claim 4, characterized in that the compound is any one selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25

7. The radionuclide is １７７ Lu, ２２５ Ac, ６８ Ga, ６４ Cu, ８９ Zr, ９０ Y. ９９ｍ Tc, １８８ Re, or １１１ 5. The radionuclide-labeled compound targeting SSTR2 according to claim 4, characterized in that the compound is selected from the group consisting of In, In;

8. A method for preparing a radionuclide-labeled compound targeting SSTR2 according to any one of claims 4 to 7, comprising:

10. A method for preparing a radionuclide-labeled compound targeting SSTR2, comprising the step of reacting the compound capable of being labeled with a radionuclide targeting SSTR2 according to claim 2 with a radionuclide-containing compound by a wet labeling method or a freeze-drying labeling method.

9. 1. A pharmaceutical composition comprising: A pharmaceutical composition comprising a compound targeting SSTR2 according to claim 1, a compound that can be labeled with a radionuclide that targets SSTR2 according to claim 2, a radionuclide-labeled compound that targets SSTR2 according to any one of claims 4 to 7, or a pharmaceutically acceptable hydrate, solvate, or salt thereof.

10. Use of a compound targeting SSTR2 as described in claim 1, a radionuclide-labelable compound targeting SSTR2 as described in claim 2, a radionuclide-labeled compound targeting SSTR2 as described in claim 4, or a pharmaceutically acceptable hydrate, solvate, or salt thereof, or a pharmaceutical composition as described in claim 9, in the preparation of a drug for diagnosing or treating a disease characterized by SSTR2 overexpression in an animal or human individual, wherein the disease characterized by SSTR2 overexpression is selected from neuroendocrine tumors, gastrointestinal tumors, lung cancer, hepatocellular carcinoma, head and neck cancer, ovarian cancer, myeloma, bladder cancer, clear cell renal cell carcinoma, oncogenic osteomalacia, or sarcoma.

11. The use according to claim 10, wherein the neuroendocrine tumor is a glioma.

12. The use according to claim 11, wherein the glioma is a neuroglioma.

13. 13. The use according to claim 12, wherein the glioma is an astrocytoma.

14. 11. The use according to claim 10, wherein the gastrointestinal tumor is selected from pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, or cholangiocarcinoma.

15. 11. The use of claim 10, wherein the head and neck cancer is selected from nasopharyngeal cancer, esophageal cancer, hypopharyngeal cancer, or laryngeal cancer.

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