Compounds targeting somatostatin receptors and uses thereof

Abstract

This invention proposes compounds targeting somatostatin receptor 2 and their uses. The compounds of this invention, which are compounds of Formula I or tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs of compounds of Formula I, possess high selectivity and targeting, enabling precise identification and binding to somatostatin receptor 2. Rapid imaging can be achieved shortly after administration, and these compounds can be used for the diagnosis and treatment of diseases overexpressing somatostatin receptor 2.

Description

Technical Field

[0001] This invention relates to the field of biomedicine, and more specifically, to compounds that target somatostatin receptors and their uses. Background Technology

[0002] Radionuclide drug conjugates (RDCs) deliver radionuclides precisely to tumor sites by binding a targeting ligand to a radionuclide and utilizing the specific binding of the ligand to a highly expressed receptor on the surface of tumor cells. This enables precise diagnosis or treatment of tumors and has become an important research direction in the field of precision oncology in recent years.

[0003] Somatostatin (SST) is a class of cyclic polypeptide hormones composed of 14 or 28 amino acids (i.e., SST14 and SST28), widely distributed in the human central nervous system (such as the cerebral cortex, pituitary gland, and hypothalamus) and peripheral tissues (such as the pancreas and digestive tract). Its biological functions are diverse, regulating the secretion of various hormones such as growth hormone and insulin, and participating in the regulation of cell proliferation and angiogenesis. These functions are all mediated by the somatostatin receptor (SSTR) on the surface of target cells. SSTR belongs to the G protein-coupled receptor (GPCR) family. After SST binds to SSTR, it mainly regulates the activity of adenylate cyclase (AC) through the inhibitory G protein (Gi), thereby altering intracellular cAMP concentration, transmitting exogenous signals, and influencing tumor growth and proliferation.

[0004] Five SSTR subtypes have been identified so far, among which SSTR2 is the most widely used in clinical practice. It is highly expressed in a variety of tumors such as neuroendocrine tumors, neuroblastoma, and small cell lung cancer, especially in neuroendocrine neoplasms (NEN). Most NEN patients are diagnosed at an advanced stage and cannot undergo radical surgery. Therefore, SSTR2 has become a potential candidate target for the treatment of various tumors.

[0005] The core of somatostatin-based radionuclide-targeted therapy lies in the high affinity and specificity of SST and SSTR binding. However, the biological half-life of natural SST in the human body is extremely short, making it unsuitable for imaging and treatment after radionuclide labeling. Therefore, developing RDCs with stronger targeting, higher tumor uptake rates, and better target-to-substrate ratios targeting SSTR2 can meet the higher clinical demands for precision tumor diagnosis and treatment, and has significant scientific and application value. Summary of the Invention

[0006] This invention aims to at least partially address one of the technical problems existing in the prior art. Therefore, this invention proposes a targeting compound against somatostatin receptor 2 (SSTR2). This compound can specifically bind to tumor cells that highly express SSTR2, achieving tumor diagnosis and treatment through precise targeting, effectively improving diagnostic sensitivity and treatment accuracy.

[0007] Therefore, in a first aspect, the present invention provides a compound. According to embodiments of the present invention, the compound is a compound of Formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of a compound of Formula I:

[0008] in, Ra is selected from -S-, -O-, C 1~6 Alkylene, C 2~6 imidene group, C 2~6 Ethyne group, -SC 1~6 Alkylene, C 1~6 Alkylene-NH-, -[SL]2-Ar-, -SLS-, 5- to 8-membered heteroaryl, wherein C 1~6 Alkylene, C 2~6 imidene group, C 2~6 Ethyne group, -SC 1~6 Alkylene, C 1~6 Alkyl-NH-, -[SL]2-Ar-, -SLS-, and 5- to 8-membered heteroaryl groups are optionally substituted with one or more R3 groups; L is C 1~6 Alkylene, where Ar is a 6-8 arylene group; R1 and R2 are each independently selected from C 1~10 Alkylene; R3 is independently selected from H, halogen, oxo (=O), and C. 1~6 alkyl; Z is a chelating group derived from the chelating agent.

[0009] The compounds of this invention exhibit high affinity for SSTR2, which enhances their targeting and uptake in tumor tissues, enabling rapid formation of clear tumor images shortly after administration. Therefore, the compounds of this invention possess excellent SSTR2 targeting and specificity, allowing for rapid imaging shortly after administration, and can be used for the diagnosis and treatment of SSTR2 overexpression diseases.

[0010] According to embodiments of the present invention, the compound represented by Formula I may further include at least one of the following additional technical features: According to an embodiment of the present invention, in the compound represented by Formula I, Ra is selected from -S-, -O-, and C. 1~4 Alkylene, C 2~5 imidene group, C 2~5 Ethyne group, -SC 1~4 Alkylene, C 1~4 Alkylene-NH-, -[SL]2-Ar-, -SLS-, 5- to 6-membered heteroaryl, wherein C 1~4 Alkylene, C 2~5 imidene group, C 2~5 Ethyne group, -SC 1~4 Alkylene, C 1~4 Alkyl-NH-, -[SL]2-Ar-, -SLS-, and 5- to 6-membered heteroaryl groups are optionally substituted with one or more R3 groups; L is C 1~4 Alkylene, where Ar is a 6-membered arylene; undefined groups are as described in any of the embodiments of this invention.

[0011] According to an embodiment of the present invention, in the compound represented by Formula I, Ra is selected from -S-, -O-, and C. 1~3 Alkylene, C 2~4 imidene group, C 2~4 Ethyne group, -SC 1~3 Alkylene, C 1~3 Alkylene-NH-, -[SL]2-Ar-, -SLS-, 5- to 6-membered heteroaryl, wherein C 1~3 Alkylene, C 2~4 imidene group, C 2~4 Ethyne group, -SC 1~3 Alkylene, C 1~3 Alkyl-NH-, -[SL]2-Ar-, -SLS-, and 5- to 6-membered heteroaryl groups are optionally substituted with one or more R3 groups; L is C 1~3 Alkylene, Ar is phenylene; undefined groups are as described in any embodiment of the present invention.

[0012] According to an embodiment of the present invention, in the compound represented by Formula I, Ra is selected from -S-, -O-, and C. 1~3 Alkylene, C 2~4 imidene group, C 2~4 Ethyne group, -SC 1~3 Alkylene, C 1~3 Alkylene-NH-, -[SL]2-Ar-, 5-membered heteroaryl, wherein C 1~3 Alkylene, C 2~4 imidene group, C 2~4 Ethyne group, -SC 1~3 Alkylene, C 1~3The alkylene-NH-, -[SL]2-Ar-, and 5-membered heteroaryl groups are optionally substituted with one or more R3 groups; L is C. 1~3 Alkylene, Ar is phenylene; undefined groups are as described in any embodiment of the present invention.

[0013] According to an embodiment of the present invention, in the compound shown in Formula I, R1 and R2 are each independently selected from C 1~5 Alkylene groups, undefined groups as described in any embodiment of the present invention.

[0014] According to an embodiment of the present invention, in the compound shown in Formula I, R1 and R2 are each independently selected from C 1~4 Alkylene groups, undefined groups as described in any embodiment of the present invention.

[0015] According to an embodiment of the present invention, in the compound shown in Formula I, R1 and R2 are each independently selected from C 1~3 Alkylene groups, undefined groups as described in any embodiment of the present invention.

[0016] According to embodiments of the present invention, in the compound shown in Formula I, R3 is independently selected from H, halogen, oxo, and C. 1~4 Alkyl groups, undefined groups as described in any embodiment of the invention.

[0017] According to embodiments of the present invention, in the compound shown in Formula I, R3 is independently selected from H, halogen, oxo, and C. 1~3 Alkyl groups, undefined groups as described in any embodiment of the invention.

[0018] According to an embodiment of the present invention, in the compound shown in Formula I, Ra is selected from a 5-membered heteroaryl group, wherein the heteroatom in the 5-membered heteroaryl group can be at least one of N, O, and S, and the number of heteroatoms can be 1, 2, 3, 4, or a range consisting of any of the above values.

[0019] According to embodiments of the present invention, in the compound shown in Formula I, the chelating agent in Z is selected from 1,4,7,10-tetraazacyclododecane-N,N',N",N'''-tetraacetic acid (DOTA), N,N"-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N"-diacetic acid (HBED-CC), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 2-(4,7-bis(carboxymethyl)-1,4,7-triazonon-1-yl)glutaric acid (NODAGA), 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-N,N',N'''-tetraacetic acid (DOTA), N,N"-bis[2-hydroxy-5-(carboxymethyl)benzyl]ethylenediamine-N,N"-diacetic acid (HBED-CC), 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-N,N'',N'''-tetraacetic acid (DOTA), N,N"-bis[2-hydroxy-5-(carboxymethyl)-1,4,7,10-tetraazacyclododecane-N ... Alkyl-1-yl)glutaric acid (DOTAGA), 1,4,7-triazacyclononanephosphinoic acid (TRAP), 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphinoic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphinoic acid] (NOPO), 3,6,9,15-tetraazabicyclo[9.3.1.]pentadecano-1(15),11,13-trien-3,6,9-triacetic acid (PCTA), N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutyryl}amino)pentyl]-N-hydroxy Benzyl succinamide (DFO), diethylenetriaminepentaacetic acid (DTPA), trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA), 1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (O-Do3A), p-isocyanothiobenzyl-DTPA (SCN-Bz-DTPA), 1-(p-isocyanothiobenzyl)-3-methyl-DTPA (1B3M), 2-(p-isocyanothiobenzyl)-4-methyl-DTPA (1M3B), 1-(2)-methyl-4-isocyanothiobenzyl-DTPA (MX-DTPA), [(R)-2-amino-3-( At least one of the following: [4-isothiocyanophenyl]propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid (p-SCN-Bn-CHX-A"-DTPA), 6-hydrazinopyridine-3-carboxylic acid (HYNIC), 2-(4-isothiocyanophenyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA), and 2-[(4-isothiocyanophenyl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bn-DOTA); undefined groups as described in any embodiment of the invention.

[0020] According to an embodiment of the present invention, in the compound represented by Formula I, Ra is selected from -S-, C 2~4 alkenyl, -SC 1~3 Alkylene, C 1~3Alkylene-NH-, -[SL]2-Ar-, -SLS-, 5-membered heteroaryl, wherein C 2~4 alkenyl, -SC 1~3 Alkylene, C 1~3 The alkylene group -NH-, -[SL]2-Ar-, -SLS-, and the 5-membered heteroaryl group are optionally substituted with one or more R3 groups; L is C 1~3 Alkylene, Ar is phenylene; undefined groups are as described in any embodiment of the present invention.

[0021] According to an embodiment of the present invention, in the compound represented by Formula I, Ra is selected from -S-, , , , , , m is selected from any positive integer between 1 and 5. , Undefined groups are as described in any embodiment of this invention.

[0022] According to an embodiment of the present invention, in the compound represented by Formula I, Ra is selected from... m is selected from 1, 2, 3, 4, 5.

[0023] According to an embodiment of the present invention, in the compound shown in Formula I, R1 and R2 are each independently selected from C 1~3 Alkylene; undefined groups as described in any embodiment of the invention.

[0024] According to embodiments of the present invention, in the compound shown in Formula I, R1 and R2 are independently selected from methylene, ethylene, propylene, and isopropylene, respectively; undefined groups are as described in any embodiment of the present invention.

[0025] According to embodiments of the present invention, in the compound shown in Formula I, R3 is independently selected from H and oxo groups; undefined groups are as described in any embodiment of the present invention.

[0026] According to embodiments of the present invention, in the compound shown in Formula I, the chelating agent in Z is selected from 1,4,7,10-tetraazacyclododecane-N,N',N",N'''-tetraacetic acid, N,N"-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N"-diacetic acid, 1,4,7-triazacyclononane-1,4,7-triacetic acid, 2-(4,7-bis(carboxymethyl)-1,4,7-triazonon-1-yl)glutaric acid, 2-(4,7,10-tris(carboxymethyl)-1,4,7, At least one of 10-tetraazacyclododecane-1-yl)glutaric acid, [(R)-2-amino-3-(4-isothiocyanophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid, 2-(4-isothiocyanophenyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid, and 2-[(4-isothiocyanophenyl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; undefined groups as described in any embodiment of the invention.

[0027] According to an embodiment of the present invention, in the compound represented by Formula I, Z is selected from... , , , , , , , At least one of the following; undefined groups as described in any embodiment of the invention.

[0028] According to an embodiment of the present invention, in the compound represented by Formula I, Z is selected from... Undefined groups are as described in any embodiment of this invention.

[0029] According to embodiments of the present invention, the compound is a compound of formula Ia or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of a compound of formula Ia:

[0030] Wherein, Z, R1, R2, and Ra are as defined in this invention.

[0031] According to embodiments of the present invention, the compound is a compound of Formula II or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of a compound of Formula II.

[0032] in, Rb is selected from -S-, C 2~4 alkenyl, -SC 1~3 Alkylene, C1~3 Alkylene-NH-, -[SL]2-Ar-, -SLS-, 5-membered heteroaryl, wherein C 2~4 alkenyl, -SC 1~3 Alkylene, C 1~3 The alkylene group -NH-, -[SL]2-Ar-, -SLS-, and the 5-membered heteroaryl group are optionally substituted with one or more R4 groups; L is C 1~3 Alkylene, Ar is phenylene; R4 is independently selected from H and oxo; Z is a chelating group derived from the chelating agent.

[0033] According to an embodiment of the present invention, in the compound represented by Formula II, Rb is selected from -S-, , , , , , m is selected from any positive integer between 1 and 5. , .

[0034] According to an embodiment of the present invention, in the compound represented by Formula II, Rb is selected from -S- and -SC-. 1~3 Alkylene, C 1~3 Alkylene-NH-, -[SL]2-Ar-, the -SC 1~3 Alkylene, C 1~3 Alkylene-NH-, -[SL]2-Ar- are optionally substituted with one or more R4 groups; undefined groups are as described in any of the embodiments of the present invention.

[0035] According to an embodiment of the present invention, in the compound represented by Formula II, Rb is selected from -S-, , , , , Undefined groups are as described in any embodiment of this invention.

[0036] According to an embodiment of the present invention, in the compound represented by Formula II, Rb is selected from -S-, , , Undefined groups are as described in any embodiment of this invention.

[0037] According to an embodiment of the present invention, in the compound shown in Formula II, the chelating agent in Z is selected from 1,4,7,10-tetraazacyclododecane-N,N',N",N'''-tetraacetic acid, N,N"-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N"-diacetic acid, 1,4,7-triazacyclononane-1,4,7-triacetic acid, 2-(4,7-bis(carboxymethyl)-1,4,7-triazonon-1-yl)glutaric acid, 2-(4,7,10-tris(carboxymethyl)-1,4,7 At least one of the following: 10-tetraazacyclododecane-1-yl)glutaric acid, [(R)-2-amino-3-(4-isothiocyanophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid, 2-(4-isothiocyanophenyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid, and 2-[(4-isothiocyanophenyl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; undefined groups as described in any embodiment of the invention.

[0038] According to an embodiment of the present invention, in the compound represented by Formula II, Z is selected from... , , , , , , , At least one of the following; undefined groups as described in any embodiment of the invention.

[0039] According to an embodiment of the present invention, in the compound represented by Formula II, Z is selected from... Undefined groups are as described in any embodiment of this invention.

[0040] According to embodiments of the present invention, the compound is a compound of formula II-a or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of a compound of formula II-a.

[0041] Wherein, Z and Rb are as defined in this invention.

[0042] According to embodiments of the present invention, the compounds represented by Formula I or Formula II, or stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs of the compounds represented by Formula I or Formula II, may be any of the following compounds or stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs of any of the following compounds:

[0043]

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050]

[0051]

[0052]

[0053]

[0054]

[0055]

[0056] .

[0057] According to embodiments of the present invention, the compounds represented by Formula I or Formula II, or stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs of the compounds represented by Formula I or Formula II, may be any of the following compounds or stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs of any of the following compounds:

[0058]

[0059]

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072] .

[0073] In a second aspect, the present invention provides a complex. According to an embodiment of the invention, the complex is formed by complexing the compound described in the first aspect, or its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, with M; wherein M is selected from at least one of radionuclides or non-radioactive elements.

[0074] According to an embodiment of the present invention, the radionuclide is selected from... 67 / 68 Ga、 18 F, 94m / 99m Tc, 89 Zr、 111 In、 45 Ti、 59 Fe、 60 / 61 / 62 / 64 / 67 Cu、 71 / 72 / 74 As、 43 / 44 / 47 Sc、 82m Rb、 52 Mn, 86 / 90 Y、 76 Br、 177 Lu、 153 Sm、 89 Sr、 123 / 124 / 131 I, 137 Cs、 161 Tb, 166 Ho、 177 Yb、 105 Rh、 186 / 188 Re、 212 / 213 Bi、 211 At、 223 Ra、 225 Ac、 212 Pb, 149 Pm and 227 Th.

[0075] According to an embodiment of the present invention, the radionuclide is selected from... 68 Ga、 18F, 177 Lu、 64 Cu、 161 Tb, 225 Ac、 89 Zr、 99m Tc.

[0076] It should be noted that in the text, " 67 / 68 "Ga" indicates 67 Ga and 68 Similarly, for the two Ga nuclides, " 94m / 99m "Tc" indicates 94m Tc and 99m Tc has two nuclides; 60 / 61 / 62 / 64 / 67 "Cu" indicates 60 Cu、 61 Cu、 62 Cu、 64 Cu、 67 Five nuclides of Cu; 71 / 72 / 74 As、 43 / 44 / 47 Sc、 86 / 90 Y、 123 / 124 / 131 I, 186 / 188 Re、 212 / 213 The representation of combinations such as Bi is similar.

[0077] According to an embodiment of the present invention, the radionuclide 18 F is through 18 FAl is formed by complexing the compound with the compound or its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs.

[0078] According to an embodiment of the present invention, M is complexed with a chelating group in the compound or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of the compound.

[0079] Furthermore, those skilled in the art will understand that the features and advantages described above for the compound also apply to this complex, and will not be repeated here.

[0080] In a third aspect, the present invention provides an imaging agent. According to embodiments of the invention, the imaging agent comprises the compound described in the first aspect, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or a complex described in the second aspect.

[0081] Furthermore, those skilled in the art will understand that the features and advantages described above for the compounds and complexes also apply to this imaging agent, and will not be repeated here.

[0082] In a fourth aspect, the present invention provides a pharmaceutical composition. According to embodiments of the invention, the pharmaceutical composition comprises the compound described in the first aspect, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof, or a complex described in the second aspect, or an imaging agent described in the third aspect.

[0083] According to embodiments of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

[0084] In an optional embodiment of the present invention, pharmaceutically acceptable excipients refer to pharmaceutical excipients conventional in the pharmaceutical field, such as absorption enhancers, isotonic agents, stabilizers, regulators, etc.

[0085] In an alternative embodiment of the present invention, a pharmaceutically acceptable carrier refers to a drug carrier conventional in the pharmaceutical field.

[0086] In an alternative embodiment of the invention, examples of suitable pharmaceutically acceptable carriers and excipients are well known in the art. Pharmaceutical compositions comprising such carriers and excipients can be formulated using known conventional methods.

[0087] In some alternative embodiments, the pharmaceutical composition of the present invention may also contain other active ingredients for therapeutic purposes.

[0088] The pharmaceutical compositions of the present invention can be administered in various ways, such as orally or intravenously. Preferably, the pharmaceutical compositions of the present invention are in solution form. Clinical dosing regimens are determined by the attending physician and clinical factors. As is known in the medical field, the dosage for any given patient depends on many factors, including the patient's physique, body surface area, age, the drug to be administered, sex, time and route of administration, general health, and other concurrently administered drugs. The pharmaceutical compositions of the present invention can be administered topically or systemically. Preferably, they can be administered intravenously or subcutaneously. The pharmaceutical compositions of the present invention can also be administered directly to the target site, for example, by targeted administration to internal or external target sites.

[0089] Furthermore, those skilled in the art will understand that the features and advantages described above for the compounds and complexes also apply to this pharmaceutical composition, and will not be repeated here.

[0090] In a fifth aspect of the invention, the invention provides for the use of the compound described in the first aspect, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or a complex described in the second aspect, or an imaging agent described in the third aspect, or a pharmaceutical composition described in the fourth aspect, in the preparation of a medicament for the diagnosis and / or treatment of a disease characterized by overexpression of somatostatin receptor 2.

[0091] According to an embodiment of the present invention, the diagnostic method is selected from radionuclide imaging.

[0092] According to an embodiment of the present invention, the diagnostic method is selected from positron emission tomography or single-photon emission computed tomography.

[0093] According to an embodiment of the present invention, the treatment is selected from radiotherapy.

[0094] According to an embodiment of the present invention, the disease is selected from at least one of tumors, nervous system diseases, and metabolic diseases.

[0095] According to embodiments of the present invention, the disease is selected from at least one of neuroendocrine tumors, neuroblastoma, melanoma, thyroid cancer, meningioma, breast cancer, gastrointestinal tumors, liver cancer, nasopharyngeal carcinoma, pancreatic cancer, small bowel cancer, colon cancer, rectal cancer, head and neck cancer, ovarian cancer, esophageal cancer, myeloma, cervical cancer, prostate cancer, bladder cancer, laryngeal cancer, bile duct cancer, renal cell carcinoma, sarcoma, lung cancer, thymic carcinoma, glioma, neuroglioma, astrocytoma, and lymphoma.

[0096] In an optional embodiment of the present invention, the neuroendocrine tumor is selected from at least one of gastrointestinal neuroendocrine tumors, pancreatic neuroendocrine tumors, bronchopulmonary neuroendocrine tumors, thymic neuroendocrine tumors, and pituitary neuroendocrine tumors.

[0097] In an optional embodiment of the present invention, the neuroendocrine tumor is selected from at least one of gastrinoma, glucagonoma, insulinoma, somatostatinoma, medullary thyroid carcinoma, growth hormone-secreting tumor, prolactinoma, thyrotropinoma, pheochromocytoma / paraganglioma, Merkel cell carcinoma, pituitary adenoma, parathyroid adenoma, and small cell lung cancer.

[0098] In a sixth aspect of the invention, a method for imaging tissues or cells of somatostatin receptor 2 is provided. According to embodiments of the invention, the method comprises: administering to the tissue or cells a compound described in the first aspect, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof, or a complex described in the second aspect, or an imaging agent described in the third aspect, or a pharmaceutical composition described in the fourth aspect, and imaging the tissue or cells after administration.

[0099] According to an embodiment of the present invention, the imaging is performed by positron emission tomography or single-photon emission computed tomography.

[0100] In a seventh aspect of the invention, a method for diagnosing and / or treating a disease characterized by somatostatin receptor 2 is provided. According to embodiments of the invention, the method comprises administering to a patient a pharmaceutically acceptable dose of the compound of the first aspect, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug, or the complex of the second aspect, or the imaging agent of the third aspect, or the pharmaceutical composition of the fourth aspect.

[0101] According to an embodiment of the present invention, the diagnostic method is selected from radionuclide imaging.

[0102] According to an embodiment of the present invention, the diagnostic method is selected from positron emission tomography or single-photon emission computed tomography.

[0103] According to an embodiment of the present invention, the treatment is selected from radiotherapy.

[0104] According to an embodiment of the present invention, the disease is selected from at least one of tumors, nervous system diseases, and metabolic diseases.

[0105] According to embodiments of the present invention, the disease is selected from at least one of neuroendocrine tumors, neuroblastoma, melanoma, thyroid cancer, meningioma, breast cancer, gastrointestinal tumors, liver cancer, nasopharyngeal carcinoma, pancreatic cancer, small bowel cancer, colon cancer, rectal cancer, head and neck cancer, ovarian cancer, esophageal cancer, myeloma, cervical cancer, prostate cancer, bladder cancer, laryngeal cancer, bile duct cancer, renal cell carcinoma, sarcoma, lung cancer, thymic carcinoma, glioma, neuroglioma, astrocytoma, and lymphoma.

[0106] In an optional embodiment of the present invention, the neuroendocrine tumor is selected from at least one of gastrointestinal neuroendocrine tumors, pancreatic neuroendocrine tumors, bronchopulmonary neuroendocrine tumors, thymic neuroendocrine tumors, and pituitary neuroendocrine tumors.

[0107] In an optional embodiment of the present invention, the neuroendocrine tumor is selected from at least one of gastrinoma, glucagonoma, insulinoma, somatostatinoma, medullary thyroid carcinoma, growth hormone-secreting tumor, prolactinoma, thyrotropinoma, pheochromocytoma / paraganglioma, Merkel cell carcinoma, pituitary adenoma, parathyroid adenoma, and small cell lung cancer.

[0108] In an alternative embodiment of the invention, the pharmaceutically acceptable dose may be selected from the effective dose (or effective amount).

[0109] The effective amount of the compound described in this invention can vary depending on the administration method and the severity of the disease to be treated. A preferred effective amount can be determined by those skilled in the art based on various factors (e.g., through clinical trials). These factors include, but are not limited to: pharmacokinetic parameters of the active ingredient, such as bioavailability, metabolism, and half-life; the severity of the disease to be treated, the patient's weight, the patient's immune status, and the route of administration. For example, due to the urgency of the treatment condition, several separate doses may be administered daily, or the dose may be reduced proportionally.

[0110] The compounds or pharmaceutical compositions of the present invention can be incorporated into suitable pharmaceuticals, which can be prepared in various forms, such as liquids. Various routes of administration of the compounds, pharmaceutical compositions, or pharmaceuticals of the present invention are contemplated, including intravenous, intramuscular, and subcutaneous injection, but the present invention is not limited to these exemplified routes of administration.

[0111] In an eighth aspect of the invention, the invention provides for the use of the compound described in the first aspect, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or a complex described in the second aspect, or an imaging agent described in the third aspect, or a pharmaceutical composition described in the fourth aspect, in the diagnosis and / or treatment of diseases characterized by the expression of somatostatin receptor 2.

[0112] According to an embodiment of the present invention, the diagnostic method is selected from radionuclide imaging.

[0113] According to an embodiment of the present invention, the diagnostic method is selected from positron emission tomography or single-photon emission computed tomography.

[0114] According to an embodiment of the present invention, the treatment is selected from radiotherapy.

[0115] According to an embodiment of the present invention, the disease is selected from at least one of tumors, nervous system diseases, and metabolic diseases.

[0116] According to embodiments of the present invention, the disease is selected from at least one of neuroendocrine tumors, neuroblastoma, melanoma, thyroid cancer, meningioma, breast cancer, gastrointestinal tumors, liver cancer, nasopharyngeal carcinoma, pancreatic cancer, small bowel cancer, colon cancer, rectal cancer, head and neck cancer, ovarian cancer, esophageal cancer, myeloma, cervical cancer, prostate cancer, bladder cancer, laryngeal cancer, bile duct cancer, renal cell carcinoma, sarcoma, lung cancer, thymic carcinoma, glioma, neuroglioma, astrocytoma, and lymphoma.

[0117] In an optional embodiment of the present invention, the neuroendocrine tumor is selected from at least one of gastrointestinal neuroendocrine tumors, pancreatic neuroendocrine tumors, bronchopulmonary neuroendocrine tumors, thymic neuroendocrine tumors, and pituitary neuroendocrine tumors.

[0118] In an optional embodiment of the present invention, the neuroendocrine tumor is selected from at least one of gastrinoma, glucagonoma, insulinoma, somatostatinoma, medullary thyroid carcinoma, growth hormone-secreting tumor, prolactinoma, thyrotropinoma, pheochromocytoma / paraganglioma, Merkel cell carcinoma, pituitary adenoma, parathyroid adenoma, and small cell lung cancer.

[0119] Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. Attached Figure Description

[0120] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which: Figure 1 This is a graph showing the LCMS (liquid chromatography-mass spectrometry) detection results of compound 1 according to Example 1 of the present invention; Figure 2 This is a chromatogram of the HPLC (high performance liquid chromatography) detection results of compound 1 according to Example 1 of the present invention; Figure 3 This is an LCMS detection result diagram of compound 2 according to Example 1 of the present invention; Figure 4 This is a chromatogram of the HPLC detection results of compound 2 according to Example 1 of the present invention; Figure 5 This is an LCMS detection result diagram of compound 3 according to Example 1 of the present invention; Figure 6 This is a chromatogram of the HPLC detection results of compound 3 according to Example 1 of the present invention; Figure 7 This is an LCMS detection result diagram of compound 4 according to Example 1 of the present invention; Figure 8 This is a chromatogram of the HPLC detection results of compound 4 according to Example 1 of the present invention; Figure 9 This is an LCMS detection result diagram of compound 5 according to Example 1 of the present invention; Figure 10 This is a chromatogram of the HPLC detection results of compound 5 according to Example 1 of the present invention; Figure 11 This is according to Embodiment 2 of the present invention. 68HPLC detection results of Ga-compound 1; Figure 12 This is according to Embodiment 2 of the present invention. 68 HPLC detection results of Ga-compound 2; Figure 13 This is according to Embodiment 2 of the present invention. 68 HPLC detection results of Ga-compound 3; Figure 14 This is according to Embodiment 2 of the present invention. 68 HPLC detection results of Ga-compound 4; Figure 15 This is according to Embodiment 2 of the present invention. 68 HPLC detection results of Ga-compound 5; Figure 16 This is according to Embodiment 2 of the present invention. 177 HPLC test results of Lu-compound 1; Figure 17 This is according to Embodiment 2 of the present invention. 177 HPLC test results of Lu-compound 5; Figure 18 After administration according to Example 5 of the present invention 177 Lu-compound 1 and 177 SPECT / CT imaging results of Lu-compound 5 on AR42J model mice; Figure 19 These are different time intervals after drug administration according to Example 6 of the present invention. 177 Figure showing the uptake of Lu-compound 5 in different tissues of AR42J model mice. Detailed Implementation

[0121] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention.

[0122] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0123] To facilitate understanding of the invention, certain technical and scientific terms are specifically defined below. Unless otherwise expressly defined elsewhere in this document, all other technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains.

[0124] In this document, the terms “comprising” or “including” are open-ended expressions, meaning that they include the contents specified in this invention, but do not exclude other aspects.

[0125] In this document, the terms “optionally,” “optionally,” or “optionally” generally refer to an event or condition that may, but may not, occur, and the description includes both cases in which the event or condition occurs and cases in which the event or condition does not occur.

[0126] Terms and Definitions Unless otherwise stated, the definitions of groups and terms recorded in this specification and claims, including definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures should fall within the scope of this specification.

[0127] Generally, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specific substituent. Unless otherwise indicated, a substituted group may have one substituent at each substituted position of the group. When more than one position in a given structural formula can be replaced by one or more substituents selected from a specific group, then the substituents may be substituted at each substituted position in the same or different ways.

[0128] The term "unsubstituted" means that the specified group does not have substituents.

[0129] As described in this invention, the compounds of this invention may optionally be substituted with one or more substituents, such as the general formula compounds above, or as the specific examples, subclasses, and classes of compounds included in this invention as described in the embodiments. It should be understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted." Generally, the term "optionally," whether or not it precedes the term "substituted," indicates that the hydrogen atoms in the given structure are not substituted or that one or more hydrogen atoms are substituted by a specific substituent. Unless otherwise indicated, an optional substituent group may have one substituent substituted at each substituted position of the group. When more than one position in the given structural formula is substituted by one or more substituents selected from a specific group, the substituents may be substituted at the same or different positions.

[0130] Additionally, it should be noted that, unless otherwise explicitly stated, the descriptive terms “each…independently is”, “…each independently is”, and “…independently is” used in this invention are interchangeable and should be interpreted broadly. They can mean that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0131] Unless otherwise stated, conventional methods within the scope of the art, such as mass spectrometry, NMR, IR, and UV / Vis spectroscopy, and pharmacological methods, are employed. Unless specifically defined, the terminology used herein in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry is known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and in the treatment of patients. For example, reactions and purifications can be carried out using the manufacturer's instructions for use of kits, or in accordance with methods known in the art or the description of this invention. The techniques and methods described herein are generally carried out according to conventional methods well known in the art, based on descriptions in several summary and more specific documents cited and discussed in this specification. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0132] When a substituent is described using a conventional chemical formula written from left to right, that substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, CH2O is equivalent to OCH2. As used herein, or Indicates the linking site of a functional group.

[0133] Unless otherwise specified, use wedge-shaped solid line keys ( ) and wedge-shaped dashed key ( ) represents the absolute configuration of a solid center, using a straight solid line key ( ) and straight dashed key ( ) indicates the relative configuration of the center of the solid.

[0134] The numerical ranges described in this specification and claims, when interpreted as "integers," should be understood to include the two endpoints of the range and every integer within that range. For example, "integers from 1 to 6" should be understood to include every integer of 1, 2, 3, 4, 5, and 6. When interpreted as "numbers," the numerical range should be understood to include the two endpoints of the range, every integer within that range, and every decimal within that range. For example, "numbers from 1 to 10" should be understood to include not only every integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, but also at least the sum of each of these integers with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, and 0.9.

[0135] The term "stereoisomer" refers to isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, non-corresponding isomers, and conformational isomers.

[0136] Depending on the choice of raw materials and methods, the compounds of the present invention can exist as one or a mixture of possible isomers, for example as purely optical isomers, or as mixtures of isomers, such as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral centers (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (–) are symbols used to specify the plane-polarized rotation induced by the compound, where (–) or L indicates that the compound is levorotatory. Compounds with the prefix (+) or D are dextrorotatory.

[0137] When the bonds of the chiral carbon in the formulas of this invention are depicted as straight lines, it should be understood that both the (R) and (S) configurations of the chiral carbon and the resulting enantiomerically pure compounds and mixtures thereof are included within the scope of the general formula. The illustration of racemic or enantiomerically pure compounds in this document is derived from Maehr, J. Chem. Ed. 1985, 62:114-120. The absolute configuration of a stereocenter is represented by wedge-shaped and dashed bonds.

[0138] The term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom between two positions within a molecule. The compounds of this invention can exhibit tautomerism. Tautomers can exist in two or more interconvertible forms. Proton-transfer tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium form; attempts to isolate a single tautomer typically yield a mixture whose physicochemical properties are consistent with those of the mixture of compounds. The equilibrium position depends on the intramolecular chemical characteristics. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketone form is dominant; while in phenols, the enol form is dominant. This invention encompasses all tautomeric forms of the compounds.

[0139] The term "solvent" refers to a compound of the present invention or a salt thereof comprising a stoichiometric or nonstoichiometric solvent bound by intermolecular noncovalent forces, and a hydrate when the solvent is water.

[0140] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0141] The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable, non-toxic salt of an acid or base, including salts of inorganic acids and bases, and salts of organic acids and bases.

[0142] In addition to pharmaceutically acceptable salts, the present invention also contemplates other salts. These may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts, or may be used for the identification, characterization, or purification of the compounds of the present invention.

[0143] The term "prodrug" refers to a compound of the present invention that can be converted into a biologically active form under physiological conditions or by solvation. The prodrugs of the present invention are prepared by modifying functional groups in the compound; this modification can be performed conventionally or removed in vivo to obtain the parent compound. Prodrugs comprise compounds formed by attaching a hydroxyl or amino group to any group within the compound of the present invention. When a prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is cleaved to form a free hydroxyl group and a free amino group.

[0144] The term "pharmaceutical composition" refers to a formulation of the compounds of the present invention with a medium generally accepted in the art for delivering a bioactive compound to a mammal (e.g., a human). This medium includes pharmaceutically acceptable carriers. The purpose of a pharmaceutical composition is to facilitate administration to the organism, thereby promoting the absorption of the active ingredient and the exertion of its bioactivity.

[0145] The term "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, flow aid, sweetener, diluent, preservative, dye / coloring agent, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that is permitted by the relevant government regulatory authority to be acceptable for human or animal use.

[0146] The term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of the term "excipient" include, without limitation, binders, disintegrants, lubricants, flow aids, stabilizers, fillers, and diluents. Excipients enhance the handling properties of pharmaceutical formulations, i.e., by increasing flowability and / or adhesion, making the formulation more suitable for direct compression.

[0147] In this document, the term "treatment" refers to the use of a drug to achieve a desired pharmacological and / or physiological effect. This effect may be preventative in terms of complete or partial prevention of a disease or its symptoms, and / or therapeutic in terms of partial or complete cure of a disease and / or adverse effects caused by the disease. As used herein, "treatment" encompasses diseases in mammals, particularly humans, including: (a) prevention of disease or the onset of a condition in individuals susceptible to disease but not yet diagnosed with it; (b) suppression of disease, such as inhibiting disease progression; or (c) alleviating disease, such as reducing symptoms associated with the disease. As used herein, "treatment" encompasses any use of a drug to treat, cure, alleviate, improve, reduce, or suppress a disease in an individual, including but not limited to the administration of the drugs described herein to individuals in need.

[0148] The term "prevention" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0149] The term "patient" refers to any animal, preferably a mammal, that is about to receive or has already received administration of the compound or composition according to embodiments of the invention. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being preferred.

[0150] For pharmaceuticals or pharmacologically active agents, the terms "effective dose," "effective amount," or "therapeutic effective amount" refer to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. For the oral dosage forms of this invention, the "effective amount" of one active substance in the composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. A suitable effective amount in any given case can be determined by a person skilled in the art through routine testing.

[0151] This document also includes isotopically labeled compounds of the present invention that are identical to those compounds described herein except that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Exemplary isotopes that may also be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as... 2 H, 3 H, 13 C 14 C 15 N、 16 O、 17 O、 31 P, 32 P, 36 S, 18 F and 37 Cl. All isotopic variations of the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

[0152] Compounds of the present invention comprising other isotopes of the aforementioned isotopes and / or other atoms, as well as pharmaceutically acceptable salts of said compounds, are included within the scope of this invention. Isotope-labeled compounds of the present invention, such as radioactive isotopes, are also included. 3 H and 14 The incorporation of tritium into the compounds of this invention can be used for drug and / or substrate tissue distribution analysis. Due to its ease of preparation and detection, tritium-substituted compounds... 3 H, and carbon-14, i.e. 14 C isotopes are particularly preferred. In addition, heavier isotopes, such as deuterium, are used. 2 H substitution can offer therapeutic advantages stemming from greater metabolic stability, such as increased in vivo half-life or reduced dose requirements. Therefore, it may be preferred in some cases.

[0153] The term "alkyl" should be understood to mean a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or their isomers. In particular, the group has 1, 2 or 3 carbon atoms (“C1-C3 alkyl”), such as methyl, ethyl, n-propyl or isopropyl.

[0154] In this document, "alkylene" refers to a divalent group formed by removing another hydrogen atom from an alkyl group, and can be substituted or unsubstituted. In some embodiments, C 1-4 Alkylene, C 1-3 Alkylene, C 1-2 Alkylenes and methylene groups are preferred. Unsubstituted alkylenes include, but are not limited to: methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2-), and so on. Exemplary substituted alkylenes, for example, those substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- ), substituted propylidenes (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), etc. In some embodiments, straight-chain alkylene groups are preferred.

[0155] In this document, the term "alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group having at least one carbon-carbon sp2 double bond, including the orientation of "cis" and "trans", or the orientation of "E" and "Z". The alkenyl group may optionally be substituted by one or more substituents described in this invention. In one embodiment, the alkenyl group comprises 2-6 carbon atoms; in another embodiment, the alkenyl group comprises 2-5 carbon atoms; in yet another embodiment, the alkenyl group comprises 2-4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), etc. "Alkenylene" refers to a divalent group formed by removing another hydrogen atom from the alkenyl group, and may be substituted or unsubstituted.

[0156] In this document, the term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group containing 2-6 carbon atoms, wherein there is at least one carbon-carbon sp triple bond, wherein the alkynyl group may optionally be substituted by one or more substituents described in this invention. In one embodiment, the alkynyl group contains 2-5 carbon atoms; in another embodiment, the alkynyl group contains 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), 1-propynyl (-C≡C-CH3), etc. "Idemynyl" refers to a divalent group formed by removing one hydrogen atom from the alkynyl group, and may be substituted or unsubstituted.

[0157] In this document, the term "aryl" refers to an aromatic hydrocarbon substituent, which may be a monocyclic or polycyclic ring (e.g., one to three rings) fused together or covalently linked. The term "heteroaryl" refers to a plurality of aryl groups (or rings) comprising one to four heteroatoms selected from N, O, and S (in the case of polycyclic rings, in each monocyclic ring), wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Heteroaryl groups may be attached to the remainder of the compound via carbon atoms or heteroatoms. Non-limiting examples of aryl and heteroaryl groups include: phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrole, 2-pyrrole, 3-pyrrole, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isooxazolyl, 4-isooxazolyl, 5-isooxazolyl, 2-thiazolyl. The substituents in the above aryl and heteroaryl ring systems are selected from the acceptable substituent group described below. The terms "aryl" and "heteroaryl" refer to the divalent forms of the aryl and heteroaryl groups, respectively.

[0158] In this article, the term "oxo" refers to =O. When oxo is a substitution on the carbon chain, they together form the carbonyl moiety [-C(=O)-]. When oxo is a substitution on the ring, one or more atoms on the ring are replaced by -C(O)-, such as the 2-pyridone group.

[0159] In this article, the term "halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0160] In this paper, the structural formula "-[SL]2-Ar-" indicates that two SL units are connected to both sides of Ar respectively, which can be represented as -[SL]-Ar-[SL]-.

[0161] The compounds and preparation methods of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention and should not be construed as limiting the scope of protection of the present invention. All technical solutions implemented based on the content of the present invention are covered within the scope of protection intended by the present invention.

[0162] Unless otherwise specified, the experimental methods used in the following examples are conventional methods in the art; the reagents, raw materials, instruments, equipment, etc. used in the following examples are all commercially available.

[0163] The full names of the chemical substances used in this embodiment are shown in Table 1: Table 1: Compound Abbreviations and Corresponding Full Names

[0164] The amino acids and their structures used in polypeptide synthesis are shown in Table 2: Table 2: Amino acids and their structures

[0165] Example 1: Synthesis of the compound 1. Synthesis of Compound 1

[0166] 1.1 Synthesis of polypeptides: The peptide was synthesized using standard Fmoc chemical methods.

[0167] (1) Weigh out Fmoc-protected Rink Amide Resin (0.4 mmol, 1000 mg) and add it to the reaction column. Add 5 mL DMF and 5 mL DCM to the reaction column to swell the resin, remove the solvent, rinse with DMF and remove the solvent again.

[0168] (2) Deprotection: Add 50.0 mL of DMF solution containing 20% ​​piperidine to the resin, agitate with nitrogen for 15 min, wash the resin with DMF, and dry it to obtain the resin.

[0169] (3) Coupling of amino acids: Weigh Fmoc-D-Tyr(tBu)-OH (1.20 mmol, 3.00 eq) and HBTU (1.14 mmol, 2.85 eq) into the above resin, add 50.0 mL of DMF, and then add DIEA (2.40 mmol, 6.00 eq) dropwise into the reaction column. Purge with nitrogen to make the resin bulge evenly. After reacting at 20 °C for 60 min, remove the reaction solution, add DMF to wash, and discharge waste until no liquid flows out.

[0170] (4) Repeat steps 2 and 3 to condense the amino acids / coupling substrates numbered 2 to 6 in Table 3.

[0171] Table 3: Amino Acid / Conjugation Substrates and Conjugation Reagents

[0172] (5) De-Fmoc: Add 50.0 mL of DMF solution containing 20% ​​piperidine to the resin and agitate with nitrogen for 15 min. Wash the resin with DMF and remove the solvent by vacuum.

[0173] (6) De-OAll: Weigh Pd(PPh3)4 (0.4 mmol, 1.00 eq), dissolve it in DMF / DCM (1:1, v / v), add benzylsilane (124 μL, 5.00 eq), shake well and transfer to the reaction column. After reacting at room temperature for 2 h, remove the solvent and wash with DMF, then remove the solvent again.

[0174] (7) Cycloning: Weigh PyAop (1.52 mmol, 1.00 eq) and HOAT (1.52 mmol, 1.00 eq), dissolve them in DMF, add DIEA (3.2 mmol, 2.00 eq), then transfer the above mixed solution to the reaction column, react at room temperature for 1 h, remove the solvent, wash with DMF, and remove the solvent again.

[0175] (8) Coupling of amino acids: Add DMF solution containing 3% hydrazine hydrate to the reaction column, shake well, react for 3 min and then remove the solvent. Wash the resin with DMF, remove the solvent, and condense the amino acid / coupling substrate with serial number 7 in Table 3 according to step 3.

[0176] (9) Coupling of amino acids: Following steps 2 and 3, condense the amino acid / coupling substrate with serial number 8 in Table 3. Then shrink the resin with MeOH, discharge the waste until no liquid flows out, pour out the resin and dry it for later use.

[0177] 1.2 Peptide cleavage: At room temperature, the dried resin was added to the prepared cutting solution (92.5% TFA / 2.5% H2O / 2.5% TIS / 2.5% 3-Mpr, 20.0 mL) for cutting. The reaction solution was then added to frozen isopropyl ether, centrifuged to settle, and dried to obtain crude compound 1.

[0178] 1.3 Purification of peptides: The crude compound 1 was purified by preparative high-performance liquid chromatography (HPLC) (A: aqueous solution containing 0.075% TFA, B: acetonitrile) to obtain the final product compound 1 (70.7 mg, purity 95.1%, in the form of TFA salt). MS cal.: 1518.1, MS observed: [M / 3+H] + = 506.8.

[0179] LCMS of compound 1 as follows Figure 1 As shown.

[0180] HPLC of compound 1 as follows Figure 2 As shown.

[0181] 2. Synthesis of Compound 2

[0182] 2.1 Peptide Synthesis: (1) Weigh out Fmoc-protected Rink-Amide Resin (0.4 mmol, 1000 mg) and add it to the reaction column. Add 5 mL DMF and 5 mL DCM to the reaction column to swell the resin, remove the solvent, rinse with DMF and remove the solvent again.

[0183] (2) Deprotection: Add 50.0 mL of DMF solution containing 20% ​​piperidine to the resin and agitate with nitrogen for 15 min. Wash the resin with DMF and dry it under vacuum to obtain the resin.

[0184] (3) Coupling of amino acids: Weigh Fmoc-D-Tyr(tBu)-OH (1.20 mmol, 3.00 eq) and HBTU (1.14 mmol, 2.85 eq) into the above resin, add 50.0 mL of DMF, and then add DIEA (2.40 mmol, 6.00 eq) dropwise into the reaction column. Purge with nitrogen to make the resin bulge evenly. After reacting at 20 °C for 60 min, remove the reaction solution, add DMF to wash, and discharge waste until no liquid flows out.

[0185] (4) Repeat steps 2 and 3 to condense the amino acids / coupling substrates numbered 2 to 9 in Table 4.

[0186] Table 4: Amino Acid / Conjugation Substrates and Conjugation Reagents

[0187] Shrink the resin with MeOH, discharge the waste until no more liquid flows out, pour out the resin and dry it for later use.

[0188] 2.2 Peptide cleavage: At room temperature, the dried resin was added to the prepared cutting solution (92.5% TFA / 2.5% H2O / 2.5% TIS / 2.5% 3-Mpr, 20.0 mL) for cutting. The reaction solution was added to frozen isopropyl ether, centrifuged to settle, and then dried.

[0189] 2.3 Cyclation of peptides: The dried product was dissolved in a 1:1 (v / v) mixture of acetonitrile and purified water, and DIPEA (7.20 eq) and 1,3-di(bromomethyl)benzene (1.20 eq) were added. After the reaction was complete, mercaptoethylamine (3.60 eq) was added to the reaction solution to obtain crude compound 2.

[0190] 2.4 Purification of peptides: The crude compound 2 was purified by preparative high-performance liquid chromatography (HPLC) (A: aqueous solution containing 0.075% TFA, B: acetonitrile) to obtain the final product compound 2 (120.6 mg, purity 97.8%, in the form of TFA salt). MS cal.: 1654.3, MS observed: [M / 3+H] + = 552.3.

[0191] LCMS of compound 2 as follows Figure 3 As shown.

[0192] HPLC analysis of compound 2 Figure 4 As shown.

[0193] 3. Synthesis of Compound 3

[0194] 3.1 Peptide Synthesis: (1) Weigh out Fmoc-protected Rink-Amide Resin (0.4 mmol, 1000 mg) and add it to the reaction column. Add 5 mL DMF and 5 mL DCM to the reaction column to swell the resin, remove the solvent, rinse with DMF and remove the solvent again.

[0195] (2) Deprotection: Add 50.0 mL of DMF solution containing 20% ​​piperidine to the resin and agitate with nitrogen for 15 min. Wash the resin with DMF and dry it under vacuum to obtain the resin.

[0196] (3) Coupling of amino acids: Weigh Fmoc-D-Tyr(tBu)-OH (1.20 mmol, 3.00 eq) and HBTU (1.14 mmol, 2.85 eq) into the above resin, add 50.0 mL of DMF, and then add DIEA (2.40 mmol, 6.00 eq) dropwise into the reaction column. Purge with nitrogen to make the resin bulge evenly. After reacting at 20 °C for 60 min, remove the reaction solution, add DMF to wash, and discharge waste until no liquid flows out.

[0197] (4) Repeat steps 2 and 3 to condense the amino acids / coupling substrates numbered 2 to 6 in Table 5.

[0198] Table 5: Amino Acids and Coupling Reagents

[0199] (5) De-Fmoc: Add 50.0 mL of DMF solution containing 20% ​​piperidine to the resin and agitate with nitrogen for 15 min. Wash the resin with DMF and dry it to obtain the resin.

[0200] (6) De-OAll: Weigh Pd(PPh3)4 (0.4 mmol, 1.00 eq), add DMF / DCM (1:1, v / v) to dissolve, add benzylsilane (124 μL, 5.00 eq), shake well and transfer to the reaction column. After reacting at room temperature for 2 h, remove the solvent and wash with DMF, then remove the solvent.

[0201] (7) Cycloning: Weigh PyAop (1.52 mmol, 1.00 eq) and HOAT (1.52 mmol, 1.00 eq), dissolve them in DMF, add DIEA (3.2 mmol, 2.00 eq), then transfer the above mixed solution to the reaction column, react at room temperature for 1 h, remove the solvent, wash with DMF, and remove the solvent again.

[0202] (8) Coupling of amino acids: Add DMF solution containing 3% hydrazine hydrate to the reaction column, shake well, react for 3 min and then remove the solvent. Wash the resin with DMF, remove the solvent, and condense the amino acid / coupling substrate in Table 5 according to step 3.

[0203] (9) Coupling of amino acids: Following steps 2 and 3, condense the amino acid / coupling substrate with serial number 8 in Table 5. Then shrink the resin with MeOH, discharge the waste until no liquid flows out, pour out the resin and dry it for later use.

[0204] 3.2 Peptide cleavage: At room temperature, the dried resin was added to the prepared cutting solution (92.5% TFA / 2.5% H2O / 2.5% TIS / 2.5% 3-Mpr, 20.0 mL) for cutting. The reaction solution was then added to frozen isopropyl ether, centrifuged to settle, and dried to obtain crude compound 3.

[0205] 3.3 Purification of peptides: The crude compound 3 was purified by preparative high-performance liquid chromatography (HPLC) (A: aqueous solution containing 0.075% TFA, B: acetonitrile) to obtain the final product compound 3 (86.8 mg, purity 98.2%, in the form of TFA salt). MS cal.: 1529.1, MS observed: [M / 3+H] + = 510.5.

[0206] LCMS of compound 3 as follows Figure 5 As shown; HPLC analysis of compound 3, such as Figure 6 As shown.

[0207] 4. Synthesis of Compound 4

[0208] 4.1 Peptide Synthesis: (1) Weigh out Fmoc-protected Rink-Amide Resin (0.4 mmol, 1000 mg) and add it to the reaction column. Add 5 mL DMF and 5 mL DCM to the reaction column to swell the resin, remove the solvent, rinse with DMF and remove the solvent again.

[0209] (2) Deprotection: Add 50.0 mL of DMF solution containing 20% ​​piperidine to the resin and agitate with nitrogen for 15 min. Wash the resin with DMF and dry it under vacuum to obtain the resin.

[0210] (3) Coupling of amino acids: Weigh Fmoc-D-Tyr(tBu)-OH (1.20 mmol, 3.00 eq) and HBTU (1.14 mmol, 2.85 eq) into the above resin, add 50.0 mL of DMF, and then add DIEA (2.40 mmol, 6.00 eq) dropwise into the reaction column. Purge with nitrogen to make the resin bulge evenly. After reacting at 20 °C for 60 min, remove the reaction solution, add DMF to wash, and discharge waste until no liquid flows out.

[0211] (4) Repeat steps 2 and 3 to condense the amino acids / coupling substrates numbered 2-6 in Table 6: Table 6: Amino Acids and Coupling Reagents

[0212] (5) De-Fmoc: Add 50.0 mL of DMF solution containing 20% ​​piperidine to the resin and agitate with nitrogen for 15 min. Wash the resin with DMF and dry it to obtain the resin.

[0213] (6) De-OAll: Weigh Pd(PPh3)4 (0.4 mmol, 1.00 eq), dissolve it in DMF / DCM (1:1, v / v), add benzylsilane (124 μL, 5 eq), shake well, transfer to the reaction column, react at room temperature for 2 h, then remove the solvent, wash with DMF, and remove the solvent again.

[0214] (7) Cycloning: Weigh PyAop (1.52 mmol, 1.00 eq) and HOAT (1.52 mmol, 1.00 eq), dissolve them in DMF, add DIEA (3.2 mmol, 2.00 eq), then transfer the above mixed solution to the reaction column, react at room temperature for 1 h, remove the solvent, wash with DMF, and remove the solvent again.

[0215] (8) Coupling of amino acids: Add DMF solution containing 3% hydrazine hydrate to the reaction column, shake well, react for 3 min and then remove the solvent. Wash the resin with DMF, remove the solvent, and follow step 3 to condense the amino acid / coupling substrate number 7 in Table 6.

[0216] (9) Coupling of amino acids: Following steps 2 and 3, condense the amino acid / coupling substrate with serial number 8 in Table 6. Then shrink the resin with MeOH, discharge the waste until no liquid flows out, pour out the resin and dry it for later use.

[0217] 4.2 Peptide cleavage: At room temperature, the dried resin was added to the prepared cutting solution (92.5% TFA / 2.5% H2O / 2.5% TIS / 2.5% 3-Mpr, 20.0 mL) for cutting. The reaction solution was then added to frozen isopropyl ether, centrifuged to settle, and dried to obtain crude compound 4.

[0218] 4.3 Purification of peptides: The crude compound 4 was purified by preparative high-performance liquid chromatography (HPLC) (A: aqueous solution containing 0.075% TFA, B: acetonitrile) to obtain the final product compound 4 (90.6 mg, purity 95.5%, in the form of TFA salt). MS cal.: 1529.1, MS observed: [M / 3+H] + = 510.4.

[0219] LCMS of compound 4, such as Figure 7 As shown; HPLC analysis of compound 4, such as Figure 8 As shown.

[0220] 5. Synthesis of Compound 5

[0221] 5.1 Peptide Synthesis: (1) Weigh out Fmoc-protected Rink-Amide Resin (0.4 mmol, 1000 mg) and add it to the reaction column. Add 5 mL DMF and 5 mL DCM to the reaction column to swell the resin, remove the solvent, rinse with DMF and remove the solvent again.

[0222] (2) Deprotection: Add 50.0 mL of DMF solution containing 20% ​​piperidine to the resin and agitate with nitrogen for 15 min. Wash the resin with DMF and dry it under vacuum to obtain the resin.

[0223] (3) Coupling of amino acids: Weigh Fmoc-D-Tyr(tBu)-OH (1.20 mmol, 3.00 eq) and HBTU (1.14 mmol, 2.85 eq) into the above resin, add 50.0 mL of DMF, and then add DIEA (2.40 mmol, 6.00 eq) dropwise into the reaction column. Purge with nitrogen to make the resin bulge evenly. After reacting at 20 °C for 60 min, remove the reaction solution, add DMF to wash, and discharge waste until no liquid flows out.

[0224] (4) Repeat steps 2 and 3 to condense the amino acids / coupling substrates numbered 2-6 in Table 7: Table 7: Amino Acids and Coupling Reagents

[0225] (5) De-Fmoc: Add 50.0 mL of DMF solution containing 20% ​​piperidine to the resin and agitate with nitrogen for 15 min. Wash the resin with DMF and dry it to obtain the resin.

[0226] (6) De-OAll: Weigh Pd(PPh3)4 (0.4 mmol, 1.00 eq), dissolve it in DMF / DCM (1:1, v / v), add benzylsilane (124 μL, 5.00 eq), shake well and transfer to the reaction column. After reacting at room temperature for 2 h, remove the solvent and wash with DMF, then remove the solvent again.

[0227] (7) Cycloning: Weigh PyAop (1.52 mmol, 1.00 eq) and HOAT (1.52 mmol, 1.00 eq), dissolve them in DMF, add DIEA (3.2 mmol, 2.00 eq), then transfer the above mixed solution to the reaction column, react at room temperature for 1 h, remove the solvent, wash with DMF, and remove the solvent again.

[0228] (8) Coupling of amino acids: Add DMF solution containing 3% hydrazine hydrate to the reaction column, shake well, react for 3 min and then remove the solvent. Wash the resin with DMF, remove the solvent, and condense the amino acid / coupling substrate with serial number 7 in Table 7 according to step 3.

[0229] (9) Coupling of amino acids: Following steps 2 and 3, condense the amino acid / coupling substrate with serial number 8 in Table 7. Then shrink the resin with MeOH, discharge the waste until no liquid flows out, pour out the resin and dry it for later use.

[0230] 5.2 Peptide cleavage: At room temperature, the dried resin was added to the prepared cutting solution (92.5% TFA / 2.5% H2O / 2.5% TIS / 2.5% 3-Mpr, 20.0 mL) for cutting. The reaction solution was then added to frozen isopropyl ether, centrifuged to settle, and dried to obtain crude compound 5.

[0231] 5.3 Purification of peptides: The crude compound 5 was purified by preparative high-performance liquid chromatography (HPLC) (A: aqueous solution containing 0.075% TFA, B: acetonitrile) to obtain the final product compound 5 (75.6 mg, purity 97.5%, in the form of TFA salt). MS cal.: 1532.1, MS observed: [M / 2+H] + = 766.9.

[0232] LCMS of compound 5 as follows Figure 9 As shown; HPLC analysis of compound 5, such as Figure 10 As shown.

[0233] Example 2: Labeling of compounds 1. 68 Labeling processes for Ga compounds Add 1 mL of sodium acetate / acetic acid buffer solution (pH=7.2) to the reaction flask, then add 60 μL of an aqueous solution of the compound (containing 60 μg), mix thoroughly, and then add 1 mL of... 68 The GaCl3 solution was mixed thoroughly with 0.1 M hydrochloric acid and reacted at 80 °C for 10 min. After the reaction was complete, the reaction solution was purified by passing it through a C18 column and filtered through a sterile membrane to obtain the labeled product.

[0234] Sampling and testing, measured by HPLC 68 Ga-compound 1, 68 Ga-compound 2, 68 Ga-compound 3. 68 Ga-compound 4, 68 The radiochemical purity test results of Ga-compound 5 are as follows: Figures 11-15 As shown, the radiochemical purities are 96.12%, 95.70%, 98.09%, 96.08%, and 96.89%, respectively.

[0235] 2. 177 Labeling processes for Lu-compounds Add 1 mL of sodium acetate / acetic acid buffer solution (pH=7.2) to the reaction flask, add 50 μL of the compound aqueous solution (containing 50 μg), mix thoroughly, and add 1 mL of […]. 177 The pH of the reaction solution was adjusted to 4-5 using a 0.05 M hydrochloric acid solution of Lu-LuCl3. The reaction solution was then reacted at 80 °C for 15 min, and the reaction was terminated. The labeled product was obtained by filtration through a sterile filter membrane.

[0236] Sampling and testing, measured by HPLC 177 Lu-compound 1, 177 The radiochemical purity test results of Lu-compound 5 are as follows: Figures 16-17 As shown, the radiochemical purities are 96.63% and 96.95%, respectively.

[0237] Example 3: Compound Affinity Experiment The binding affinity of compounds to the SSTR2 receptor was determined using a radioligand-receptor competitive binding assay.

[0238] SSTR2 / CHO-K1 cells were loaded at 1×10 5 Cells were seeded at a density of 10 cells / well into 96-well plates (purchased from Corning). DMSO solutions of the test compound were added to the 96-well plates in 3-fold serial dilutions. Radioactive ligands were then added. 125 I-Somatostatin-14 (NEX389, purchased from Revvity) was incubated at 25 °C for 180 min.

[0239] After incubation, the liquid in the 96-well plate was filtered, washed, and dried. Then, scintillation solution (purchased from Revvity) was added, and the plate was used in TopCount mode on the MicroBeta counter (MicroBeta2, 2450-0060). 125 The I-program reads the plate and determines the required concentration of the analyte at 50% inhibition rate (IC50) using a four-parameter logistic dose-response model. 50 ).

[0240] The experimental results are shown in Table 8. All the compounds disclosed in this invention exhibit a certain affinity for the SSTR2 receptor protein, with compound 5 showing the highest IC50. 50 The value was 1.73 nM, reaching the nM level, indicating that compound 5 has a strong affinity for the SSTR2 receptor protein.

[0241] Table 8: IC50 of compounds 50 value

[0242] Example 4: 68 PET / CT Imaging Experiments of Ga-Compounds on AR42J Tumor Model Mice The AR42J tumor model mice used in this embodiment were obtained from Biocytogen Jiangsu Gene Biotechnology Co., Ltd. This model is a xenograft model constructed by inoculating AR42J rat pancreatic exocrine cells into Balb / c nude mice.

[0243] The AR42J tumor model mice were selected and divided into groups for the experiment. Mice in each group were given the same drug, with each mouse receiving 80 μCi of the drug. 68 Ga-compound 1, 68 Ga-compound 2, 68 Ga-compound 3. 68 Ga-compound 4, 68 Ga-Compound 5.

[0244] Mice that had been pre-anesthetized were placed in a MicroPET / CT imaging chamber (SNPC-303 Super Nova, Ping Sheng Medical Technology (Kunshan) Co., Ltd.) and kept under anesthesia. MicroPET / CT scans were performed at different times after drug administration.

[0245] After reconstruction by the equipment software, the scanned image is obtained. The region of interest (ROI) is analyzed to determine the uptake of the radioactive tracer and obtain the %ID / g value.

[0246] The results are shown in Table 9. The drug exhibited tumor uptake 30 minutes after administration and maintained relatively stable uptake at the tumor site for 1 hour after administration. Simultaneously, the drug-to-target ratio was good. 68 Ga-compound 4 and 68 One hour after administration, the ratio of tumor uptake to muscle uptake of Ga-compound 5 exceeded 3, enabling high-quality imaging and providing more accurate diagnostic information. Experimental results indicate that the drug disclosed in this invention possesses good tumor targeting properties and has the potential to serve as a tumor visualization diagnostic agent.

[0247] Table 9: 68 Radioactive uptake of Ga compounds in different tissues of a mouse tumor model

[0248] Example 5: 177 SPECT / CT Imaging Experiment of Lu-Compounds in AR42J Tumor Model Mice The AR42J tumor model mice used in this embodiment were obtained from Biocytogen Jiangsu Gene Biotechnology Co., Ltd. This model is a xenograft model constructed by seeding AR42J rat pancreatic exocrine cells into Balb / c nude cells.

[0249] The AR42J tumor model mice were randomly selected into groups for the experiment. Mice in each group were given the same drug, with each mouse receiving 1 mCi of the drug. 177 Lu-compound 1, 177 Lu-compound 5. SPECT / CT scans were performed after drug administration to obtain scan images.

[0250] See Table 10 and Figure 18 It can be seen that 4 hours after administration, 177 Lu-compound 1, 177 Compound 5 of the Lu-type compound exhibits good targeting in vivo, showing high uptake at the tumor site (indicated by the arrow), enabling precise radiation therapy to the tumor lesion. It is primarily excreted rapidly through the kidneys, demonstrating... 177 Lu-compound 1,177 Lu-compound 5 has potential applications in the treatment of tumors expressing SSTR2.

[0251] Table 10: 177 Radioactive uptake of Lu-compounds in different tissues of tumor model mice

[0252] Example 6: 177 In vitro tissue distribution of Lu-compounds in AR42J tumor model mice Nine AR42J tumor model mice were randomly selected and administered the following treatments: 177 Three animals were dissected at 4 h, 24 h, and 48 h after administration of Lu-compound 5 drug at a dose of 0.3 mCi. Fifteen tissues and organs were collected, including the brain, heart, kidney, large intestine, small intestine, liver, lung, pancreas, ovary, muscle, spleen, stomach, fat, tumor, and thyroid gland, and gamma radiation counts were measured.

[0253] See Figure 19 As shown in Table 11, 177 Compound 5 of the Lu-type compound showed high uptake at the tumor site 4 hours after administration, but very low uptake at other non-target organs besides the kidneys. Significant uptake was still observed at the tumor site 48 hours after administration. This indicates... 177 Lu-compound 5 can specifically target tumors, maintain uptake and retention time in tumors, while having low uptake in non-target organs and can be rapidly cleared by the kidneys, indicating that the radiopharmaceutical provided by this invention has the potential for therapeutic application in tumors expressing SSTR2.

[0254] Table 11: 177 Radioactive uptake of Lu-compound 5 in different tissues of tumor model mice

[0255] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., refer to specific features, structures, materials, or characteristics described in connection with that embodiment or example, which are included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0256] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A compound that is a compound of Formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of a compound of Formula I: in, Ra is selected from -S-, -O-, C 1~6 Alkylene, C 2~6 imidene group, C 2~6 Ethyne group, -SC 1~6 Alkylene, C 1~6 Alkylene-NH-, -[SL]2-Ar-, -SLS-, 5- to 8-membered heteroaryl, wherein C 1~6 Alkylene, C 2~6 imidene group, C 2~6 Ethyne group, -SC 1~6 Alkylene, C 1~6 Alkyl-NH-, -[LSL]2-Ar-, -SLS-, and 5- to 8-membered heteroaryl groups are optionally substituted with one or more R3 groups; L is C 1~6 Alkylene, where Ar is a 6-8 arylene group; R1 and R2 are each independently selected from C 1~10 Alkylene; R3 is independently selected from H, halogen, oxo, and C. 1~6 alkyl; Z is a chelating group derived from the chelating agent.

2. The compound according to claim 1, characterized in that, The compound satisfies one or more of the following conditions: (1) Ra is selected from -S-, -O-, C 1~3 Alkylene, C 2~4 imidene group, C 2~4 Ethyne group, -SC 1~3 Alkylene, C 1~3 Alkylene-NH-, -[SL]2-Ar-, -SLS-, 5- to 6-membered heteroaryl, wherein C 1~3 Alkylene, C 2~4 imidene group, C 2~4 Ethyne group, -SC 1~3 Alkylene, C 1~3 Alkyl-NH-, -[SL]2-Ar-, -SLS-, and 5- to 6-membered heteroaryl groups are optionally substituted with one or more R3 groups; L is C 1~3 Alkylene, Ar is phenylene; (2) R1 and R2 are independently selected from C 1~5 Alkylene; (3) R3 is independently selected from H, halogen, oxo, and C. 1~3 alkyl; (4) In Z, the chelating agent is selected from 1,4,7,10-tetraazacyclododecane-N,N',N",N'''-tetraacetic acid, N,N"-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N"-diacetic acid, 1,4,7-triazacyclononane-1,4,7-triacetic acid, 2-(4,7-bis(carboxymethyl)-1,4,7-triazononon-1-yl)glutaric acid, 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutaric acid, 1,4,7-triazacyclononanephosphonic acid, 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphonic acid]-4,7-bis[methyl(2-hydroxy-5 ... [Methyl)phosphonic acid], 3,6,9,15-tetraazabicyclo[9.3.1.]pentadecan-1(15),11,13-trien-3,6,9-triacetic acid, N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutyryl}amino)pentyl]-N-hydroxysuccinamide, diethylenetriaminepentaacetic acid, trans-cyclohexyl-diethylenetriaminepentaacetic acid, 1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid, p-isocyanothiobenzyl-DTPA, 1-(p-isocyanothiobenzyl)-3-methyl-DTPA, 2-(p-isocyanothiobenzyl)-4-methyl-DTPA At least one of the following: 1-(2)-methyl-4-isocyanothiobenzyl-DTPA, [(R)-2-amino-3-(4-isothiocyanophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid, 6-hydrazylpyridine-3-carboxylic acid, 2-(4-isothiocyanophenyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid, and 2-[(4-isothiocyanophenyl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid.

3. The compound according to claim 2, characterized in that, The compound satisfies one or more of the following conditions: (1) Ra is selected from -S- and C 2~4 alkenyl, -SC 1~3 Alkylene, C 1~3 Alkylene-NH-, -[SL]2-Ar-, -SLS-, 5-membered heteroaryl, wherein C 2~4 alkenyl, -SC 1~3 Alkylene, C 1~3 The alkylene group -NH-, -[SL]2-Ar-, -SLS-, and the 5-membered heteroaryl group are optionally substituted with one or more R3 groups; L is C 1~3 Alkylene, Ar is phenylene; (2) R1 and R2 are independently selected from C 1~3 Alkylene; (3) R3 is independently selected from H and oxo; (4) In Z, the chelating agent is selected from 1,4,7,10-tetraazacyclododecane-N,N',N",N'''-tetraacetic acid, N,N"-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N"-diacetic acid, 1,4,7-triazacyclononane-1,4,7-triacetic acid, 2-(4,7-bis(carboxymethyl)-1,4,7-triazonon-1-yl)glutaric acid, 2-(4,7,10-tris(carboxymethyl)-1,4,7 At least one of the following: 10-tetraazacyclododecane-1-yl)glutaric acid, [(R)-2-amino-3-(4-isothiocyanophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid, 2-(4-isothiocyanophenyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid, and 2-[(4-isothiocyanophenyl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid.

4. The compound according to any one of claims 1-3, characterized in that, Ra is selected from -S-, , , , , , m is selected from any positive integer between 1 and 5. , ; Optionally, Z is selected from , , , , , , , At least one of them.

5. The compound according to claim 1, characterized in that, The compound is a compound of Formula II or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of a compound of Formula II. Wherein, Z is selected from 1,4,7,10-tetraazacyclododecane-N,N',N",N'''-tetraacetic acid, N,N"-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N"-diacetic acid, 1,4,7-triazacyclononane-1,4,7-triacetic acid, 2-(4,7-bis(carboxymethyl)-1,4,7-triazonon-1-yl)glutaric acid, 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutaric acid, 1,4,7-triazacyclononanephosphonic acid, 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphonic acid]-4,7-bis[methyl(2-hydroxymethyl)] Phosphine, 3,6,9,15-tetraazabicyclo[9.3.1.]pentadecan-1(15),11,13-trien-3,6,9-triacetic acid, N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutyryl}amino)pentyl]-N-hydroxysuccinamide, diethylenetriaminepentaacetic acid, trans-cyclohexyl-diethylenetriaminepentaacetic acid, 1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid, p-isocyanothiobenzyl-DTPA, 1-(p-isocyanothiobenzyl)-3-methyl-DTPA, 2-(p-isocyanothiobenzyl)-4-methyl-DTPA At least one of the following: 1-(2)-methyl-4-isocyanothiobenzyl-DTPA, [(R)-2-amino-3-(4-isothiocyanophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid, 6-hydrazylpyridine-3-carboxylic acid, 2-(4-isothiocyanophenyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid, and 2-[(4-isothiocyanophenyl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; Rb is selected from -S-, C 2~4 alkenyl, -SC 1~3 Alkylene, C 1~3 Alkylene-NH-, -[SL]2-Ar-, -SLS-, 5-membered heteroaryl, wherein C 2~4 alkenyl, -SC 1~3 Alkylene, C 1~3 The alkylene group -NH-, -[SL]2-Ar-, -SLS-, and the 5-membered heteroaryl group are optionally substituted with one or more R4 groups; L is C 1~3 Alkylene, Ar is phenylene; R4 is independently selected from H and oxo; Optional, Rb is selected from -S-, , , , , , m is selected from any positive integer between 1 and 5. , .

6. The compound according to claim 5, characterized in that, Rb is selected from -S- and -SC. 1~3 Alkylene, C 1~3 Alkylene-NH-, -[SL]2-Ar-, the -SC 1~3 Alkylene, C 1~3 Alkylene-NH-, -[SL]2-Ar- are optionally substituted with one or more R4; Optional, Rb is selected from -S-, , , , , ; Optional, Rb is selected from -S-, , , .

7. The compound according to claim 1, characterized in that, It is a compound represented by the following formula, or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof: 。 8. The compound according to claim 1, characterized in that, It is a compound represented by the following formula, or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof: 。 9. A complex, characterized in that, The complex is formed by complexing M with the compound of any one of claims 1-8, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug; Wherein, M is selected from at least one of a radioactive nuclide or a non-radioactive element; Optionally, the radionuclide is selected from... 67 / 68 Ga、 18 F, 94m / 99m Tc, 89 Zr、 111 In、 45 Ti、 59 Fe、 60 / 61 / 62 / 64 / 67 Cu、 71 / 72 / 74 As、 43 / 44 / 47 Sc、 82m Rb、 52 Mn, 86 / 90 Y、 76 Br、 177 Lu、 153 Sm、 89 Sr、 123 / 124 / 131 I, 137 Cs、 161 Tb, 166 Ho、 177 Yb、 105 Rh、 186 / 188 Re、 212 / 213 Bi、 211 At、 223 Ra、 225 Ac、 212 Pb, 149 Pm and 227 Th; Preferably, the radionuclide is selected from... 68 Ga、 18 F, 177 Lu、 64 Cu、 161 Tb, 225 Ac、 89 Zr、 99m Tc; Preferably, the radionuclide 18 F is through 18 FAl is formed by complexing the compound with the compound or the tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound; Optionally, M is complexed with a chelating group in the compound or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of the compound.

10. An imaging agent, characterized in that, include: The compound of any one of claims 1-8, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the complex of claim 9.

11. A pharmaceutical composition, characterized in that, include: The compound of any one of claims 1-8, or its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the complex of claim 9, or the imaging agent of claim 10; Optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

12. Use of the compound of any one of claims 1-8, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or a complex of claim 9, or an imaging agent of claim 10, or a pharmaceutical composition of claim 11, in the preparation of a medicament for the diagnosis and / or treatment of a disease characterized by overexpression of somatostatin receptor 2.

13. The use according to claim 12, characterized in that, The diagnostic method is selected from radionuclide imaging; Optionally, the diagnostic method is selected from positron emission tomography or single-photon emission computed tomography. Optionally, the treatment is selected from radiotherapy; Optionally, the disease is selected from at least one of tumors, nervous system diseases, and metabolic diseases; Optionally, the disease is selected from at least one of the following: neuroendocrine tumors, neuroblastoma, melanoma, thyroid cancer, meningioma, breast cancer, gastrointestinal tumors, liver cancer, nasopharyngeal carcinoma, pancreatic cancer, small bowel cancer, colon cancer, rectal cancer, head and neck cancer, ovarian cancer, esophageal cancer, myeloma, cervical cancer, prostate cancer, bladder cancer, laryngeal cancer, bile duct cancer, renal cell carcinoma, sarcoma, lung cancer, thymic carcinoma, glioma, neuroglioma, astrocytoma, and lymphoma; Optionally, the neuroendocrine tumor is selected from at least one of gastrointestinal neuroendocrine tumors, pancreatic neuroendocrine tumors, bronchopulmonary neuroendocrine tumors, thymic neuroendocrine tumors, and pituitary neuroendocrine tumors. Optionally, the neuroendocrine tumor is selected from at least one of gastrinoma, glucagonoma, insulinoma, somatostatinoma, medullary thyroid carcinoma, growth hormone-secreting tumor, prolactinoma, thyrotropinoma, pheochromocytoma / paraganglioma, Merkel cell carcinoma, pituitary adenoma, parathyroid adenoma, and small cell lung cancer.

14. A method for imaging tissues or cells expressing somatostatin receptor 2, characterized in that, include: The application of the compound of any one of claims 1-8, or its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the complex of claim 9, or the imaging agent of claim 10, or the pharmaceutical composition of claim 11, to the tissue or cells. And to image the tissues or cells after drug administration.

15. The method according to claim 14, characterized in that, The imaging was performed using positron emission tomography or single-photon emission computed tomography.

Images