PSMA binders and their applications

Abstract

This invention provides compounds having the structure shown in Formula I, or pharmaceutically acceptable salts, esters, or solvates thereof, including complexes of said compounds or pharmaceutically acceptable salts, esters, or solvates thereof as ligands and radiolabeled radionuclides, and their uses. Compared with existing compounds, the compounds of this invention exhibit better effects in tumor targeting performance, pharmacokinetics, and regulation of lipophilicity.

Description

Technical Field

[0001] This invention belongs to the field of radiopharmaceuticals, specifically relating to a compound that can bind to prostate-specific membrane antigen (PSMA) and its uses. Background Technology

[0002] Prostate cancer (PCa) is one of the most common cancers in men. It usually progresses slowly, but if it becomes malignant or metastasizes, it becomes extremely difficult to treat. Metastasis, recurrence, and androgen resistance are the main causes of death in prostate cancer patients.

[0003] Currently, the main diagnostic methods for prostate cancer include prostate-specific antigen (PSA) testing, digital rectal examination, and transrectal ultrasound, CT, MRI, and whole body bone scan (WBBS) imaging. In most cases, the diagnostic accuracy is low, making it unsuitable for early diagnosis and difficult to determine whether metastasis has occurred. Furthermore, the distinction between prostate cancer and benign diseases (such as benign prostatic hyperplasia and prostatitis) remains unclear, leading to missed diagnoses and misdiagnoses.

[0004] Prostate-specific membrane antigen (PSMA) is a protein highly specifically expressed on the surface of prostate cancer cells. Its expression is further elevated in metastatic hormone-resistant prostate cancer (PCa), but only in small amounts in normal tissues. This makes PSMA an ideal biomarker for radionuclide imaging and / or targeted therapy in prostate cancer. Because metastatic hormone-resistant PCa is highly malignant, has a poor prognosis, and represents an inevitable stage in PCa development, PSMA has become a major target for PCa diagnosis and / or treatment. A monoclonal antibody radionuclide imaging agent targeting PSMA has been successfully marketed and approved by the US Food and Drug Administration (FDA) for prostate cancer imaging. However, its binding site to PSMA is located within the cell membrane, primarily binding to necrotic tumor tissue rather than living tumor cells, limiting its widespread application (see: CN 111777663 A).

[0005] Despite some progress made in recent years, the diagnosis, management, and / or treatment of prostate cancer (PCa) remain highly challenging. There is still a need to develop novel diagnostic or imaging agents that can target PCa tumor cells in a highly selective manner, exhibiting favorable pharmacokinetic properties and / or other effects, to enable rapid and non-invasive tumor visualization and treatment, thereby achieving early diagnosis and / or treatment of PCa.

[0006] In view of this, the present invention is hereby proposed. Summary of the Invention

[0007] In view of the problems and / or shortcomings of the existing technology, the purpose of this invention is to provide an improved PSMA compound and its uses.

[0008] According to one aspect of the invention, a compound of formula I or a pharmaceutically acceptable salt, ester, or solvate thereof is provided.

[0009] Preferred

[0010] in,

[0011] R1, R2, and R3 are independently selected from H, substituted or unsubstituted aryl groups, substituted or unsubstituted heteroaryl groups, and substituted or unsubstituted heterocyclic groups (preferably, the heterocyclic group is a nitrogen-containing heterocyclic group containing 2 to 50 carbons, for example: 3 carbons, 4 carbons, 5 carbons, 6 carbons, 10 carbons, 15 carbons, 20 carbons, 25 carbons, 30 carbons, etc.). The substituents in the substituted aryl group, the substituents in the substituted heteroaryl group, and the substituents in the substituted heterocyclic group are independently selected from deuterium, tritium, halogens (e.g., fluorine, chlorine, bromine, iodine, etc.), and C1-C2 groups. 10 Alkyl, deuterated C1-C 10 Alkyl, tritium C1-C 10 Alkyl and halogenated C1-C 10 Alkyl, C1-C 10 Alkyl groups, deuterated C1-C 10 Alkyl groups, tritium groups (C1-C) 10 Alkyl or halogenated C1-C 10 Alkoxy; preferably, the substituents in the substituted aryl group, the substituents in the substituted heteroaryl group, and the substituents in the substituted heterocyclic group are independently selected from deuterium, tritium, halogen, C1-C4 alkyl, deuterated C1-C4 alkyl, tritated C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, deuterated C1-C4 alkoxy, tritated C1-C4 alkoxy, or halogenated C1-C4 alkoxy.

[0012] Preferably, R1, R2, and R3 are independently selected from H, substituted or unsubstituted aryl groups, and at least one of R1, R2, and R3 is a substituted or unsubstituted aryl group; more preferably, R1, R2, and R3 are independently selected from H, substituted or unsubstituted aryl groups, and at least one of R1, R2, and R3 is a substituted or unsubstituted aryl group, wherein the substituent in the substituted aryl group is selected from deuterium, tritium, halogen, C1-C4 alkyl, deuterated C1-C4 alkyl, tritated C1-C4 alkyl, halogenated C1-C4 alkyl, etc. C4 alkyl, C1-C4 alkoxy, deuterated C1-C4 alkoxy, tritated C1-C4 alkoxy, or halogenated C1-C4 alkoxy; more preferably, at least one of R1, R2, and R3 is an unsubstituted aryl group; or, at least one of R1, R2, and R3 is a substituted aryl group, wherein the substituent in the substituted aryl group is selected from deuterium, tritium, deuterated C1-C4 alkyl, tritated C1-C4 alkyl, deuterated C1-C4 alkoxy, or tritated C1-C4 alkoxy.

[0013] R6 is H or -(CH2) k -COOH, where k is an integer selected from 0 to 10, preferably an integer selected from 1 to 4, such as 1, 2, 3 or 4;

[0014] R4 is R 41 It is -COOH, -SO2H, -SO3H, -SO4H, -PO2H, -PO3H or -PO4H2; preferably, R4 is R 41 It is -COOH (carboxyl group);

[0015] R5 is Preferred or

[0016] m and n are independently selected from 0 or 1;

[0017] a, b, c, d, e, and f are independently selected from integers from 0 to 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10); preferably, a, b, c, d, e, and f are independently selected from integers from 0 to 4 (e.g., 0, 1, 2, 3, 4);

[0018] X is a chelating agent; preferably, the chelating agent contains a carboxyl group, a hydroxyl group, or a mercapto group; preferably, X is 1,4,7,10-tetraazacyclododecane-1,4,7,10-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-triazolyl-1-yl)glutaric acid (NODAGA), or 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutaric acid (DOTAGA). 1,4,7-Triazacyclononanephosphonic acid (TRAP), 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphonic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphonic acid] (NOPO), 3,6,9,15-tetraazabicyclo[9,3,1]pentadecane-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-hydroxysuccinamide (DFO) or diethylenetriaminepentaacetic acid (DTPA) or derivatives thereof;

[0019] R A For H or Preferred R A for

[0020] g, h, i, and j are independently selected from integers from 0 to 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); preferably, g, h, i, and j are independently selected from integers from 0 to 4 (e.g., 0, 1, 2, 3, or 4); more preferably, g is an integer from 1 to 4, h is an integer from 0 to 4, i is an integer from 1 to 4, and j is 0 or 1.

[0021] R 51 The group is selected from substituted or unsubstituted aryl groups, substituted or unsubstituted heteroaryl groups, and substituted or unsubstituted heterocyclic groups (preferably, the heterocyclic group is a nitrogen-containing heterocyclic group containing 2 to 50 carbons), wherein the substituents in the substituted aryl group, the substituents in the substituted heteroaryl group, and the substituents in the substituted heterocyclic group are independently selected from deuterium, tritium, halogens, and C1-C6 groups. 10 Alkyl, deuterated C1-C 10 Alkyl, tritium C1-C 10 Alkyl and halogenated C1-C 10 Alkyl, C1-C 10 Alkyl groups, deuterated C1-C 10 Alkyl groups, tritium groups (C1-C)10 Alkyl or halogenated C1-C 10 Alkoxy group; preferably, the substituents in the substituted aryl group, the substituents in the substituted heteroaryl group, and the substituents in the substituted heterocyclic group are independently selected from deuterium, tritium, halogen, C1-C4 alkyl, deuterated C1-C4 alkyl, tritated C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, deuterated C1-C4 alkoxy, tritated C1-C4 alkoxy, or halogenated C1-C4 alkoxy.

[0022] Preferably, R 51 The aryl group is selected from substituted or unsubstituted aryl groups, wherein the substituent of the substituted aryl group is selected from deuterium, tritium, halogen, C1-C4 alkyl, deuterated C1-C4 alkyl, tritated C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, deuterated C1-C4 alkoxy, tritated C1-C4 alkoxy, or halogenated C1-C4 alkoxy.

[0023] More preferably, R 51 The substituted aryl group is selected from deuterium, tritium, halogen, C1-C4 alkyl, deuterated C1-C4 alkyl, tritated C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, deuterated C1-C4 alkoxy, tritated C1-C4 alkoxy, or halogenated C1-C4 alkoxy.

[0024] Even more preferably, R 51 The substituted aryl group is selected from fluorine, chlorine, bromine, iodine, deuterium, tritium, deuterated C1-C4 alkyl, tritated C1-C4 alkyl, deuterated C1-C4 alkoxy or tritated C1-C4 alkoxy.

[0025] Even more preferably, R 51 The substituted aryl group is a deuterium, deuterated methyl, or deuterated methoxy group.

[0026] The compound is not one of the following compounds:

[0027]

[0028] Preferably, the compound represented by Formula I has the following structure:

[0029]

[0030] Preferred

[0031] Preferably, m is 1, n is 0, a is an integer from 0 to 4, b is an integer from 0 to 4, and c is an integer from 1 to 4.

[0032] Preferably, the aryl group is an aryl group containing 6 to 14 carbons;

[0033] More preferably, the aryl group is phenyl, naphthyl, or anthracene.

[0034] In another preferred embodiment, m is 1, n is 0, a is 0, b is 0, 1, or 2, c is an integer from 1 to 4, g is an integer from 1 to 4, h is 0, 1, or 2, i is an integer from 1 to 4, and j is 0; preferably, m is 1, n is 0, a is 0, b is 0, c is 1, g is 3 or 4, h is 0, i is 3 or 4, and j is 0; more preferably, m is 1, n is 0, a is 0, b is 0, c is 1, g is 3, h is 0, i is 4, and j is 0.

[0035] In yet another preferred embodiment, m is 1, n is 0, a is an integer from 1 to 4, b is 0, 1 or 2, c is an integer from 1 to 4, g is an integer from 1 to 4, h is 0, 1 or 2, i is an integer from 1 to 4, and j is 1; preferably, m is 1, n is 0, a is 4, b is 0 or 2, c is 1 or 2, g is 3, h is 0 or 2, i is 1 or 2, and j is 1;

[0036] In another preferred embodiment, m is 1, n is 1, a is an integer from 1 to 4, b is 1 or 2, c is an integer from 1 to 4, d is an integer from 1 to 4, g is an integer from 1 to 4, h is 0, 1 or 2, i is an integer from 1 to 4, and j is 1; preferably, m is 1, n is 1, a is 4, b is 2, c is 1, d is 1, g is 3, h is 0 or 2, i is 1 or 2, and j is 1;

[0037] In yet another preferred embodiment, m is 0, n is 0, and a is 0; preferably, m is 0, n is 0, a is 0, and R A R1, R2, and R3 are independently selected from H or substituted aryl groups, and at least one of R1, R2, and R3 is a substituted aryl group, wherein the substituent of the substituted aryl group is selected from deuterium, tritium, deuterated C1-C4 alkyl, tritated C1-C4 alkyl, deuterated C1-C4 alkoxy, or tritated C1-C4 alkoxy.

[0038] Preferably, the aryl group is an aryl group containing 6 to 14 carbons, and / or the substituent in the substituted aryl group is deuterium, deuterated methyl, or deuterated methoxy.

[0039] More preferably, the aryl group is phenyl, naphthyl, or anthracene, and / or the substituent in the substituted aryl group is deuterium.

[0040] In a preferred embodiment, at least one of R1, R2, R3 is a substituted aryl group, a substituted heteroaryl group, or a substituted heterocyclic group (preferably, the heterocyclic group is a nitrogen-containing heterocyclic group containing 2 to 50 carbons), and the substituents in the substituted aryl group, the substituted heteroaryl group, and the substituted heterocyclic group are independently selected from deuterium, tritium, halogens, and C1-C2 carbons. 10 Alkyl, deuterated C1-C 10 Alkyl, tritium C1-C 10 Alkyl and halogenated C1-C 10 Alkyl, C1-C 10 Alkyl groups, deuterated C1-C 10 Alkyl groups, tritium groups (C1-C) 10 Alkyl or halogenated C1-C 10 Alkoxy group; preferably, the substituents in the substituted aryl group and the substituents in the substituted heterocyclic group are independently selected from deuterium, tritium, halogen, C1-C4 alkyl, deuterated C1-C4 alkyl, tritated C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, deuterated C1-C4 alkoxy, tritated C1-C4 alkoxy, or halogenated C1-C4 alkoxy.

[0041] Preferably, the compound of formula I has the following structure:

[0042]

[0043] Preferred

[0044] In formulas IV and V, preferably, e is an integer from 1 to 4, and f is an integer from 1 to 4; more preferably, e is 2, and f is 1 or 2.

[0045] Preferably, in Formulas IV and V, R1, R2, and R3 are independently selected from H, substituted or unsubstituted aryl groups, and at least one of R1, R2, and R3 is a substituted or unsubstituted aryl group, wherein the substituent of the substituted aryl group is selected from deuterium, tritium, deuterated C1-C4 alkyl, tritated C1-C4 alkyl, deuterated C1-C4 alkoxy, or tritated C1-C4 alkoxy; preferably, the aryl group is an aryl group containing 6 to 14 carbons, and / or, the substituent of the substituted aryl group is deuterium, deuterated methyl, or deuterated methoxy; more preferably, the aryl group is phenyl, naphthyl, or anthracene, and / or, the substituent of the substituted aryl group is deuterium.

[0046] Preferably, in Formulas IV and V, R1, R2, and R3 are independently selected from H, substituted or unsubstituted aryl groups, and at least one of R1, R2, and R3 is a substituted or unsubstituted aryl group, wherein the substituent of the substituted aryl group is selected from deuterium, tritium, deuterated C1-C4 alkyl, tritated C1-C4 alkyl, deuterated C1-C4 alkoxy, or tritated C1-C4 alkoxy; preferably, the aryl group is an aryl group containing 6 to 14 carbons, and / or, the substituent of the substituted aryl group is deuterium, deuterated methyl, or deuterated methoxy; more preferably, the aryl group is phenyl, naphthyl, or anthracene, and / or, the substituent of the substituted aryl group is deuterium.

[0047] The compound represented by Formula I is any of the following compounds:

[0048]

[0049]

[0050]

[0051]

[0052]

[0053]

[0054]

[0055]

[0056] Replace X or DOTA in the compound with

[0057] or,

[0058] Replace X or DOTA in the compound with

[0059] or,

[0060] Replace X or DOTA in the compound with

[0061] or,

[0062] Replace X or DOTA in the compound with

[0063] or,

[0064] Replace X or DOTA in the compound with

[0065] or,

[0066] Replace X or DOTA in the compound with

[0067] or,

[0068] Replace X or DOTA in the compound with

[0069] or,

[0070] Replace X or DOTA in the compound with

[0071] According to another aspect of the invention, the use of the compound described in the invention or a pharmaceutically acceptable salt, ester or solvate thereof for the preparation of radiolabeled complexes is provided.

[0072] According to another aspect of the invention, a radiolabeled complex is provided, comprising: the compound according to the invention or a pharmaceutically acceptable salt, ester or solvate thereof, and a radionuclide.

[0073] Preferably, the radionuclide is selected from... 94 Tc, 99 mTc, 90 In、 111 In、 67 Ga、 68 Ga、 86 Y、 90 Y、 177 Lu、 151 Tb, 186 Re、 188 Re、 64 Cu、 67 Cu、 55 Co、 57 Co、 43 Sc、 44 Sc、 47 Sc、 225 Ac、 213 Bi、 212 Bi、 212 Pb, 227 Th、 153 Sm、 166 Ho、 152 Gd, 153 Gd, 157 Gd, 166 Dy or 55 Fe.

[0074] According to another aspect of the present invention, a pharmaceutical composition is provided comprising: a compound according to the present invention or a pharmaceutically acceptable salt, ester or solvate thereof and a pharmaceutically acceptable excipient; or, a radiolabeled complex according to the present invention and a pharmaceutically acceptable excipient.

[0075] According to another aspect of the present invention, a kit is provided, comprising any one of the following ① to ③:

[0076] ① The compound according to the present invention or its pharmaceutically acceptable salt, ester or solvate;

[0077] ② The radiolabeled complex according to the present invention;

[0078] ③ The pharmaceutical composition according to the present invention.

[0079] According to another aspect of the invention, the use of the compound described in the invention or a pharmaceutically acceptable salt, ester or solvate thereof in the preparation of a medicament for imaging in a patient is provided.

[0080] According to another aspect of the invention, the use of the radiolabeled complex according to the invention in the preparation of a pharmaceutical agent for imaging in a patient is provided.

[0081] According to another aspect of the invention, the use of the pharmaceutical composition according to the invention in the preparation of a medicament for imaging in a patient is provided.

[0082] According to another aspect of the invention, the kit according to the invention is provided for use in the preparation of a pharmaceutical agent for imaging in a patient.

[0083] According to another aspect of the invention, the use of the compound described in the invention or a pharmaceutically acceptable salt, ester or solvate thereof in the preparation of an agent for the diagnosis, treatment and / or prevention of prostate cancer, pancreatic cancer, kidney cancer or bladder cancer is provided (e.g., for the diagnosis and / or treatment of prostate cancer and / or its metastases).

[0084] According to another aspect of the invention, the use of the radiolabeled complex according to the invention in the preparation of pharmaceutical agents for the diagnosis, treatment and / or prevention of prostate cancer, pancreatic cancer, kidney cancer or bladder cancer is provided (e.g., for the diagnosis and / or treatment of prostate cancer and / or its metastases).

[0085] According to another aspect of the invention, the use of the pharmaceutical composition according to the invention in the preparation of a medicament for the diagnosis, treatment and / or prevention of prostate cancer, pancreatic cancer, kidney cancer or bladder cancer is provided (e.g., for the diagnosis and / or treatment of prostate cancer and / or its metastases).

[0086] According to another aspect of the invention, the kit described in the invention is provided for use in the preparation of medicaments for the diagnosis, treatment and / or prevention of prostate cancer, pancreatic cancer, kidney cancer or bladder cancer (e.g., for the diagnosis and / or treatment of prostate cancer and / or its metastases).

[0087] According to another aspect of the invention, the use of the compound described in the invention or a pharmaceutically acceptable salt, ester or solvate thereof in the preparation of a medicament for imaging, diagnosis, staging, evaluation and / or treatment of PSMA-targeting tumors is provided.

[0088] According to another aspect of the invention, the use of the radiolabeled complex according to the invention is provided in the preparation of pharmaceutical agents for imaging, diagnosis, staging, evaluation and / or treatment of PSMA-targeted tumors.

[0089] According to another aspect of the invention, the use of the pharmaceutical composition according to the invention in the preparation of a medicament for imaging, diagnosis, staging, evaluation and / or treatment of PSMA-targeting tumors is provided.

[0090] According to another aspect of the invention, the kit described herein is provided for use in the preparation of pharmaceutical agents for imaging, diagnosis, staging, evaluation, and / or treatment of PSMA-targeted tumors.

[0091] According to another aspect of the invention, the use of the compound described in the invention or a pharmaceutically acceptable salt, ester or solvate thereof in the preparation of a medicament for detecting the presence of cells and / or tissues expressing prostate-specific membrane antigen (PSMA) is provided.

[0092] According to another aspect of the invention, the use of the radiolabeled complex according to the invention in the preparation of a pharmaceutical agent for detecting the presence of cells and / or tissues expressing prostate-specific membrane antigen (PSMA) is provided.

[0093] According to another aspect of the invention, the use of the pharmaceutical composition according to the invention in the preparation of a medicament for detecting the presence of cells and / or tissues expressing prostate-specific membrane antigen (PSMA) is provided.

[0094] According to another aspect of the invention, the kit according to the invention is provided for use in the preparation of a pharmaceutical agent for detecting the presence of cells and / or tissues expressing prostate-specific membrane antigen (PSMA).

[0095] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0096] "Aryl" refers to an aryl group having 6 to 20 carbon atoms, preferably C6-C. 14Aryl groups are typically 5 to 8 quinones (e.g., 5, 6, 7, 8 quinones) monocyclic, 5 to 12 quinones (e.g., 5, 6, 7, 8, 9, 10, 11, 12 quinones) bicyclic, or 10 to 15 quinones (e.g., 10, 11, 12, 13, 14, 15 quinones) tricyclic systems, which can be bridged or spirocyclic. Non-limiting examples include phenyl, naphthyl, or anthracene.

[0097] “C1-C 10 "Alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group with 1 to 10 carbon atoms, preferably an alkyl group with 1 to 8 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8), more preferably an alkyl group with 1 to 6 carbon atoms, and even more preferably an alkyl group with 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and their various branched isomers;

[0098] “C1-C 10 "Alkoxy" refers to RO, where R is C1-C. 10 Alkyl group, where O is oxygen. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy. Preferably, they are C1-C6 alkoxy, more preferably C1-C4 alkoxy.

[0099] "Deuteration" refers to a group obtained by partially or completely replacing hydrogen atoms in a substituted group with deuterium atoms;

[0100] "Halogenated" refers to a group obtained by partially or completely replacing a hydrogen atom in a halogenated group with a halogen atom.

[0101] "Halogen" refers to fluorine, chlorine, bromine, or iodine;

[0102] "Heterocyclic group" refers to a saturated or unsaturated non-aromatic heterocycle containing 2 to 50 carbon atoms (preferably 2 to 10 carbon atoms) and 1 to 4 heteroatoms (e.g., 1, 2, 3, 4) selected from N, O or S. It can be a 3 to 10-membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic, a 4 to 12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic, or a 10 to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system, and contains 1 to 4 heteroatoms (e.g., 1, 2, 3, 4) selected from N, O or S, preferably a 3 to 8-membered heterocyclic group.

[0103] The selectively substituted 1 to 4 (e.g., 1, 2, 3, 4) N and S atoms in the ring of the "heterocyclic group" can be oxidized to various oxidation states; the "heterocyclic group" can be attached to a heteroatom or a carbon atom; the "heterocyclic group" can be a bridged ring or a spirocyclic ring. Non-limiting examples of "heterocyclic groups" include epoxyethyl, epoxypropyl, azirropropyl, oxacyclobutyl, azirrobutyl, thioherrobutyl, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxhexacycloyl, azirroheptyl, oxacycloheptyl, thioherroheptyl, oxazorphinyl, diazorphinyl, thioazorphinyl, pyridinyl, piperidinyl, homopiperidinyl, furanyl, and thiophene. alkyl, pyranyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thiaxylalkyl, 1,3-dithiaalkyl, dihydrofuranyl, dithiapentanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiaranyl, tetrahydropyrroleyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, Benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxopentyl, pyrazolinyl, dithiaalkyl, dithiamonyl, dihydrothiophenyl, pyrazolinyl, imidazolinyl, imidazolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3.1] [0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinazinyl, N-pyridylurea, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptyl.

[0104] "Heteroaryl" refers to a monocyclic system of 3 to 8 members (e.g., 3, 4, 5, 6, 7, 8), a bicyclic system of 5 to 12 members (e.g., 5, 6, 7, 8, 9, 10, 11, 12), or a tricyclic system of 10 to 15 members (e.g., 10, 11, 12, 13, 14, 15), and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O, or S, preferably 5 to 8 members; it can be a bridged ring or a spirocyclic ring, and non-limiting embodiments include cyclopyridyl, furanyl, thiophene, pyranyl, pyrrolidinyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinylbenzimidazolyl, benzopyridyl, and pyrrolopyridyl.

[0105] "Pharmaceutically acceptable salt" means that the compounds of the present invention retain the bioavailability and properties of free acids or free bases, wherein the free acid is obtained by reacting with a non-toxic inorganic or organic base, and the free base is obtained by reacting with a non-toxic inorganic or organic acid.

[0106] "Pharmaceutical composition" refers to a mixture of one or more compounds described in this invention, their pharmaceutically acceptable salts or prodrugs, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic agents.

[0107] A "solvent" refers to a compound or its pharmaceutically acceptable salt in which molecules of a suitable solvent are bound in a crystal lattice. The suitable solvent is physiologically permissible at the administered dose. Examples of suitable solvents are ethanol, water, etc. When water is used as the solvent, the molecule is called a "hydrate".

[0108] "Ester" refers to the esterification of the free acid group in the compounds of this invention. Suitable esters include various alkyl esters, such as saturated or unsaturated C1-C esters. 18 C1-C of fatty acids 10 Alkyl esters. Attached Figure Description

[0109] Figure 1 This is the MS spectrum of compound VWT0008 of the present invention.

[0110] Figure 2 This is the MS spectrum of compound VWT0011B of the present invention.

[0111] Figure 3 The MS spectrum of compound VWT0012 of this invention is shown.

[0112] Figure 4 for 68 TLC scan of Ga-VWT0001.

[0113] Figure 5 for 68 TLC scan of Ga-VWT0004.

[0114] Figure 6 for 68 TLC scan of Ga-VWT0010B.

[0115] Figure 7 for 68 TLC scan of Ga-VWT0012.

[0116] Figure 8 for 68 TLC scan of Ga-VWT0015.

[0117] Figure 9 for 68 TLC scan of Ga-VWT0078.

[0118] Figure 10 for 68Distribution of Ga-VWT0001 in LNCaP-bearing mice.

[0119] Figure 11 for 68 Distribution of Ga-VWT0004 in LNCaP-bearing mice.

[0120] Figure 12 for 68 Distribution of Ga-VWT0010B in LNCaP-bearing mice.

[0121] Figure 13 for 68 Distribution of Ga-VWT0012 in LNCaP-bearing mice.

[0122] Figure 14 for 68 Distribution of Ga-VWT0015 in LNCaP-bearing mice.

[0123] Figure 15 for 68 Distribution of Ga-VWT0078 in LNCaP-bearing mice. Detailed Implementation

[0124] The present invention will now be clearly and completely described in conjunction with specific embodiments. Those skilled in the art will understand that the embodiments described below are some, but not all, embodiments of the present invention, and are only used to illustrate the present invention, and should not be regarded as a limitation on the scope of protection of the present invention.

[0125] In this invention, unless otherwise specified, the conditions shall be performed according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

[0126] Regarding the definitions of terms used in this invention, unless otherwise stated, the initial definitions provided herein apply to the term throughout the text; for terms not specifically defined herein, the meanings that a person skilled in the art would give them should be given based on the disclosure and / or context.

[0127] The references mentioned in this article are incorporated into this article in their entirety by way of citation.

[0128] Compound (PSMA-617) was purchased from Advanced Biochemical Compounds (ABX GmbH, Radeberg, Germany), see: CN 110740757 A; or, prepared by known methods in the prior art, see: 1. Martina Beneˇsová, Martin et al.Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety for Imagingand Endoradiotherapy of Prostate Cancer.The Journal of NuclearMedicine.Vol.56,No.6,June 2015; 2.International patent application WO 2021 / 013978A1.

[0129] For example:

[0130]

[0131]

[0132] One of the synthetic routes for PSMA-617

[0133] (1) Following a similar method as described above, the corresponding deuterated compound was used in the synthesis process to prepare compound VWT0001.

[0134]

[0135] (2) The compound VWT0002 is prepared by reacting PSMA-617 precursor with gadobutrol (or gadoterol) or by reacting compound (8) with gadobutrol (or gadoterol) and then removing the protecting group on the carboxyl group.

[0136]

[0137] (3) Combining compound (8) with ( (Reaction generation) to produce reaction The amino protecting group (Fmoc) was then removed, followed by reaction with DOTA to remove the protecting group on the carboxyl group, thus preparing compound VWT0005. (4)

[0139]

[0140] Synthesize according to the above method It reacts with compound (8) to produce Then remove the protecting group of hydrazine (NH-NH) The compound VWT0003 was then prepared by reacting it with DOTA and removing the protecting group on the carboxyl group.

[0141] The above methods Replace with VWT0006 is then prepared.

[0142] (5) Following a method similar to that described in "One of the synthetic routes for PSMA-617", the following preparation was obtained:

[0143] Prepared according to the following method

[0144] and The reaction was carried out, and then the amino protecting group (Fmoc) was removed. After that, it was reacted with DOTA and the protecting group on the carboxyl group was removed to prepare compound VWT0009.

[0145] Similarly, VWT0007, VWT0008, VWT0010B, VWT0011B, and VWT0012 can also be prepared.

[0146] Example 1

[0147] Preparation of compound VWT0001

[0148] (1) Preparation of VWT000201

[0149]

[0150] 28.99 g of compound 135641 was added to 400 mL of dichloromethane (DCM), and the mixture was cooled to 0 °C under nitrogen protection. Then, N,N-diisopropylethylamine (41.55 g), compound 135681 (14.31 g), and compound 135661 (20.00 g) were added. After the addition was complete, the mixture was reacted overnight at room temperature. The mixture was washed with water, separated, and the organic phase was distilled and then separated by column chromatography (n-hexane:ethyl acetate = 7:3) to give 20.00 g of the target product VWT000201. ESI-MS: 622.40 [M+H] + ].

[0151] (2) Preparation of VWT000202

[0152]

[0153] 18.3 g of compound VWT000201, along with 100 ml of methanol and 6.85 g of palladium on carbon, were added to a three-necked flask. Hydrogen gas was bubbled through the flask, and the mixture was reacted at room temperature for 3 hours. After filtration and concentration, the product was separated by column chromatography (DCM:methanol = 9:1) to yield 8.68 g of the target product VWT000202. ESI-MS: 488.40 [M+H] + ].

[0154] (3) Preparation of VWT000101 / VWT000102 / VWT000103

[0155]

[0156] VWT000101:

[0157] Compound 135701 (5.00 g), 100 ml dichloromethane, and 19.5 g piperidine were added to a three-necked flask. The mixture was stirred overnight at room temperature, filtered, and the filter cake was mixed with 125 ml of water. The pH was adjusted to <7 with hydrochloric acid and then to 6 with ammonia. The mixture was filtered again and the filter cake was dried at 50 °C to give 2.66 g of the target product VWT000101. ESI-MS: 216.28 [M+H] + ].

[0158] VWT000102:

[0159] Add VWT000101 (1.00g) and 15.00g of deuterated phosphoric acid to a three-necked flask, heat to 120℃ and react overnight. After the reaction is complete, cool to room temperature, adjust the pH to 7 with 5% sodium bicarbonate, and filter to obtain 0.69g of the target product VWT000102.

[0160] VWT000103:

[0161] VWT000102 (0.60 g), sodium bicarbonate (0.60 g), Fmoc-OSu (1.44 g), 30 ml of dioxane, and 30 ml of water were added to the reaction flask. The mixture was reacted at room temperature for 3 h. Hydrochloric acid was added to adjust the pH to about 4. Water and ethyl acetate were added for separation and extraction. After drying with anhydrous sodium sulfate, the mixture was concentrated to obtain 1.24 g of the target product VWT000103.

[0162] (4) Preparation of VWT000104

[0163]

[0164] Compound VWT000103 (0.90 g based on pure substance), DIPEA (2.93 g), HATU (1.79 g), and DMF (5 ml) were added to the reaction flask. A DMF (1.5 ml) solution of VWT000202 (0.79 g) was added at room temperature. After the addition was complete, the mixture was reacted at room temperature for 3 h. Then, ethyl acetate and water were added, and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the oily substance VWT000104.

[0165] (5) Preparation of VWT000105

[0166]

[0167] 1.5 g of VWT000104 was added to a three-necked flask, dissolved in 30 ml of DCM, and 3.00 g of piperidine was added. The mixture was reacted overnight at room temperature, concentrated, and purified by column chromatography to obtain 1.1 g of the target product VWT000105. ESI-MS: 693.46 [M+H] + ].

[0168] (6) Preparation of VWT000106

[0169]

[0170] Compound 135721 (0.85 g), DIPEA (2.88 g), HATU (1.75 g), and DMF (5 ml) were added to a single-necked flask. After the addition was complete, the mixture was stirred for 20 min. Then, a DMF (2 ml) solution of VWT000105 (1.1 g) was added. The mixture was reacted at room temperature for 3 h. Water and ethyl acetate were added, and the mixture was extracted by separation. The organic phase was dried over anhydrous sodium sulfate and then concentrated to obtain the oily substance VWT000106.

[0171] (7) Preparation of VWT000107

[0172]

[0173] VWT000106 (equivalent to 1.675 g), 50 mL of dichloromethane, and 2.709 g of piperidine were added to a single-necked flask. The mixture was reacted overnight at room temperature, and purified by column chromatography to obtain 1.2 g of the target product VWT000107. ESI-MS: 831.61 [M+H] + ].

[0174] (8) Preparation of VWT000108

[0175]

[0176] Add DOTA-ester (84 mg), DMF (3 ml), DIPEA (20 mg), and HATU (56 mg) to a single-necked flask. Stir for 20 min after addition, add VWT000107 (30 mg), keep warm for 3 h, concentrate and dilute with DCM, and prepare TLC separation to obtain 66 mg of the target product VWT000108.

[0177] (9) Preparation of VWT0001

[0178]

[0179] VWT000108 (200 mg) was added to a single-necked flask, dissolved in DCM (20 ml), and TFA (4 ml) was added. The mixture was incubated for 6 hours, concentrated, and ethyl acetate was added. Filtering yielded 135 mg of a gray solid. HPLC purification was performed to obtain the target product VWT0001. ESI-MS: [M+2] / 2 = 525.3, [M+1]+ = 1049.6, C 49 H 64 D7N9O 16 .

[0180]

[0181] Example 2

[0182] Another preparation method of compound VWT0001

[0183]

[0184] in,

[0185] Fmoc-Lys(Mtt)-OH (CAS No.: 167393-62-6, dosage 0.6g); H-Glu(OtBu)-OtBu-HCl (CAS No.: 32677-01-3, dosage 0.45g); Fmoc-Rx-OH (same as VWT000103 in Example 1, dosage 0.44g); Fmoc-tranexamic acid-OH (dosage 0.57g); DOTA (dosage 0.85g); VWT0001 was prepared according to conventional methods in the art.

[0186] Example 3

[0187] Compound VWT0003 was prepared by means similar to those in Example 1 and / or Example 2, except that some of the raw materials were replaced, or by means of conventional methods in the art.

[0188] Among them, Fmoc-2Nal-OH (CAS No.: 112883-43-9); Fmoc-Hynic-PEG1-OH.

[0189] Example 4

[0190] Preparation of compound VWT0004

[0191] Following a method similar to Example 1 and / or Example 2, replace Fmoc-Rx-OH (identical to VWT000103 in Example 1) with VWT0004 was prepared.

[0192]

[0193] Example 5

[0194] Preparation of compound VWT0005

[0195] Following a method similar to Example 1 and / or Example 2, replace some of the raw materials. Wherein, Ry-COOH is... (That is: Ry is) VWT00202 is

[0196] (1) Synthesis of compound 5a:

[0197]

[0198] The first component was bonded using CTC resin (resin loading): 0.5 g of resin (polystyrene (PS) triphenylmethyl chloride, initial degree of substitution: 1.09 mmol / g) was swollen in DMF (4 ml) for 30 min, followed by washing twice with DMF (4 ml, 1 min). The resin was then treated for 3 h with a mixture of Fmoc-2Nal-OH (715.3 mg, 1.635 mmol, 3 eq.) and DIPEA (422.5 mg, 3.270 mmol, 6 eq.) in DMF (4 ml), followed by washing with DMF (4 ml, 6 × 1 min). The resin was then treated for 1 h with a mixture of methanol (0.5 ml, 1 vol) and DIPEA (422.5 mg, 3.270 mmol, 6 eq.) in DMF (4 ml), followed by washing with DMF (4 ml, 6 × 1 min). Then, it was treated with piperidine / DMF (1:4, 4 ml, 30 min), followed by washing with DMF (4 ml, 8 × 1 min) to obtain 2Nal-OCTC resin.

[0199] Fmoc-tranexamic acid was coupled sequentially in the PyBOP / HOBt / DIPEA condensation system according to the amino acid sequence. The resin was washed with DMF (4 ml, 6 × 1 min), then treated with piperidine / DMF (1:4, 4 ml, 30 min), followed by washing with DMF (4 ml, 8 × 1 min). Fmoc-Lys(ivDde)-OH was coupled in the DIC / HOBt condensation system. The resin was washed with DMF (4 ml, 6 × 1 min), then treated with piperidine / DMF (1:4, 4 ml, 30 min), and washed with DMF (4 ml, 8 × 1 min) to obtain compound 5a.

[0200] (2) Synthesis of compound 5b peptide resin:

[0201]

[0202] Compound 5a was coupled with DOTA(tBu)3 in a DIC / HOBt condensation system. The resin was washed with DMF (4 ml, 6 × 1 min), and then treated with 8% hydrazine hydrate / DMF solution for 0.5 h to remove the ivDde protecting group. After washing with DMF (4 ml, 12 × 1 min), compound 5b was obtained.

[0203] (3) Synthesis of compound 5c peptide resin:

[0204]

[0205] Compound 5b was coupled with Ry-COOH in a DIC / HOBt condensation system, and the resin was washed with DMF (4 ml, 6 × 1 min). The resin was then washed alternately with 4 ml of MTBE and DCM in a washing order of MTBE / DCM / MTBE = 2 / 2 / 2. After washing, the resin was vacuum dried and cleaved in a TFA / DCM = 1 / 99 lysis buffer to obtain the fully protected peptide fragment compound 5c.

[0206] (4) VWT0005 Synthesis:

[0207]

[0208] Compound 5c and compound VWT00202 were coupled in a PyBOP / HOBt / DIPEA condensation system to obtain a fully protected peptide. The fully protected peptide was then treated with 95% TFA / 5% H2O lysis buffer for 3 h, crystallized with methyl tert-butyl ether, centrifuged, and dried to obtain crude VWT0005. After HPLC purification, the target product VWT0005 was obtained.

[0209] Example 6

[0210] Preparation of compound VWT0006

[0211] Following a similar method to Example 3, Fmoc-Hynic-PEG1-OH was replaced with Fmoc-Hynic-PEG2-OH to prepare VWT0006.

[0212]

[0213] Example 7

[0214] Preparation of compound VWT0008

[0215] VWT0008 was prepared by replacing some of the raw materials in accordance with the methods of Example 1 and / or Example 2, or by following conventional methods in the art.

[0216]

[0217] Among them, Fmoc-S-9-anthraylalanine (CAS No.: 268734-27-6).

[0218] Example 8

[0219] Preparation of compound VWT0010B

[0220] (1) VWT0010B was prepared by replacing some of the raw materials, following a method similar to that in Example 5, or by using conventional methods in the art. Wherein, Fmoc-Gly-OH (CAS No.: 29022-11-5); R z -COOH is (i.e.: R) z for Synthesis of compound 10a peptide resin:

[0221]

[0222] The first component was bonded using CTC resin (resin loading): 0.5 g of resin (polystyrene (PS) triphenylmethyl chloride, initial degree of substitution: 1.09 mmol / g) was swollen in DMF (4 ml) for 30 min, followed by washing twice with DMF (4 ml, 1 min). The resin was then treated for 3 h with a mixture of Fmoc-S-9-anthraylalanine (797.1 mg, 1.635 mmol, 3 eq.) and DIPEA (422.5 mg, 3.270 mmol, 6 eq.) in DMF (4 ml), followed by washing with DMF (4 ml, 6 × 1 min). The resin was then treated for 1 h with a mixture of methanol (0.5 ml, 1 vol) and DIPEA (422.5 mg, 3.270 mmol, 6 eq.) in DMF (4 ml), followed by washing with DMF (4 ml, 6 × 1 min). Then, it was treated with piperidine / DMF (1:4, 4 ml, 30 min) and then washed with DMF (4 ml, 8 × 1 min) to obtain S-Ala(9-anth)-OCTC resin.

[0223] Fmoc-tranexamic acid was coupled sequentially according to the amino acid sequence in the PyBOP / HOBt / DIPEA condensation system. The resin was washed with DMF (4 ml, 6 × 1 min), then treated with piperidine / DMF (1:4, 4 ml, 30 min), followed by washing with DMF (4 ml, 8 × 1 min). Fmoc-Lys(ivDde)-OH was coupled in the DIC / HOBt condensation system, and the resin was washed with DMF (4 ml, 6 × 1 min). This was followed by treatment with piperidine / DMF (1:4, 4 ml, 30 min), and washing with DMF (4 ml, 8 × 1 min). Following the stepwise coupling of Fmoc-Gly-OH and Rz-COOH in the DIC / HOBt condensation system, the resin was treated with 8% hydrazine hydrate / DMF solution for 0.5 h to remove the ivDde protecting group. The resin was then washed with DMF (4 ml, 12 × 1 min) to obtain compound 10a.

[0224] (2) Synthesis of compound 10b:

[0225]

[0226] Compound 10a was coupled with DOTA(tBu)3 in a DIC / HOBt condensation system. The resin was washed with DMF (4 ml, 6 × 1 min). The resin was then washed alternately with 4 ml of MTBE and DCM in the order of MTBE / DCM / MTBE = 2 / 2 / 2. After washing, the resin was dried under vacuum and cleaved in a TFA / DCM = 1 / 99 lysis buffer to obtain the fully protected peptide fragment compound 10b.

[0227] (3) VWT0010B Synthesis:

[0228]

[0229] Compound 10b was coupled with compound VWT00202 in a PyBOP / HOBt / DIPEA condensation system to obtain a fully protected peptide. The fully protected peptide was then treated with 95% TFA / 5% H2O lysis buffer for 3 h, crystallized with methyl tert-butyl ether, centrifuged, and dried to obtain crude VWT0010B. After HPLC purification, the target product VWT0010B was obtained.

[0230] Example 9

[0231] Preparation of compound VWT0011B

[0232] VWT0011B is prepared by replacing some of the raw materials in accordance with the methods of Examples 7 and / or 8, or by following conventional methods in the art.

[0233]

[0234] Example 10

[0235] Preparation of compound VWT0012

[0236] VWT0012 was prepared by replacing some of the raw materials in accordance with the methods of Examples 7 and / or 9, or by following conventional methods in the art.

[0237]

[0238] Example 11

[0239] Preparation of compound VWT0075

[0240] VWT0075 was prepared by replacing some of the raw materials in accordance with the methods of Examples 7 and / or 8, or by following conventional methods in the art (e.g., see: WO2020252598A1, etc.).

[0241]

[0242] Example 12

[0243] Preparation of compound VWT0076

[0244] VWT0076 was prepared by replacing some of the raw materials in accordance with the methods of Examples 7 and / or 8, or by following conventional methods in the art.

[0245]

[0246] Among them, Fmoc-deuterated diphenyl Ala-OH is

[0247] Example 13

[0248] Preparation of compound VWT0078

[0249] VWT0078 was prepared by replacing some of the raw materials in accordance with the methods of Examples 7 and / or 8, or by following conventional methods in the art.

[0250]

[0251] Example 14

[0252] Preparation of compound VWT0080

[0253] VWT0080 was prepared by replacing some of the raw materials in a manner similar to that in Example 13, or by following conventional methods in the art.

[0254]

[0255] Example 15

[0256] Similar to Embodiment 1 or existing technology (CN 110740757 A, 1. Martina Beneˇsová, Martin) et al. Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety for Imaging and Endoradiotherapy of Prostate Cancer. The Journal of Nuclear Medicine. Vol. 56, No. 6, June 2015; or WO2021 / 013978A1) similarly synthesize the following compounds:

[0257] Table 1

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266] The MS spectra of compounds VWT0008, VWT0011B, and VWT0012 are as follows: Figures 1-3 As shown.

[0267] Example 16

[0268] Referring to Chinese patent applications CN 110740757 A and CN 105636924 B, as well as other prior art (e.g., Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety for Imaging and Endoradiotherapy of Prostate Cancer. The journal of nuclear medicine. Vol. 56, No. 6. June 2015), the compounds of the present invention were subjected to experiments on performance and efficacy, such as: studying the binding ability of the novel tumor radioligand drug of the present invention to cells, understanding its tumor targeting, tissue distribution, and therapeutic effect on tumors in tumor-bearing mice; radiolabeling ( 177 Lu tag, 68 Ga mark), IC 50 Determination of the value, determination of competitive binding affinity (in vitro competitive experiment), in vivo distribution experiment (LNCaP model), imaging studies, etc.

[0269] Cell information: LNCaP (human prostate cancer cells), source: Shanghai Cell Resource Center for Life Sciences, Chinese Academy of Sciences.

[0270] LNCaP tumor-bearing mice (grade: SPF; weight: 20-25g), source: Shanghai Heyuan Biotechnology Co., Ltd.

[0271] 1. Antigen affinity test of PSMA-targeting compounds

[0272] (1) Radiolabeling and separation and purification

[0273] Take 100 μg of PSMA antibody stock solution, add 200 μL of phosphate buffer solution (concentration 0.02 mol / L, pH = 7.4) and 500 μCi of Na+. 125 Mix solution I, add 20 μL of chloramine T solution (5 mg / mL), and react at room temperature for 70 s on a mixer. Add 200 μL of sodium metabisulfite solution (5 mg / mL), and then add phosphate buffer solution to make up to 2.5 mL, continuing the reaction for 5 minutes. Transfer the reaction solution to a 10 K ultrafiltration tube, centrifuge at 5000 rpm for 15 min, and repeatedly add 2.5 mL of phosphate buffer solution and centrifuge until the radioactivity of the filtrate no longer increases, indicating that the reaction solution no longer contains free radioactive substances. 125 Ion, radiochemical purity reaches 100%.

[0274] (2) Antigen affinity test

[0275] PSMA-positive LNCaP cells were expanded in vitro to a sufficient quantity, digested, and seeded into 24-well plates. After complete cell confluence, the cells were used for experiments. The compound was diluted with culture medium to 1 μM (1000 nM), and then serially diluted to 200, 40, 8, 1.6, 0.32, 0.064, and 0.0128 nM. 100,000 CPM of [a specific compound] was added to each 0.5 mL of the compound dilution. 125 I-PSMA mAb. Aspirate the existing culture medium from the 24-well plate, then carefully add the compound and... 125 The new culture medium containing I-PSMA mAb was added to the control group, which contained only I-PSMA mAb. 125 Fresh medium for I-PSMA mAb was incubated at 37°C for 4 hours. The medium was then removed, and the cells were washed three times with PBS. 0.3 mL of 2M NaOH was added to lyse the cells, and the cells were transferred to centrifuge tubes. Another 0.3 mL of 2M NaOH was added to wash the wells of the plate, and the cells were transferred to the same centrifuge tubes. The radioactivity count in each centrifuge tube was measured, a curve was fitted, and the IC50 was calculated. 50 .

[0276] Radioactivity and IC of each compound 50 The test results are shown in Tables 2 and 3, respectively.

[0277] Table 2: Results of two tests for radioactivity

[0278]

[0279] Table 2: Results of two tests for radioactivity (continued)

[0280]

[0281] Table 2: Results of two tests for radioactivity (continued)

[0282]

[0283]

[0284] Table 2: Results of two tests for radioactivity (continued)

[0285]

[0286] Table 3: IC 50 Test results

[0287] <![CDATA[IC 50 / nM]]> 1.808 4.492 33.44 0.8659 3.814 3.835 0.7303 compound VWT0011B VWT0012 VWT0015 VWT0075 VWT0076 VWT0078 VWT0080 <![CDATA[IC 50 / nM]]> 1.087 1.038 2.647 2.573 16.71 1.979 2.795

[0288] VWT0015 is a known compound with the following structural formula:

[0289]

[0290] 2. Animal Experiment Design

[0291] (1) 68 Ga-labeled precursor compounds

[0292] Preheat to 97℃, and take the activity values ​​according to Table 4 below. 68 Add GaCl3 solution to an EP tube, then add the appropriate volume of diluted precursor solution, and make up the difference with sodium acetate buffer. Incubate at 97°C and 800 rpm for 15 min. After the reaction, determine the radiochemical purity by TLC; a purity greater than 95% is usable.

[0293] Table 4: 68 Data sheet of Ga-labeled precursor compounds

[0294] <![CDATA 68 GaCl3 activity (MBq)]]> 37 37 37 37 37 37 Number of precursor moles (nmol) 1.5 1.5 1.5 1.5 1.5 1.5 Precursor molecular weight (g / mol) 1049.2 1078.25 1456.67 1705.36 1042.15 1528.75 Precursor mass (μg) 1.6 1.6 2.2 2.6 1.6 2.29 Precursor concentration (μg / μL) 0.1 0.1 0.1 0.1 0.1 0.1 Precursor volume (μL) 16 16 22 26 16 23

[0295] 68 After Ga-labeling the PSMA-targeting compound, its radiochemical purity was determined by TLC. The results are shown in the table below. Figures 4-9 ( Figure 4 for 68 TLC scan of Ga-VWT0001; Figure 5 for 68 TLC scan of Ga-VWT0004; Figure 6 for 68 TLC scan of Ga-VWT0010B; Figure 7 for 68 TLC scan of Ga-VWT0012; Figure 8 for 68 TLC scan of Ga-VWT0015; Figure 9 for 68 (TLC scan of Ga-VWT0078).

[0296] The results showed that the radiochemical purity of each compound was greater than 95%, making them suitable for animal administration.

[0297] (2) Tumor targeting and tissue distribution of the compound

[0298] LNCaP tumor-bearing mice were anesthetized with isoflurane and then injected via the tail vein. 68Two animals were injected with 3.7 MBq (approximately 100 μCi) of the Ga-labeled compound, with a total volume of 0.2 mL. Scans were performed at 1, 2, and 3 hours post-administration using static 10-minute PET and medium-resolution whole-body CT. Animal weight, injection dose, injection time, and residual dose were recorded according to a log, along with the time of injection and residual dose measurement. Scan images were generated using PMOD software, and the uptake of the compound in various animal tissues was quantified.

[0299] 68 Ga-VWT0001 68 Ga-VWT0004 68 Ga-VWT0010B, 68 Ga-VWT0012 68 Ga-VWT0015 68 The distribution of Ga-VWT0078 in LNCaP-bearing mice is as follows: Figures 10-15 As shown in Table 5, the uptake of various tissues in the animals was quantified using PMOD software. The results are expressed in ID% / g.

[0300] Table 5: Quantitative results of animal tissue uptake

[0301]

[0302]

[0303] The results show that, compared with existing compounds, the compounds of the present invention have better effects in tumor targeting performance, pharmacokinetics, and regulation of lipophilicity.

[0304] Of course, the present invention can also have other various embodiments. Without departing from the spirit and essence of the present invention, those skilled in the art can make various corresponding changes and / or modifications according to the present invention, and these corresponding changes and / or modifications should all fall within the protection scope of the appended claims.

Claims

1. A compound having the following structure or a pharmaceutically acceptable salt thereof, characterized in that, The compound is any one of the following compounds: 28、 29 or 30。 2. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof for the preparation of radiolabeled complexes.

3. A radiolabeled complex comprising: The compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a radionuclide.

4. The radiolabeled complex according to claim 3, characterized in that, The radionuclides mentioned are selected from 94 Tc, 99 mTc, 111 In、 67 Ga、 68 Ga、 86 Y、 90 Y、 177 Lu、 151 Tb, 186 Re、 188 Re、 64 Cu、 67 Cu、 55 Co、 57 Co、 43 Sc、 44 Sc、 47 Sc、 225 Ac、 213 Bi、 212 Bi、 212 Pb, 227 Th、 153 Sm、 166 Ho、 152 Gd, 153 Gd, 166 Dy or 55 Fe.

5. A pharmaceutical composition comprising: The radiolabeled complex and pharmaceutically acceptable excipients as described in claim 3 or 4.

6. A kit comprising any one of the following: ① to ③ ① The compound according to claim 1 or a pharmaceutically acceptable salt thereof; ② The radiolabeled complex according to claim 3 or 4; ③ The pharmaceutical composition according to claim 5.

7. Use of the radiolabeled complex according to claim 3 or 4 or the pharmaceutical composition according to claim 5 in the preparation of a medicament for imaging in a patient.

8. Use of the radiolabeled complex according to claim 3 or 4 or the pharmaceutical composition according to claim 5 in the preparation of a medicament for the diagnosis, treatment and / or prevention of prostate cancer.

9. Use of the radiolabeled complex according to claim 3 or 4 or the pharmaceutical composition according to claim 5 in the preparation of a medicament for imaging, diagnosis, staging, evaluation and / or treatment of PSMA-targeted tumors.

10. Use of the radiolabeled complex according to claim 3 or 4 or the pharmaceutical composition according to claim 5 in the preparation of a medicament for detecting the presence of cells and / or tissues expressing prostate-specific membrane antigen PSMA.

Images