PSMA-targeted radiopharmaceuticals and their synthesis and applications

Abstract

Provided are PSMA-targeted radiopharmaceuticals and their synthesis and applications, specifically, a compound or a pharmaceutically acceptable salt, ester, or solvate thereof, whose structure is shown in Formula (I), which can diagnose and / or treat one or more tumors, cancers, or cells that express PSMA. TIFF2026507561000081.tif66170

Description

[Technical Field]

[0001] The present invention relates to the field of diagnostics, specifically, the present invention relates to PSMA-targeted radiopharmaceuticals and their synthesis and applications. [Background technology]

[0002] Prostate cancer is a common malignant tumor of the male genitourinary system and the second most common male tumor worldwide. In recent years, the incidence and detection rates of prostate cancer have been increasing year by year, and the mortality rate has also been increasing year by year. Currently, many newly diagnosed patients have tumors that progress locally or metastasize, resulting in the loss of the opportunity for curative treatment. Therefore, the treatment of advanced-stage patients is one of the key issues in the current research field of prostate cancer treatment.

[0003] Prostate-specific membrane antigen (PSMA) PSMA (prostate cancer antigen) is a unique cell surface type II transmembrane glycoprotein with a binding site in its extramembrane domain. Upon binding with its associated ligand, it exhibits significantly enhanced cellular uptake activity. PSMA is positively expressed in almost all prostate cancers, and its expression level increases with increasing tumor stage and grade, with expression significantly elevated in late-stage and castration-resistant prostate cancer (CRPC). This unique expression and uptake activity characteristics of PSMA after ligand binding make it an important and ideal specific marker for prostate cancer, providing an extracellular target for reliable targeted molecular imaging and precise therapy. Research and development of small molecule drug conjugates targeting PSMA for prostate cancer has considerable theoretical feasibility and promising practical application for the treatment of metastatic castration-resistant prostate cancer. Summary of the Invention [Problem to be solved by the invention]

[0004] While research into targeted tumor therapy has progressed rapidly, researchers have further developed and perfected it, proposing a new tumor treatment concept: integrated tumor diagnostics and therapy (theranostics). Integrated diagnostics and therapy combine diagnostic and therapeutic reagents into a single system, simultaneously achieving the effects of imaging diagnosis and treatment. This therapeutic strategy plays an important role in the field of personalized drug administration, effectively improving drug bioavailability and targeting, as well as enhancing antitumor activity and reducing toxicity. At the same time, imaging diagnostics can visualize the drug delivery process in the body, facilitating understanding of drug distribution in the body. Information on disease status before and after treatment can be collected, further guiding drug use, enabling real-time monitoring of tumor treatment effects and personalized drug administration. The integration of tumor-targeted diagnosis and treatment has become an important emerging branch in the field of biomedical research. New technologies integrating imaging diagnosis and targeted therapy built with such multifunctional diagnostic agents are expected to play an important role in the future diagnosis and treatment of human tumors and other serious diseases. With good future application potential, this is currently a hot spot and cutting-edge area of ​​international biomedical research. [Means for solving the problem]

[0005] In a first aspect, the present invention provides a compound or a pharmaceutically acceptable salt, ester or solvate thereof, the structure of which is shown in formula (I): [ka] wherein L is selected from a polyethylene glycol chain, a hydrophilic amino acid chain, or a carbon chain; X is selected from a 6-12 aryl group or a 5-12 heteroaryl group, wherein the 6-12 aryl group or the 5-12 heteroaryl group contains one, two or three OH, halogen or C 1-6 optionally substituted with alkyl groups, R and Y are each independently selected from H, an optionally substituted amino acid, or a chelating agent, and at least one of R and Y is a chelating agent.

[0006] In some implementations of the invention, the polyethylene glycol chain is a chain formed from one or more polyethylene glycol units (-O-(CH2)2-O-), for example a chain formed from 1, 2, 3, 4, 5, 6, 7 or 8 polyethylene glycol units (-O-(CH2)2-O-), with the remaining variables being as defined herein.

[0007] In some embodiments of the present invention, the hydrophilic amino acid chain is a chain formed by condensation of one or more of the same or different hydrophilic amino acids, for example, a chain formed by condensation of 1, 2, 3, 4, 5, 6, 7, or 8 hydrophilic amino acids, and the hydrophilic amino acid is a general term for amino acids having high hydrophilicity in their side chains, for example, hydrophilic amino acids include those selected from threonine (Thr), serine (Ser), cysteine ​​(Cys), asparagine (Asn), glutamine (Gln), tyrosine (Tyr), lysine (Lys), arginine (Arg), histidine (His), aspartic acid (Asp), or glutamic acid (Glu), and the remaining variables are as defined in the present invention.

[0008] In some implementations of the present invention, the carbon chain is formed from one or more substituted or unsubstituted straight or branched chain alkyl groups, for example, a substituted or unsubstituted straight or branched chain alkyl group consisting of 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, with the remaining variables being as defined herein.

[0009] In some implementations of the invention, L is [ka] and the remaining variables are as defined herein.

[0010] In some implementations of the present invention, R and Y are each independently H, [ka] wherein R and Y are not simultaneously H, and at least one of R and Y is a chelating agent.

[0011] In another aspect, the present invention provides a compound or a pharmaceutically acceptable salt, ester or solvate thereof, the structure of which is shown in formula (II) according to an embodiment of the present invention: [ka] wherein X is selected from a 6-12 aryl group or a 5-12 heteroaryl group, and the 6-12 aryl group or the 5-12 heteroaryl group contains one, two or three OH, halogen or C 1-6 optionally substituted with alkyl groups, Z is [ka] -COOH, -OH, C 1-6 alkyl groups and aryl groups of 6 to 12, 1-6 The alkyl group or 6-12 aryl group may contain 1, 2 or 3 OH, halogen or C 1-6 optionally substituted with alkyl groups, R' and Y' are each independently selected from H, an optionally substituted amino acid, or a chelating agent, and R' and Y' are not both H, and at least one of R' and Y' is a chelating agent. is.

[0012] In some implementations of the present invention, R' and Y' are each independently H, [ka] wherein R' and Y' are not simultaneously H, and at least one of R' and Y' is a chelating agent.

[0013] In some implementations of the invention, R', Y' are each independently an optionally substituted amino acid or chelating group, and the substituents are [ka] and the remaining variables are as defined herein.

[0014] In some implementations of the invention, X is [ka] and the remaining variables are as defined herein.

[0015] In some implementations of the invention, Z is [ka] -COOH, -OH, -CH(CH3)OH, [ka] and the remaining variables are as defined herein.

[0016] In some implementations of the invention, the chelating agent is 1,4,7,10-tetrazacyclododecane-N,N',N``,N```-tetraacetic acid, 1,4,7-triazacyclononane-1,4,7-triaacetic acid, 2-(4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)glutaric acid, 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetrazacyclododecane-1 -yl)glutaric acid, 1,4,7-triazacyclononanephosphonic acid, 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphonic acid]-4,7-bis[methyl(2-carboxymethyl)phosphonic 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, p-isothiocyanatobenzyl-diethylenetriaminepentaacetic acid, 1-(isothiocyanatobenzyl)-3-methyl-diethylenetriaminepentaacetic acid, 1-(isothiocyanatobenzyl)-4-methyl-diethylenetriaminepentaacetic acid, 1-(2)-methyl-4-isocyanatobenzyl-diethylenetriaminepentaacetic acid, 1-oxa-4,7,10-triazacyclododecane-4,7,10-triaacetic acid, 6-hydrazinonicotinic acid succinimidyl ester hydrochloride and mercaptoacetyltriglycine, (R)-2-amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid, and the remaining variables are as defined herein.

[0017] In another aspect of the present invention, the present invention further provides a complex. According to an embodiment of the present invention, the complex is a compound as described above or a pharmaceutically acceptable salt, ester or solvate thereof, and A radionuclide or a non-radioactive element A' is coordinated to form the compound, the structure of which is shown in formula (III): [ka] wherein Y' is a chelator and R' is H, an optionally substituted amino acid or a chelator.

[0018] In another aspect of the present invention, the present invention further provides a complex. According to an embodiment of the present invention, the complex is formed by coordinating the compound described above or a pharmaceutically acceptable salt, ester or solvate thereof with a radionuclide or a non-radioactive element A', and its structure is shown in formula (IV): [ka] wherein R' is a chelator and Y' is H, an optionally substituted amino acid, or a chelator.

[0019] In another aspect, the present invention further provides a compound or a pharmaceutically acceptable salt, ester, or solvate thereof, the structure of which is: [ka] [ka] [ka] [ka] [ka] [ka] [ka] It is characterized in that it is any one selected from the following.

[0020] In a further aspect, the present invention further provides a complex, which is formed by coordinating the compound described above or a pharmaceutically acceptable salt, ester or solvate thereof, or a complex represented by formula (III) or formula (IV) described above, with a radionuclide or a non-radioactive element B'.

[0021] In some implementations of the present invention, radionuclide or non-radioactive element A' and radionuclide or non-radioactive element B' are the same or different.

[0022] In some means of the invention, said radionuclide A' or B' is each independently 68 Ga, 18 F, 99m Tc, 89 Zr, 111 In, 45 Ti, 59 Fe, 64 Cu, 94m Tc, 67 Ga, 71 / 72 / 74 As, 43 / 44 Sc, 82m Rb, 52 Mn, 86 Y, 76 Br, 177 Lu, 90 Y, 153 Sm, 67 Cu, 89 Sr, 137 Cs, 166 Ho, 177 Yb, 105 Rh, 186 / 188 Re, 47 Sc, 212 / 213 Bi, 225 Ac, 212 Pb, 149 Pm and 227 Th, and the remaining variables are as defined herein.

[0023] In some implementations of the present invention, the non-radioactive elements A' or B' are each independently selected from Ga, Fe, and Gd, with the remaining variables being as defined herein.

[0024] In some implementations of the invention, the radionuclide is 18 F, 68 Ga, 177 Lu, and the remaining variables are as defined herein.

[0025] In some implementations of the present invention, the radionuclide 18 The coordinate bond of F is radioactive fluoride The radioisotope is preferably formed through aluminum. 18 FAl, and the remaining variables are as defined herein.

[0026] In some implementations of the present invention, the structure of the complex is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] It is one of the following:

[0027] In a further aspect, the present invention further proposes a pharmaceutical composition, which according to an embodiment of the present invention comprises the compound as described above, or the complex as described above, or a pharmaceutically acceptable salt, ester or solvate thereof, a pharmaceutically acceptable carrier, and an adjuvant.

[0028] In a further aspect, the present invention further proposes the use of the aforementioned compound or the aforementioned complex or a pharmaceutically acceptable salt, ester or solvate thereof or the aforementioned pharmaceutical composition in the preparation of one or more reagents and / or medicaments for diagnosing and / or treating tumors, cancers or cells expressing PSMA.

[0029] In a further aspect, the present invention further proposes the use of the aforementioned compound or the aforementioned complex or a pharmaceutically acceptable salt, ester or solvate thereof or the aforementioned pharmaceutical composition in the diagnosis and / or treatment of tumors, cancers or cells expressing PSMA.

[0030] In a further aspect, the present invention further provides a method for diagnosing and / or treating tumors, cancers or cells expressing PSMA, in some implementations of the present invention, said method comprising the step of administering to a patient a pharmaceutically acceptable amount of the compound described above or the complex described above or a pharmaceutically acceptable salt, ester or solvate thereof or the pharmaceutical composition described above.

[0031] In a further aspect, the present invention further proposes a method for diagnosing and / or treating prostate cancer and other solid tumors and / or metastases thereof, comprising utilizing the aforementioned compound or the aforementioned complex or a pharmaceutically acceptable salt, ester or solvate thereof or the aforementioned pharmaceutical composition.

[0032] In some embodiments of the invention, the mode of diagnosis is selected from optical imaging and / or nuclide imaging, the remaining variables being as defined herein. In some embodiments of the invention, the mode of diagnosis is selected from PET (positron emission tomography) imaging and / or SPECT (single photon emission computed tomography) imaging, the remaining variables being as defined herein.

[0033] In some implementations of the invention, the treatment is selected from radiotherapy, and the remaining variables are as defined herein.

[0034] In some implementations of the invention, the cancer is selected from prostate cancer and / or other solid tumors, and the remaining variables are as defined herein.

[0035] In a further aspect, the present invention further proposes a reagent kit, which according to an embodiment of the present invention comprises the compound or the complex or a pharmaceutically acceptable salt, ester or solvate thereof, and a pharmaceutically acceptable carrier and auxiliary material.

[0036] In some implementations of the present invention, the reagent kit further comprises pharmaceutical adjuvants, the remaining variables being as defined herein.

[0037] In some implementations of the invention, the pharmaceutical adjuvants include sterile water for injection, acetic acid / sodium acetate buffer solution, and sodium ascorbate.

[0038] In some aspects of the present invention, the reagent kit is prepared by the following method: 1) Prepare a 0.2-10 mg / mL solution of the precursor of the aforementioned compound or complex using sterile water for injection as a solvent, and dispense it into 5-50 μg / vial. 2) Prepare a 0.2-0.5 mol / L acetic acid / sodium acetate buffer solution (pH 3.5-4.5) using sterile water for injection as a solvent, and dispense 0.2-2 mL per vial. 3) Prepare a 20-80 mg / mL sodium ascorbate solution using sterile water for injection as a solvent and dispense 0.1-1 mL per vial.

[0039] In some implementations of the present invention, all of the above solutions are performed in a global grade C and local grade A clean bench. [Effects of the Invention]

[0040] According to the embodiments of the present invention, the present invention has at least one of the following advantageous effects over the prior art. 1) The present invention optimizes the molecular structure by combining a large molecular weight radionuclide chelating group with a PSMA targeting group. Current experimental results show that the effectiveness of this molecule in radiodiagnosis (PET / CT or SPECT / CT scans) is not significantly different from that of currently available PSMA diagnostic varieties. 2) Another advantage of the clinical application of this invention is that when a patient is injected with a radiolabeled drug and undergoes PET / CT scan or SPECT / CT scan, the image results show that the tumor has a very high uptake to background ratio (target-background ratio), allowing clinicians to easily interpret the results. This allows for data such as tumor size, location, and malignancy to be obtained. 3) By optimizing the molecular structure, the present invention makes it possible to carry either diagnostic or therapeutic nuclides on the same molecular structure, and by using these in pairs, it has realized theranostics in the truest sense. 4) By optimizing the molecular structure, the present invention provides drug molecules with high affinity to tumor cells, good targeting, long retention time at the tumor site, rapid elimination from the circulatory system, long half-life in the body, and high cumulative dose at the tumor site, thereby reducing the single dose or administration frequency and reducing toxicity.

[0041] Definitions and General Terms The present invention specifically cites literature corresponding to the determined embodiment, and examples are accompanied by structural and chemical formula illustrations. The present invention anticipates and covers all alternatives, variations, and equivalents that may be included within the scope of the present invention as defined by the claims. Those skilled in the art will recognize many similar or equivalent methods and materials described herein that may be applicable to the practice of the present invention. The present invention is not limited to the description of the methods and materials. Numerous literature and similar materials exist that are distinct from or contradictory to the application of the present invention, including, but not limited to, definitions of terms, usage of terms, techniques described, or scope controlled by the application of the present invention.

[0042] For the purposes of the present invention, the following definitions apply unless otherwise specified: For the purposes of the present invention, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version and the Handbook of Chemical and Physical Properties, 75 th Ed., 1994. General principles of organic chemistry are also described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito, 1999, and "March's Advanced Organic Chemistry," Michael B. Smith and Jerry March, John Wiley & Sons, New York, 2007, all of which are incorporated herein by reference.

[0043] As explained in the present invention, the amino acid refers to an organic compound containing a basic amino and an acidic carboxyl group.

[0044] As described herein, the compounds of the present invention, such as the compounds of the general formula above, or the specific examples, subclasses, and groups of compounds included in the examples, are optionally substituted with one or more substituents. It should be understood that the term "optionally substituted" can be used interchangeably with the term "substituted or unsubstituted." Generally, the term "optionally," whether preceded by the term "substituted," means that one or more hydrogen atoms in the listed structure may be replaced with a specific substituent. Unless otherwise specified, one optional substituent may be substituted with one substituent at each substitutable position of that group. When a listed structural formula has multiple positions that may be substituted with one or more substituents selected from a specific group, the substituents may be substituted at each position, whether they are the same or different. The substituents include deuterium, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclic group, mercapto, nitro, aryloxy, heteroaryloxy, oxo(=O), carboxyl, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O)2-, carboxyl-substituted alkoxy, [ka] It may be, but is not limited to, the following.

[0045] Unless otherwise specified, the term "alkyl group" refers to a saturated, straight- or branched-chain monovalent hydrocarbon group of 1-20 carbon atoms, or 1-10 carbon atoms, or 1-8 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, which alkyl groups can be independently and optionally substituted with one or more substituents described herein, including, but not limited to, deuterium, amino, hydroxy, cyano, F, Cl, Br, I, mercapto, nitro, oxo (=O), and the like. Examples of alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C (CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2 CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, and the like.The term "alkyl group" and its prefix "alkane" are used herein to refer to both straight and branched saturated carbon chains. "Alkylene" is used herein to refer to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a straight or branched chain saturated hydrocarbon, examples of which include, but are not limited to, methylene, ethylene, isopropylene, etc.

[0046] The term "aryl," whether used alone or as part of "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to carbocyclic ring systems containing a total of 6-14 membered rings, including mono-, bi-, and tricyclic rings, provided that at least one ring system is aromatic, each ring system contains 3-7 membered rings, and has one or more points of attachment to the remainder of the molecule. The terms "aryl" and "aromatic ring" are used interchangeably. For example, the aromatic ring can include phenyl, naphthyl, and anthracenyl. The aryl can be substituted or unsubstituted, and the substituents can be, but are not limited to, deuterium, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocycle, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O)2-, hydroxy-substituted alkyl group-S(=O)-, hydroxy-substituted alkyl group-S(=O)2-, carboxyl-substituted alkoxy, etc.

[0047] The term "heteroaryl," whether used alone or as part of "heteroarylalkyl" or "heteroarylalkoxy," refers to monocyclic, bicyclic, and tricyclic ring systems containing, in total, 5-14 membered rings, where at least one ring system is aromatic and contains one or more heteroatoms, the heteroatoms having the meaning described herein, and each ring system contains 3-7 membered rings and has one or more points of attachment to the remainder of the molecule. The terms "heteroaryl" and "heteroaromatic heterocycle" or "heteroaromatic compound" can be used interchangeably. The heteroaryl may be substituted or unsubstituted, and the substituents may be, but are not limited to, deuterium, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl group, alkenyl, alkynyl, heterocycle, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O)2-, carboxyl-substituted alkoxy, etc.

[0048] In some other embodiments, the aromatic heterocycle is 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazol-5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrimidin-5-yl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1 ,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, 1,3,4-thiadiazolyl-2-yl, pyrazinyl, pyrazin-2-yl, 1,3,5-triazinyl, benzo[d]thiazolyl-2-yl, imidazo[1,5-a]pyridine and bicyclic rings including, but not limited to, benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl).

[0049] The term "halogen" refers to F, Cl, Br and I.

[0050] In addition, unless otherwise explicitly indicated, the terms "each independently" and "and each independently" used throughout this specification are interchangeable and should be understood in a broad sense, and may mean that specific options represented between the same symbols in different groups do not affect each other, or that specific options represented between the same symbols in the same group do not affect each other, for example, in the structure [ka] and structure [ka] Both R 6 The specific choices of R do not affect each other, and at the same time, multiple R 6 If there are multiple R 6 The specific choices between them do not affect each other, i.e., R 6 The specific options may be the same or different.

[0051] In the structural formula of the compound or said ligand described in the present disclosure, [ka] indicates that the configuration is not specified. If a chiral center is present in a chemical structure, the bond [ka] teeth [ka] or [ka] For simplicity, all of the above structural formulas are shown in one isomeric form, but the present disclosure can include all isomers, such as tautomers, rotamers, geometric isomers, diastereomers, racemates, and enantiomers.

[0052] The definitions and conventions of stereochemistry used in the present invention are generally based on the following sources: SP Pa See, e.g., Marker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric or chiral centers, and different stereoisomers exist. All stereoisomeric forms of the compounds of the present invention, including, but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, e.g., racemic mixtures, are part of the present invention. Many organic compounds exist in optically active forms, i.e., have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D, L, or R, S are used to denote the absolute configuration of the chiral centers of the molecule. The prefixes d, l, (+), and (-) designate the rotation of plane-polarized light of a compound; (-) or l indicates a levorotatory compound, and (+) or d indicates a dextrorotatory compound. These stereoisomers have the same chemical structure but differ in their configuration. Certain stereoisomers are enantiomers, and mixtures of isomers are commonly called enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can result in a lack of stereoselectivity or stereodirection in a chemical reaction. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers lacking optical activity.

[0053] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be interconverted via a low energy barrier. For example, proton tautomers (i.e., proton transfer tautomers) include tautomers due to proton transfer, such as keto-enol and imine-enamine isomerizations. Valence tautomers include tautomers involving a reorganization of bond electrons.

[0054] As used herein, the term "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art and are described in S.M. Berge et al., J. Pharmaceutical Sciences, 66, 1-19, 1977. Salts formed from pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with an amino group, such as hydrochloride, hydrobromide, phosphate, sulfate, and perchlorate, organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, and malonate, or salts obtained by other methods described in the literature, such as ion exchange methods. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, enamate, hexanoate, hydroiodide, 2-hydroxybenzoate, and the like. Salts obtained with suitable bases include dimethylsulfonate, lactoronic acid salt, lactate, laurate, lauryl sulfate, malate, malonate, mesin sulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, palmitate, palmitate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, pertinate, etc. Salts obtained with suitable bases include alkali metal, alkaline earth metal, ammonium, and N +(C 1-4 The present invention also contemplates any quaternary ammonium salt formed from a compound having an N-containing group. Water- or oil-soluble or dispersible products may be obtained by the quaternary ammonium reaction. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include halides, hydroxides, carboxylates, sulfates, etc. substances, phosphorus oxides, nitrates, C 1-8 Suitable non-toxic ammonium / quaternary ammonium salts such as sulfonates, aromatic sulfonates, etc., with amine cations that resist balance ion formation.

[0055] The term "solvate" as used herein refers to an association formed between one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed with the solvent molecule water.

[0056] The following abbreviations are used throughout this application: DOTA represents 1,4,7,10-tetrazacyclododecane-N,N`,N``,N```,-tetraacetic acid, NOTA represents 1,4,7-triazacyclononane-1,4,7-triaacetic acid, NODAGA represents 2-(4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)glutaric acid, DOTAGA represents 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetrazacyclododecan-1-yl)glutaric acid, and T RAP represents 1,4,7-triazacyclononanephosphonic acid, NOPO represents 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphonic acid]-4,7-bis[methyl(2-carboxymethyl)phosphonic acid], and DFO represents N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[5-aminopentyl)(hydroxy)amino]-4-oxobutyryl}amino)pentyl]-N-hydroxysuccinamide. DTPA represents diethylenetriaminepentaacetic acid, CHX-DTPA represents trans-cyclohexyl-diethylenetriaminepentaacetic acid, SCN-Bz-DTPA represents p-isothiocyanatobenzyl-DTPA, 1B3M represents 1-(isothiocyanatobenzyl)-3-methyl-DTPA, 1B3B represents 1-(isothiocyanatobenzyl)-4-methyl-DTPA, and MX-DTPA represents 1-(2)-methyl-4-isocyanatobenzyl-DTPA. where oxo-Do3A represents 2-oxa-4,7,10-triazacyclododecane-4,7,10-triaacetic acid, HYNIC represents 6-hydrazinonicotinic acid succinimidyl ester hydrochloride, p-SCN-Bn-CHX-A″-DTPA represents (R)-2-amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid, and MAG3 represents mercaptoacetyltriglycine.

[0057] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the following detailed description of the preferred embodiments with reference to the accompanying drawings. [Brief explanation of the drawings]

[0058] [Figure 1] 1 is an LC-MS spectrum of the NYM032 molecule according to an embodiment of the present invention. [Figure 2] 1 is an HPLC spectrum of the NYM032 molecule according to an embodiment of the present invention. [Figure 3] FIG. 1 is a radioactive thin layer chromatography scan purity analysis of 68Ga-NYM032 molecule according to an embodiment of the present invention. [Figure 4] 1 is a graph showing the body weight of ICR mice after administration according to an example of the present invention. [Figure 5] 1 shows the results of PET / CT imaging of 68Ga-NYM032 in an LNcap tumor-bearing mouse model according to an embodiment of the present invention, with the arrow indicating the tumor site. [Figure 6] 1 is an LC-MS spectrum of the NYM033 molecule according to an embodiment of the present invention. [Figure 7] 1 is an HPLC spectrum of the NYM033 molecule according to an embodiment of the present invention. [Figure 8] FIG. 1 is a radioactive thin layer chromatography scan purity analysis of 68Ga-NYM033 molecule according to an embodiment of the present invention. [Figure 9] 1 shows the results of PET / CT imaging of 68Ga-NYM033 in an LNcap tumor-bearing mouse model according to an embodiment of the present invention, with the arrow indicating the tumor site. [Figure 10] 1 shows a scan of a competitive inhibition experiment between 68Ga-NYM032 and 68Ga-NYM033 in an LNcap tumor-bearing mouse model according to an embodiment of the present invention, where A and B are 68Ga-NYM032 and 68Ga-NYM033, respectively, and the arrow indicates the tumor site. [Figure 11] 1 is a diagram showing the results of PET / CT imaging in a 68Ga-NYM032 clinical research test according to an embodiment of the present invention. [Figure 12] 1 is a diagram showing the results of PET / CT imaging in a 68Ga-NYM033 clinical research test according to an embodiment of the present invention. [Figure 13a] 1 is a diagram showing the results of PET / CT imaging 1 hour after administration of 68Ga-NYM032 and 68Ga-PSMA11 to a patient in a clinical research study according to an embodiment of the present invention. [Figure 13b] FIG. 10 is a diagram showing the results of PET / CT imaging 2 hours after administration of 68Ga-NYM032 and 68Ga-PSMA11 to patients in a clinical research study according to an embodiment of the present invention. [Figure 14a] 6A and 6B are PET / CT imaging results obtained 1 hour after administration of 68Ga-NYM032 and 68Ga-PSMA617 to patients in a clinical research study according to an embodiment of the present invention. [Figure 14b] 6A and 6B are PET / CT imaging results obtained 2 hours after administration of 68Ga-NYM032 and 68Ga-PSMA617 to patients in a clinical research study according to an embodiment of the present invention. [Figure 15] FIG. 1 is a TLC diagram of 177Lu-NYM032 according to an embodiment of the present invention. [Figure 16] 1 is a graph showing the trend of tumor volume size in a tumor-bearing mouse model after treatment with 177Lu-NYM032 and saline according to an embodiment of the present invention. [Figure 17] 1 is a graph showing the weight trend of tumor-bearing mice after treatment with 177Lu-NYM032 and saline according to an embodiment of the present invention. [Figure 18] FIG. 1 is a diagram showing the results of PET / CT imaging 1 hour after administration of 68Ga-NYM032 to a patient in a clinical research test according to an embodiment of the present invention. [Figure 19] 1A and 1B are diagrams showing the results of SPECT / CT imaging 0.5 hours, 1 hour, 24 hours, 48 ​​hours, 120 hours, and 192 hours after administration of 177Lu-NYM032 to patients in a clinical research study according to an embodiment of the present invention. [Figure 20] 10A and 10B are diagrams showing the results of SPECT / CT imaging 336 hours and 504 hours after administration of 177Lu-NYM032 to a patient in a clinical research study according to an embodiment of the present invention. [Figure 21] FIG. 1 is a pharmacokinetic curve diagram of 177Lu-NYM032 after administration to a patient in a clinical research study according to an embodiment of the present invention. [Figure 22] FIG. 1 is a graph showing the relationship between the time course of radioactivity in the internal lesions after administration of 177Lu-NYM032 to patients in a clinical research study according to an embodiment of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0059] The following examples are used in combination to illustrate the present disclosure. Those skilled in the art can understand that the following examples are only used to illustrate the present disclosure and should not be considered to limit the scope of the present disclosure. If no specific techniques or conditions are shown in the examples, they should be carried out according to the techniques or conditions described in the literature of the field or according to the product specifications. If no manufacturer is shown for the reagents or equipment used, they are conventional products that can be purchased commercially.

[0060] Example 1 Preparation process of compound NYM032 [ka]

[0061] The LC-MS spectrum is shown in FIG. 1, and the HPLC spectrum is shown in FIG. Synthetic Route: Step 1: [ka] Compound (1) (10.0 g, 29.5 mmol, 1.00 eq, HCl) was dissolved in a mixture of THF (100 mL) and HO (100 mL). FMOC-OSU (9.46 g, 28.0 mmol, 0.95 eq) and NaHCO (7.44 g, 88.5 mmol, 3.44 mL, 3.00 eq) were added and stirred at 20 °C for 1 h. Thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) showed the formation of a new compound. The reaction mixture was diluted with 500 mL of HO and extracted with ethyl acetate (500 mL x 3), three times, each time with 500 mL of ethyl acetate. The organic layer was washed with 500 mL of brine, dried over NaSO, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was triturated with MTBE (30.0 mL) at 20° C. for 2 hours to give compound (2) (14.2 g, 27.0 mmol, 91.7% yield) as a white solid.

[0062] Step 2: [ka] Compound (2) (13.0 g, 24.7 mmol, 1.00 eq) was dissolved in DCM (90.0 mL), TFA (46.2 g, 405 mmol, 1.00 eq) was added, and the mixture was stirred at 20 °C for 1 h. The pH was adjusted to 8 by adding NaHCO3 solution, and the mixture was extracted with ethyl acetate (200 mL * 3), three times, using 500 mL of ethyl acetate each time. The organic layer was washed with 200 mL of concentrated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product containing compound (3) as a yellow oil.

[0063] Step 3: [ka] Compound (4) was dissolved in THF (500 mL), DCC (26.0 g, 126 mmol, 1.00 eq) and HOSu (14.5 g, 126 mmol, 2.20 eq) were added, and the mixture was stirred at 20° C. for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give 12.0 g of a white solid containing compound (5).

[0064] Step 4: [ka] Compound (5) (12.0 g, 32.5 mmol, 1.00 eq) was dissolved in DMF (100 mL) and DIEA (12.6 g, 97.7 mmol, 17.0 mL, 3.00 eq) was added. A solution of compound (3) (6.92 g, 16.2 mmol, 0.5 eq) in DMF (100 mL) was added dropwise to the above solution and stirred at 20 °C for 2 h. The mixture was diluted with 500 mL of water, and the organic layer was washed with 500 mL of concentrated brine and then eluted with Na2O3. S The crude product was dried over O, filtered, and concentrated under reduced pressure. It was purified using preparative high-performance liquid chromatography to give compound (6) (2.90 g, 4.28 mmol) as a yellow oil.

[0065] Step 5: [ka]

[0066] Polypeptide synthesis: The polypeptide was synthesized using the Fmoc synthesis method. 1. Resin preparation: 2-CTC (0.10 mmol, 1.00 mmol, Sub 0.50 mmol / g) and Fmoc-Lys(Dde)-OH (0.05 g, 0.10 mmol, 1.00 eq) were added to a solid-phase reactor. DCM (10.0 mL) was added and the mixture was purged with N2 gas. DIEA (0.05 g, 0.40 mmol, 0.07 mL, 4.00 eq) was then added dropwise and the mixture was stirred for 2 h at room temperature (20 °C) with N2 gas. MeOH (0.20 mL) was added and the mixture was stirred for 30 min. The resin was then washed five times with DMF (50 mL * 5), using 50 mL of DMF each time. 2. 50 mL of a DMF solution containing 20% ​​piperidine was added to the reactor, and the reaction was carried out for 30.0 minutes while blowing nitrogen gas into the reactor. The resin was then washed five times with DMF. 3. Condensation: H-Glu(OtBu)-OtBu.HCl (0.09 g, 0.30 mmol, 3.00 eq), CDI (0.05 g, 0.30 mmol, 3.00 eq), and DMAP (0.04 g, 0.30 mmol, 3.00 eq) were dissolved in THF (200 mL). DIEA (0.03 g, 0.20 mmol, 0.04 mL, 2.00 eq) was added dropwise and the mixture was allowed to react at 20 °C for 1 hour. This solution was then added to the resin, and the mixture was stirred at 20 °C for 12 hours under N2 gas. The resin was then washed five times with DMF (50 mL * 5), using 50 mL of DMF each time. 4. 3% hydrazine hydroxide (50.0 mL) was added to the resin, and N2 gas was blown into the resin to react for 1 hour. Then, the resin was washed with DMF (50.0 mL * 5), and the washing was repeated 5 times, using 50 mL of DMF each time. The resin was then filtered. 5. Condensation: Fmoc-2-Nal-OH (0.07 g, 0.15 mmol, 1.50 eq) and HBTU (0.05 g, 0.14 mmol, 1.43 eq) were dissolved in 10.0 mL of DMF, the solution was added to the resin, and N2 gas was blown in. Next, DIEA (0.04 g, 0.30 mmol, 0.05 mL, 3.00 eq) was added, and the reaction was carried out for 30.0 min at 20 °C with N2 gas blown in. Next, the resin was washed with DMF (50.0 mL * 5), five times, using 50 mL of DMF each time. 6. Add 50 mL of a DMF solution containing 20% ​​piperidine to the resin, blow N2 gas into it, and let it react for 30.0 min. Then, wash the resin with DMF (50.0 mL * 5). The resin was washed twice, each time with 50 mL of DMF, and filtered to obtain the resin. 7. Repeat steps 5-6 above to sequentially couple the amino acids (numbered ch) in Table 1.

[0067] [Table 1] 8. The resin was added with a 20% DMF solution containing piperidine and stirred for 30.0 min to remove the Fmoc protecting group. The deprotection reaction was monitored with ninhydrin detection reagent, and after completion of the reaction, the resin was washed five times with DMF. 9. Polypeptide cleavage and purification: The polypeptide bearing side chain protecting groups and the cleavage solution (90% TFA, 2.5% HO, 2.5% 3-mercaptopropionic acid, 5% TIS) were added to a flask and stirred at room temperature for 2 hours to deprotect the polypeptide. The mixture was then precipitated with tert-butyl methyl ether (TME), allowed to stand at -20 °C for 5.0 min, filtered to collect the filter cake, which was then washed twice with tert-butyl methyl ether and dried under vacuum for 2 hours. The crude product was purified by preparative high-performance liquid chromatography (A: 0.075% TFA in HO, B: ACN) to obtain the final product NYM032 (10.2 mg, 5.64 μmol, purity 95.1%, TFA) as a white solid.

[0068] Example 2 Compound 68Preparation process of Ga-NYM032 The synthesized NYM032 precursor is the radionuclide gallium [ 68 It can be further used as a clinical PET / CT tracer via chelation reaction with Ga 68 The Ga-NYM032 tracer was prepared and the labeling process was as follows. The whole labeling process can be completed within 20 minutes. The specific steps are as follows: 68 The Ga nuclide was eluted from the germanium gallium generator with 0.1 M hydrochloric acid solution, and 5 mL of this 68 A Ga nuclide (25 mCi) solution was added to the reaction bottle, and then 3-5 mL of a 0.3 mol / L acetic acid / sodium acetate buffer solution was added to the reaction bottle. 68 The ratio of the volume of Ga nuclide to the volume of buffer solution was 1:1, and the pH value was adjusted to 4.0-6.0. NYM032 precursor compound was added to sterile injection water in an appropriate amount to prepare a 1 mg / mL precursor solution, and then 49 nmol (100 μg) was added to a reaction bottle and reacted at 80°C for 6 minutes. After the reaction was completed, the bottle was cooled for 1 minute, and 5 mL of sterile injection water was added to the reaction bottle using a 10 mL sterile syringe to achieve the purpose of lowering the temperature of the reaction solution. The reaction mixture was diluted, and all the liquid in the reaction bottle was drawn into a syringe. A pre-activated Sep-Pak C-18 cartridge was taken and connected to the outlet end of the syringe. The reaction diluent was then pushed through the Sep-Pak C-18 cartridge, resulting in the release of the target product. 68 Ga-NYM032 was adsorbed onto the C-18 cartridge, and then the cartridge was eluted with 1 mL of 70% medical grade absolute ethanol solution. The eluate was filtered through a 0.22 μm sterile filter and then poured into a sterile vacuum bottle. 5-8 mL of saline solution was added to the eluate. 68 Ga-NYM032 sterile injection solution was obtained.

[0069] The quality control of the above product was performed using radioactive thin-layer chromatography. The carrier was glass fiber paper, and the developing solution was 0.5 M citric acid / sodium citrate buffer (pH = 5). Glass fiber paper was prepared, and a sample was gently spotted 1.5 cm from the bottom of the glass fiber paper using a pipette gun. The sample was then placed in a test tube containing 500 μL of 0.5 M citric acid / sodium citrate buffer (pH = 5), which had been added previously. The sample was then removed to a position 2.5 cm from the top of the chromatography paper, dried, and detected using a Radio-TLC thin-layer scanner. In the 0.5 M citric acid / sodium citrate buffer (pH = 5) system, the Rf value of the product was between 0.2 and 0.4. As shown in Figure 3, 68 The radiochemical purity of Ga-NYM032 was 100% as determined by radioactive thin layer chromatography scan purity analysis. [ka]

[0070] Example 3 Acute toxicity experiment in ICR mice Six- to eight-week-old ICR mice were purchased from Suzhou Hengjia Biotechnology Co., Ltd. Six mice were randomly selected and each mouse was 68 Ga-NYM032 was administered at a dose of 300-400 μCi. The animals were observed for general indicators (fur coat, activity, feeding, etc.) and mortality (time of death, etc.) on days 0, 2, 4, 6, 8, 10, 12, and 14 after administration, and weighed. On the final day of the experiment, the animals were euthanized and autopsied to examine the major organs for abnormalities. As shown in Figure 4, none of the mice died or showed any abnormalities during the 14-day observation period. Autopsy revealed no abnormalities in the organs, and all mice had regained weight after the experiment was completed. 68 Ga-NYM032 molecule has good safety and meets the usage demands of clinical research drugs.

[0071] Example 4 68 PET / CT scan tissue distribution and targeting experiment of Ga-NYM032 in LNcap model mice Eight- to nine-week-old B-NDG mice were purchased from Beijing Aosaitu Pharmaceutical Co., Ltd. A subcutaneous heterotopic transplantation model of LNcaP tumor was established using B-NDG mice. The model is a mouse model constructed using a human prostate cancer cell line. Three animals were selected for this animal model, and each animal was administered the above-mentioned 68 After administering 60-80 μCi of Ga-NYM032 and pre-anesthetizing with an appropriate concentration of isoflurane / air mixture before scanning, the animal was placed in a MicroPET / CT imaging chamber (SNPC-303 Super Nova, Pingsheng Medical Technology (Kunshan) Co., Ltd.) and maintained anesthesia with an isoflurane / air mixture. MicroPET / CT scans were performed 1, 2, and 3 hours after administration. Scan images were reconstructed using the device software and analyzed using PMOD software. The results are shown in Figure 5. 68 Biodistribution of Ga-NYM032 drug in LNcaP tumor model mice indicates that it is mainly excreted via the kidney, with high radioactivity accumulation in tumor tissue (indicated by arrow) and low uptake in other tissues.

[0072] Example 5 68 Ga-NYM032 irradiation dose estimation in the human body Four ICR mice were given radioactive drugs 68 After 100 μCi of Ga-NYM032 was administered, a 30-minute dynamic scan was performed, followed by 10-minute static scans at 1, 2, 3, and 4 hours. The tissue distribution data for each time point in the normal mouse was obtained from the scan data. The residence time in each organ in the mouse was calculated using PMOD software. The residence time in the human organs was then estimated from the mouse organ residence time. The human radiation dose was calculated using OLINDA software. The calculated total body effective dose (ED) was 0.010 mSv / MBq. Based on the clinical dose of 111 MBq (3 mCi) per person, the total effective dose was 1.221 mSv / person, which is significantly lower than the 10-15 mSv radiation dose typically associated with chest and abdominal CT scans and within the safety range. The estimated radiation dose is shown in Table 2.

[0073] [Table 2]

[0074] Example 6 Preparation process of compound NYM033 [ka]

[0075] The LC-MS spectrum is shown in FIG. 6, and the HPLC spectrum is shown in FIG.

[0076] Synthetic Route: NYM033 was also obtained by a method similar to that for NYM032. [ka]

[0077] Polypeptide synthesis: The polypeptide was synthesized using the Fmoc synthesis method. 1. Resin preparation: 2-CTC (0.30 mmol, 1.00 eq, Sub 0.50 mmol / g) and Fmoc-Lys(Dde)-OH (0.15 g, 0.30 mmol, 1.00 eq) were added to a solid-phase reactor. DCM (20 mL) was added and N2 gas was blown into the reactor. DIEA (0.15 g, 1.20 mmol, 0.21 mL, 4.00 eq) was then added dropwise and reacted at 20 °C with N2 gas for 2 hours. MeOH (0.60 mL) was added and stirred for 30 minutes. The resin was then washed with DMF (50 mL * 5), five times, using 50 mL of DMF each time. 2. 50 mL of a DMF solution containing 20% ​​piperidine was added to the reactor, and N2 gas was blown into the reactor to react for 30.0 min. The reactor was then washed with DMF (50.0 mL * 5), and the mixture was washed five times, using 50 mL of DMF each time. 3. Condensation: H-Glu(OtBu)-OtBu.HCl (0.27 g, 0.90 mmol, 3.00 eq), CDI (0.15 g, 0.90 mmol, 3.00 eq), and DMAP (0.12 g, 0.90 mmol, 3.00 eq) were dissolved in THF (20 mL). DIEA (0.09 g, 0.60 mmol, 0.12 mL, 2.00 eq) was then added dropwise and the mixture was allowed to react at 20 °C for 1 h. This solution was then added to the resin, and the mixture was stirred at 20 °C for 12 h under N2 gas. The resin was then washed with DMF (50 mL * 5), five times, using 50 mL of DMF each time. 4. 3% hydrazine hydroxide (50.0 mL) was added to the resin, and N2 gas was blown into the resin to react for 1 hour. Then, the resin was washed with DMF (50.0 mL * 5), and the resin was filtered after washing five times, using 50 mL of DMF each time. 5. Condensation: Fmoc-2-Nal-OH (0.21 g, 0.45 mmol, 1.50 eq) and HBTU (0.15 g, 0.42 mmol, 1.43 eq) were dissolved in 20 mL of DMF, the solution was added to the resin, and N2 gas was blown in. Next, DIEA (0.12 g, 0.90 mmol, 0.15 mL, 3.00 eq) was added, and the reaction was carried out for 30 min at 20 °C with N2 gas blown in. Next, the resin was washed with DMF (50 mL * 5), five times, using 50 mL of DMF each time. 6. The resin was added to 50 mL of a DMF solution containing 20% ​​piperidine, and reacted for 30.0 min while blowing N2 gas. The resin was then washed with DMF (50.0 mL * 5), 5 times, using 50 mL of DMF each time. The resin was then filtered to obtain the resin. 7. Repeat steps 5-6 above to sequentially couple the amino acids (numbered ch) in Table 3.

[0078] [Table 3] 8. Deprotection: PhSiH (10.0 eq) and Pd(PPh3)4 (0.10 eq) were dissolved in DCM (20.0 mL) and added to the resin. The resin was reacted for 1 hour under N2 gas. The resin was then washed with DMF (50.0 mL * 5), 5 times, each time using 50 mL of DMF. The resin was then filtered. 9. Condensation: Pentafluorophenol was dissolved in DCM (20.0 mL) solvent, the solution was added to the resin and N gas was blown in, then DIC (0.08 g, 0.60 mmol, 0.09 mL, 2.00 eq) was added and the reaction was carried out at 20 °C with N gas blowing for 2 h, then the resin was washed with DMF (50.0 mL * 5), and the washing was carried out five times, using 50 mL of DMF each time. 10. Condensation: 4-(2-aminoethyl)benzenesulfonic acid hydrochloride (0.14 g, 0.60 mmol, 2.00 eq) was dissolved in DMF (20.0 mL), the solution was added to the resin, and N2 gas was blown into the resin. Then, DIEA (0.15 g, 1.20 mmol, 0.21 mL, 4.00 eq) was added, and the resin was reacted at 20°C with N2 gas for 30 minutes. Then, the resin was washed with DMF (50.0 mL * 5), and the washing was repeated 5 times, using 50 mL of DMF each time. 11. A DMF solution containing 20% ​​piperidine was added to the resin and stirred for 30 minutes to remove the Fmoc protecting group. The deprotection reaction was monitored with ninhydrin detection reagent, and after completion of the reaction, the resin was washed five times with DMF. 12. Cleavage and purification of polypeptide: The polypeptide with side chain protecting groups and the cleavage solution (90% TFA, 2.5% HO, 2.5% 3-mercaptopropionic acid, 5% TIS) were added to a flask and stirred at room temperature for 2 hours*2 to deprotect the polypeptide. The mixture was then precipitated with tert-butyl methyl ether, left at -20°C for 5.0 minutes, filtered to collect the filter cake, which was then washed twice more with tert-butyl methyl ether and dried under vacuum for 2 hours. The resulting mixture was then purified by high-performance liquid chromatography (A: 0.075% TFA in HO solution, B: The crude product was purified by high-performance liquid chromatography (TF) and purified again. The crude product was purified by filtration (switching to NaHCO solution in step A) and salt-formed to give the final product NYM033 (0.1 mg, 5.31 μmol, purity 95.2%) as a white solid.

[0079] Example 7 Compound 68 Preparation process of Ga-NYM033 The synthesized NYM033 precursor is the radionuclide gallium [ 68 It can be further used as a clinical PET / CT tracer via chelation reaction with Ga 68 Ga-NYM033 tracer has been produced, and its labeling technology has matured. The labeling process is as follows. The whole labeling process can be completed within 20 minutes. The specific steps are as follows: 68 The Ga nuclide was eluted from the germanium gallium generator with 0.1 M hydrochloric acid solution, and 5 mL of this 68 A Ga nuclide (25 mCi) solution was added to the reaction bottle, and then 3-5 mL of a 0.3 mol / L acetic acid / sodium acetate buffer solution was added to the reaction bottle. 68 The ratio of the volume of Ga nuclide to the volume of buffer solution was 1:1, and the pH value was adjusted to 4.0-6.0. NYM033 precursor compound was added to sterile water for injection in an appropriate amount to prepare a 1 mg / mL precursor solution. 49 nmol (100 μg) was then added to a reaction bottle and reacted at 80°C for 6 minutes. After the reaction was completed, the reaction bottle was cooled for 1 minute. 5 mL of sterile water for injection was added to the reaction bottle using a 10 mL sterile syringe to dilute the reaction solution to achieve the goal of lowering the temperature of the reaction solution. The entire liquid in the reaction bottle was drawn into the syringe and connected to the outlet end of a pre-activated Sep-Pak C-18 cartridge. The diluted reaction solution was then pushed through the Sep-Pak C-18 cartridge to obtain the target product. 68 Ga-NYM033 was adsorbed onto the C-18 cartridge, and then the C-18 cartridge was eluted with 1 mL of 70% medical grade absolute ethanol solution. The eluate was filtered through a 0.22 μm sterile filter and then poured into a sterile vacuum bottle. 5-8 mL of saline solution was added to the eluate. 68 Ga-NYM033 sterile injection solution was obtained.

[0080] The quality control of the above product was performed using radioactive thin-layer chromatography. The carrier was glass fiber paper, and the developing solution was 0.5 M citric acid / sodium citrate buffer (pH = 5). Glass fiber paper was prepared, and a sample was gently spotted 1.5 cm from the bottom of the glass fiber paper using a pipette gun. The sample was then placed in a test tube containing 500 μL of 0.5 M citric acid / sodium citrate buffer (pH = 5), which had been added previously. The sample was then removed to a position 2.5 cm from the top of the chromatography paper, dried, and detected using a Radio-TLC thin-layer scanner. In the 0.5 M citric acid / sodium citrate buffer (pH = 5) system, the Rf value of the product was between 0.2 and 0.4. As shown in Figure 8, 68 Radioactive thin layer chromatography scan purity analysis of Ga-NYM033 showed that its radiochemical purity was 100%. [ka]

[0081] Example 8 68 PET / CT scan tissue distribution and targeting experiment of Ga-NYM033 in LNcap model mice Eight- to nine-week-old B-NDG mice were purchased from Beijing Aosaitu Pharmaceutical Technology Co., Ltd. A subcutaneous heterotopic transplantation model of LNcaP tumor was established using B-NDG mice. This model is a mouse model constructed with a human prostate cancer cell line. Three animals were selected for this animal model, and each was administered the above-mentioned 68 After administering 60-80 μCi of Ga-NYM033 and pre-anesthetizing with an appropriate concentration of isoflurane / air mixture before scanning, the animal was placed in a MicroPET / CT imaging chamber (SNPC-303 Super Nova, Pingsheng Medical Technology (Kunshan) Co., Ltd.) and maintained anesthesia with isoflurane / air mixture. MicroPET / CT scans were performed 1, 2, and 3 hours after administration. Scan images were reconstructed using the device software and analyzed using PMOD software. The results are shown in Figure 9. 68Biodistribution of Ga-NYM033 drug in LNcaP tumor model mice indicates that it is mainly excreted from the body via the kidneys, with high radioactivity accumulation in tumor tissue (indicated by arrow) and low uptake in other tissues.

[0082] Example 9 68 Ga-NYM032, 68 Competitive inhibition of Ga-NYM033 in LNcaP tumor-bearing mouse model Eight- to nine-week-old B-NDG mice were purchased from Beijing Aosaitu Pharmaceutical Technology Co., Ltd. A subcutaneous heterotopic transplantation model of LNcaP tumors was established in B-NDG mice, which is a mouse model constructed with a human prostate cancer cell line.

[0083] The experiment was divided into two groups, one for the baseline experiment and one for the block experiment. The baseline experiment was divided into two groups, and three mice were randomly selected from each group. Each mouse was administered 200 μL of approximately 40 μCi of 200 μL of 20 ... 68 The other group of mice received a tail vein injection of Ga-NYM032, approximately 40 μCi in 200 μL. 68 Ga-NYM033 was injected via the tail vein. 68 Ga-NYM032 and 68 MicroPET / CT scans were performed 1, 2, and 3 hours after the injection of Ga-NYM033. Scan images were obtained after reconstruction using the device software and analyzed using PMOD software. The block experiment was divided into two groups, with the same groups and animals as in the baseline experiment. Mice in one group were injected with the cold drug NYM032 via the tail vein, and the injection volume was 100g. 68 Ga-NYM032) injection mass was 40 times that of the hot drug injection mass. Another group of mice received a cold drug NYM033 injection via the tail vein, and the injection volume was 40 times that of the hot drug injection mass ( 68 Ga-NYM033) mass, and 30 minutes after administering the cold medicine, the corresponding groups were given the hot medicine 68 Ga-NYM032 and 68After Ga-NYM033 injection and administration of the cold drug, MicroPET / CT scans were performed 1, 2, and 3 hours later. The scan images were reconstructed using the device software and analyzed using PMOD software. As shown in Figure 10, the tumor (indicated by the arrow) showed a significant increase in size after the cold drug was administered. 68 Ga-NYM032 and 68 It is possible to block the uptake of Ga-NYM033, which leads to tumor 68 Ga-NYM032 and 68 The uptake for Ga-NYM033 was specific target uptake.

[0084] Example 10 68 Ga-NYM032, 68 Ga-NYM033 Clinical Research Trial PET / CT Imaging (1) Brief information about the patient: Patient 1 had "nocturia for 1 year, painless hematuria for 4 months, intermittent The patient was hospitalized due to "appearance in the prostate gland." Blood tests showed abnormally elevated prostate tumor index, CT and B ultrasound showed calcification with prostate proliferation, and suspicious thickening of the posterior bladder wall. Therefore, we participated in a PSMA tracer clinical research trial. 68 One hour after the injection of 3.31 mCi of Ga-NYM032, whole-body PET / CT images were taken. As shown in Figure 11, the results of the examination showed that Patient 1 had multiple foci of abnormally increased radioactivity uptake in the skull, multiple spine sites, sternum, multiple ribs, left scapula, multiple pelvis sites, upper left femur, and lower left tibia, with SUVmax of 31.7. Corresponding CT scans showed bone destruction (osteogenesis), indicating that prostate cancer was accompanied by multiple bone metastases throughout the body. The expression of PSMA receptors was increased in multiple large lymph nodes in the left clavicle region, mediastinal, retroperitoneal, and bilateral parailiac lymph nodes, which was thought to be due to metastasis. 68 The Ga-NYM032 drug can be radioactively uptaked in a short time, has good imaging effect, can detect small tumors and their metastatic lesions, and has clear imaging interface. (2) Brief information about the patient: Patient 2 has been undergoing comprehensive prostate MT treatment for more than two years. His TPSA level was recently checked at 1.38ng / ml. He has no significant discomfort. He is currently undergoing a PSMA tracer clinical research study to understand his overall condition. 68 One hour after the injection of 3.30 mCi of Ga-NYM033, whole-body PET / CT tomography was performed. As shown in Figure 12, the patient underwent comprehensive treatment for prostate cancer. The PSMA receptor expression in the right acetabulum at T4 was significantly increased, with an SUVmax of 21.7. CT scans of the corresponding areas showed no obvious bone destruction, suggesting this was due to metastasis. The right anterior chest wall showed a slight increase in radioactivity uptake accompanied by a slight nodular thickening, with an SUVmax of 3, suggesting inflammatory changes. The tumor and its metastatic lesions were 68 The Ga-NYM033 drug can be radioactively uptaked in a short time, has good imaging effect, can detect small tumors and their metastatic lesions, and has clear imaging interface.

[0085] Example 11 68 Ga-NYM032, 68 PET / CT imaging of Ga-PSMA-11 clinical research trial Brief information about the patient: Patient 3 was diagnosed with prostate cancer and underwent radical prostatectomy and endocrine therapy. Whole-body bone scintigraphy showed multiple bone metastases throughout the body. 68 Whole-body PET / CT imaging was performed 1 hour and 2 hours after injection of 2.8 mCi of Ga-NYM032. 68 Two days after Ga-NYM032 injection, the patient 68 After injection of 2.8 mCi of Ga-PSMA-11, whole-body PET / CT images were taken at 1 hour and 2 hours. As shown in Figures 13a and 13b, patient 3 had multiple metastatic bone lesions throughout his body, consistent with prostate cancer with multiple bone metastases throughout his body. 68 The radioactive uptake of Ga-NYM032 is comparable to that of currently available PSMA diagnostic strains. 68 There was no significant difference with Ga-PSMA-11, and the kidney 68 Intake of Ga-NYM032 68This was smaller than the intake of Ga-PSMA-11, further reducing the amount of radioactive exposure in the body. 68 Ga-NYM032 can be radioactively uptaked in a short time, has good imaging effect, can detect small tumors and their metastases, and has clear imaging interface, which is of clinical value.

[0086] Example 12 68 Ga-NYM032, 68 PET / CT imaging of Ga-PSMA-617 molecular clinical research trial Brief Patient Information: Patient 4 was diagnosed with prostate cancer and underwent laparoscopic radical prostatectomy. A concurrent bone scan showed increased metabolism in the right sixth rib. He was treated with noredo, constellose, and abiraterone after surgery. A bone scan revealed a lesion in the right sixth anterior rib, as well as newly increased bone lesions in the right seventh posterior rib, the right eighth posterior costovertebral joint, the left scapula, and the left mid-humerus. Denosumab treatment was then initiated, with concomitant use of polaprezinc for 10 months. Subsequent bone scan images showed multiple metastatic bone lesions throughout the body, compared with the previous whole-body bone scan, and the lesions had increased in number. The patient was then monitored while taking traditional Chinese medicine, but PSA levels continued to rise slowly. 68 Whole-body PET / CT imaging was performed 1 and 2 hours after injection of 2.8 mCi of Ga-NYM032. 68 Two days after Ga-NYM032 injection, the patient 68 After injection of 2.8 mCi of Ga-PSMA-617, whole-body PET / CT scans were performed 1 and 2 hours later. As shown in Figures 14a and 14b, patient 4 developed multiple metastatic bone lesions throughout his body, consistent with prostate cancer with multiple bone metastases throughout his body. 68 Compared with Ga-PSMA-617, 68 The radioactive uptake of Ga-NYM032 is higher, allowing it to detect more tumor metastases. At the same time, its uptake in the circulatory system, such as the heart and large blood vessels, is low, resulting in a lower background uptake. It also has a higher tumor uptake and a higher target-background ratio, which makes tumor development clearer and more distinct, making it more valuable for clinical application.

[0087] Example 13 Compound 177 Preparation process of Lu-NYM032 40-60mCi lutetium [ 177 The [Lu]-lutetium chloride solution was transferred to a 10 mL sterile reaction bottle and neutralized to pH 4-4.5 with sodium acetate (0.15 mol / L) buffer solution. The synthesized NYM032 precursor solution was transferred to the reaction bottle, mixed uniformly, and then placed in a heater and reacted at 80°C for 12 minutes. A disposable Sep-Pak C-18 cartridge was taken and activated with 10 mL of absolute ethanol and 20 mL of sterile water for injection. A 10 mL sterile syringe was taken and 5 mL of sterile water for injection was pre-aspirated, after which the entire reaction solution was drawn up. Then, the C-18 cartridge was connected and the liquid in the syringe was pushed into the C-18 cartridge, and the target product, 177 Lu-NYM032 was adsorbed onto the C-18 cartridge, and then 20 mL of sterile water for injection was used to wash the C-18 cartridge. Finally, 1.2 mL of 70% absolute ethanol solution was used to elute the C-18, resulting in the target product. 177 Lu-NYM032 is dissolved in the intermediate bottle. Using a syringe that has previously drawn 3.8 mL of saline, the saline is injected into the intermediate bottle and mixed uniformly. All of the product solution (crude product) in the intermediate bottle is sucked up and filtered into a 10 mL closed sterile syringe vial using a 0.22 μm sterile filter. 177 A sterile injection solution of Lu-NYM032 was obtained. As shown in Figure 15, the synthesis preparation time was approximately 40 min, and the radiochemical purity of the product was >95% as determined by the Radio-iTLC method. [ka]

[0088] Example 14 177 Lu-NYM032 drug therapeutic effect experiment on LNcaP tumor model Experimental animals were purchased from Beijing Aosaitu Pharmaceutical Technology Co., Ltd. A subcutaneous heterotopic transplantation model of LNcaP tumor was established in B-NDG mice, which is a mouse model constructed with a human prostate cancer cell line.

[0089] Twelve animals were randomly selected for the experiment and divided into two groups: a treatment group and a control group, with three tumor-bearing mice in each group. 177 Lu-NYM032 was injected via the tail vein in 100 μL of saline solution at a dose of 1 mCi. Each animal in the control group received a 100 μL injection of saline solution via the tail vein. The weight and tumor volume of each experimental mouse were recorded on the day of injection. Tumor size (long and short diameters) and weight were measured every three days, and the condition of the mice was observed and accurately recorded.

[0090] The major and minor diameters of the tumor measured during the evaluation period of the tumor treatment effect were used to calculate the tumor volume. The formula is as follows: tumor volume (TV) = a × b 2 The trend graph of tumor volume for each group is shown in Figure 16, and the trend of changes in mouse weight is shown in Figure 17. 177 Lu-NYM032 inhibited tumor growth more rapidly than saline, and there was no significant change in the body weight of the mice. 177 Lu-NYM032 has good antitumor effects and a good safety profile.

[0091] Example 15 177 Clinical SPECT / CT images of Lu-NYM032 molecular science study ng Brief information about the patient: Patient 5, male, 72 years old, 56 kg. He underwent B-ultrasound-guided prostate aspiration, and postoperative pathology suggested prostate cancer. He was then treated with androgen suppression therapy and chemotherapy. He will be participating in a clinical research trial of PSMA tracer. 68 Whole-body PET / CT imaging was performed 1 hour after injection of 3.75 mCi of Ga-NYM032. As shown in Figure 18, patient 5 had multiple metastatic bone lesions throughout his body, consistent with prostate cancer with multiple bone metastases throughout his body. 6824 hours after injection of Ga-NYM032 drug, the patients 177 Lu-NYM032 18.54mCi was injected, and whole-body SPECT / CT images were taken at 0.5h, 1h, 24h, 48h, 120h, 192h, 336h, and 504h. At the same time, venous blood samples were taken from the patients before administration and 1 hour, 4 hours, 24 hours, 48 ​​hours, and 120 hours after administration, and gamma counts were measured to calculate the blood concentrations at different time points. The imaging results are shown in Figures 19 and 20. 177 At 192 hours after injection of Lu-NYM032, high radioactivity uptake was still observed in the tumor and lesion area, with no decrease in SUVmax compared to 48 hours and a clear boundary. At 336 hours and 504 hours, uptake was still observed in the lesion. As shown in Figures 19 and 21, the uptake in the heart and great vessels 177 Lu-NYM032 is almost completely eliminated within 24 hours, and is the most widely available PSMA treatment. 177 Compared to Lu-PSMA-617, 177 Lu-NYM032 has a shorter half-life in the circulation and, at the same time, 177 Lu-NYM032 had a longer tumor residence time, higher tumor uptake, and higher tumor cumulative dose, allowing for a lower single dose and / or less frequent administration, resulting in reduced toxicity to healthy organs and tissues.

[0092] Based on scan data 177 The tissue distribution data of Lu-NYM032 at different time points can be obtained, and the irradiation dose of all lesions in the body at different time points can be calculated based on the PMOD software. The relationship between radioactivity and time in the lesions is shown in Figure 22.

[0093] Example 16 SPR affinity detection of NYM032 Affinity detection using SPR: PSMA protein (ACROBiosystems, concentration 0.325 mg / mL) was immobilized on a CM5 chip in acetate buffer (pH 5.0, Cytiva), and affinity detection was performed using a Biacore 8K protein interaction system. The running buffer was Tris-P+ (50 mM Tris, 150 mM NaCl, and 0.05% (v / v) P20 (Tween 20)). DMSO solutions of NYM032 molecules at different concentrations were used as the mobile phase, and the binding ability of NYM032 molecules with PSMA protein was detected. The magnitude of binding between NYM032 molecules and PSMA protein was measured using the equilibrium dissociation constant K D (K d / K a ) value, and K d is the dissociation constant, and K a is the coupling constant, K D The smaller the value, the higher the affinity between the compound and the protein. From the experimental results, the equilibrium dissociation constant K D The value was 0.318 ± 0.046 nM, and the equilibrium dissociation constant K D The values ​​were found to be below the nM level, indicating that the NYM032 molecule and PSMA protein have a strong affinity.

[0094] In the description herein, the terms "one embodiment," "some embodiments," "examples," and "specific examples" are used. A statement referring to a term such as "an example" or "some examples" means that a particular feature, structure, material, or characteristic described with reference to that example or example is included in at least one example or embodiment of the present invention. In this specification, general references to the above terms do not necessarily refer to the same example or embodiment. In addition, a particular feature, structure, material, or characteristic described may be incorporated in any suitable manner in any one or more examples or embodiments. Furthermore, those skilled in the art can combine and combine the various examples or embodiments described herein and the features of the various examples or embodiments without mutual inconsistency.

[0095] Although embodiments of the present invention have been presented and described, the above embodiments are illustrative and should not be construed as limiting the present invention, and those skilled in the art will appreciate that various changes, modifications, substitutions and variations can be made to the above embodiments within the scope of the present invention.

[0096] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and benefits from patent application number 202310126134.7, filed with the State Intellectual Property Office of China on February 16, 2023, the entire contents of which are incorporated herein by reference.

Claims

1. A compound or a pharmaceutically acceptable salt, ester, or solvate thereof, whose structure is shown in formula (I): 【Chemistry 1】 wherein L is selected from a polyethylene glycol chain, a hydrophilic amino acid chain, or a carbon chain; X is selected from 6-12 aryl groups or 5-12 heteroaryl groups, and the 6-12 aryl groups or 5-12 heteroaryl groups are selected from 1, 2 or 3 OH, halogen or C １－６ optionally substituted with an alkyl group; A compound or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein R and Y are each independently selected from H, an optionally substituted amino acid, or a chelating agent, and at least one of R and Y is a chelating agent.

2. or a pharmaceutically acceptable salt, ester, or solvate thereof, whose structure is shown in formula (II): 【Chemistry 2】 wherein X is selected from 6-12 aryl groups or 5-12 heteroaryl groups, and the 6-12 aryl groups or 5-12 heteroaryl groups contain 1, 2 or 3 OH, halogen or C １－６ optionally substituted with an alkyl group; Z is 【Transformation 3】 -COOH, -OH,C １－６ alkyl groups and aryl groups of 6 to 12 carbon atoms, １－６ The alkyl group or 6-12 aryl group may contain 1, 2 or 3 OH, halogen or C １－６ optionally substituted with an alkyl group; A compound or a pharmaceutically acceptable salt, ester or solvate thereof, wherein R' and Y' are each independently selected from H, an optionally substituted amino acid or a chelating agent, and at least one of R' and Y' is a chelating agent.

3. X is 【Chemistry 4】 Selected from Optionally, Z is 【Transformation 5】 -COOH、-OH、-CH(CH ３ )OH、 【Transformation 6】 Selected from Optionally, the chelating agent is 1,4,7,10-tetrazacyclododecane-N,N',N',N'',-tetraacetic acid, 1,4,7-triazacyclononane-1,4,7-triaacetic acid, 2-(4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)glutaric acid, 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetrazacyclododecan-1-yl)glutaric acid, 1,4,7-triazacyclononane phosphonic acid, 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphonic acid]-4,7-bis[methyl(2-carboxymethyl)phosphonic acid], N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[5-aminopentyl)(hydroxy)amino]-4-oxobutyryl}amino)pentyl]-N-hydroxysuccinamide, diethylenetriaminepentaacetic acid, trans-cyclohexyl- The compound according to claim 2, or a pharmaceutically acceptable salt, ester, or solvate thereof, characterized in that it is selected from diethylenetriaminepentaacetic acid, p-isothiocyanatobenzyl-diethylenetriaminepentaacetic acid, 1-(isothiocyanatobenzyl)-3-methyl-diethylenetriaminepentaacetic acid, 1-(isothiocyanatobenzyl)-4-methyl-diethylenetriaminepentaacetic acid, 1-(2)-methyl-4-isocyanatobenzyl-diethylenetriaminepentaacetic acid, 1-oxa-4,7,10-triazacyclododecane-4,7,10-triaacetic acid, 6-hydrazinonicotinic acid succinimidyl ester hydrochloride, mercaptoacetyltriglycine, and (R)-2-amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid.

4. A complex, wherein the complex is formed by coordinating a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt, ester or solvate thereof with a radionuclide or a non-radioactive element A', and the structure of the complex is shown in formula (III): 【Transformation 7】 wherein Y' is a chelating agent and R' is H, an optionally substituted amino acid, or a chelating agent.

5. A complex, the complex being formed by coordinating a compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt, ester or solvate thereof with a radionuclide or a non-radioactive element A', the structure of which is shown in formula (IV): 【Transformation 8】 wherein R' is a chelating agent and Y' is H, an optionally substituted amino acid, or a chelating agent.

6. A compound comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt, ester or solvate thereof, wherein the structure of the compound is: 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 A compound characterized by being any one selected from the following:

7. A complex, characterized in that the complex is formed by coordinate bonding of a compound according to any one of claims 1 to 3, or 6, or a pharmaceutically acceptable salt, ester, or solvate thereof, or a complex according to claim 4 or 5, with a radionuclide or a non-radioactive element B'.

8. wherein said radionuclide A' or B' is each independently ６８ Ga, １８ F. ９９ｍ Tc, ８９ Zr, １１１ In, ４５ Ti, ５９ Fe, ６４ Cu, ９４ｍ Tc, ６７ Ga, ７１／７２／７４ As, ４３／４４ Sc, ８２ｍ Rb, ５２ Mn, ８６ Y. ７６ Br, １７７ Lu, ９０ Y. １５３ Sm, ６７ Cu, ８９ Sr, １３７ Cs, １６６ Ho, １７７ Yb, １０５ Rh, １８６／１８８ Re, ４７ Sc, ２１２／２１３ Bi, ２２５ Ac, ２１２ Pb, １４９ Pm and ２２７ Th, Optionally, the non-radioactive elements A' or B' are each independently selected from at least one of Ga, Fe, and Gd; Optionally, the radionuclide is １８ F. ６８ Ga, １７７ Selected from Lu, Optionally, said radionuclide １８ 8. The complex according to claim 4, 5 or 7, characterized in that the coordinate bond of F is formed from the radioactive isotope aluminum fluoride.

9. A complex, the structure of which is 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 A complex characterized in that it is any one selected from the following:

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3 and 6, or a complex according to any one of claims 4 to 5 and 7 to 9, or a pharmaceutically acceptable salt, ester or solvate thereof, a pharmaceutically acceptable carrier, and an auxiliary material.

11. Use of a compound according to any one of claims 1 to 3, 6, or a complex according to any one of claims 4 to 5, 7 to 9, or a pharmaceutically acceptable salt, ester or solvate thereof, or a pharmaceutical composition according to claim 10, in the preparation of one or more reagents and / or drugs for diagnosing and / or treating tumors, cancers or cells that express PSMA.

12. Use of a compound according to any one of claims 1 to 3, 6, or a complex according to any one of claims 4 to 5, 7 to 9, or a pharmaceutically acceptable salt, ester or solvate thereof, or a pharmaceutical composition according to claim 10, in the diagnosis and / or treatment of tumors, cancers or cells expressing PSMA.

13. the diagnostic means is selected from optical imaging and / or nuclide imaging; Optionally, said diagnostic means is selected from PET imaging and / or SPECT imaging; Optionally, said treatment is selected from radiation therapy; Optionally, the cancer is selected from prostate cancer and / or other solid tumors.

13. Use according to claim 11 or 12, characterized in that

14. A method for diagnosing and / or treating tumors, cancers or cells that express PSMA, comprising the step of administering to a patient a pharmaceutically acceptable amount of a compound according to any one of claims 1-3, 6, or a complex according to any one of claims 4-5, 7-9, or a pharmaceutically acceptable salt, ester or solvate thereof, or a pharmaceutical composition according to claim 10.

15. the diagnostic means is selected from optical imaging and / or nuclide imaging; Optionally, said diagnostic means is selected from PET imaging and / or SPECT imaging; 15. The method of claim 14, wherein optionally, the treatment is selected from radiation therapy and optionally, the cancer is selected from prostate cancer and / or other solid tumors.

16. A reagent kit, comprising the compound according to any one of claims 1 to 3 and 6, or the complex according to any one of claims 4 to 5 and 7 to 9, or a pharmaceutically acceptable salt, ester or solvate thereof, and a pharmaceutically acceptable carrier and auxiliary material; Optionally, The reagent kit further comprises a pharmaceutical adjuvant; The reagent kit is characterized in that the pharmaceutical adjuvants include sterile water for injection, acetic acid / sodium acetate buffer solution and sodium ascorbate.

Images