PSMA-targeting conjugate having phosphonate backbone

Abstract

A prostate-specific membrane antigen (PSMA)-targeting conjugate having a phosphonate backbone, which is used for tumor detection after chelation of a diagnostic nuclide and is used for radiation therapy after being combined with a treatment-type nuclide. A conjugate nuclide chelation part is replaced with a fluorescent probe or a cytotoxic drug so that the PSMA-targeting conjugate can then be used for diagnosis and treatment of diseases.

Description

PSMA-targeted conjugates with phosphonate backbone Technical Field

[0001] The present disclosure relates to the fields of medical treatment and diagnosis, and in particular to a PSMA-targeted compound, chelate, composition and use thereof with a phosphonate backbone. Background Art

[0002] Radiation therapy, surgery, and chemotherapy are traditionally the three main first-line treatments for cancer. Radiopharmaceuticals (hereinafter referred to as radiopharmaceuticals) can be considered a form of internal irradiation radiotherapy. Compared to traditional radiotherapy, they have the advantage of a powerful "crossfire" and are one of the few treatment options for patients with advanced cancer metastasis. Mechanistically, radiopharmaceuticals use high-energy ionizing radiation generated by the decay of medical isotopes to disrupt DNA chains and induce cancer cell death. This requires extremely high tumor selectivity / targeting, as well as certain tumor uptake and retention, to deliver a sufficient dose of radiation only to the tumor while limiting damage to surrounding normal tissues.

[0003] Radionuclide drug conjugates (RDCs) are a major form of radiopharmaceuticals and are generally binary conjugates of chelators, linkers, and targeting ligands. The ligands can be small molecules, peptides, antibodies, etc.; the same molecule can chelate different diagnostic / therapeutic radionuclides as needed, offering the advantage of "integrated diagnosis and treatment." Therefore, some molecules with average targeting and safety but high tumor uptake still have the potential to be used in molecular imaging diagnosis.

[0004] Prostate-specific membrane antigen (PSMA) is a type II transmembrane protein composed of 750 amino acids, comprising intracellular, transmembrane, and extracellular domains. Its expression is extremely low in normal prostate and non-prostate tissues, but its expression in prostate epithelial cells of prostate cancer patients is 100-1000 times higher than in normal subjects. Its expression is particularly high in poorly differentiated, metastatic, and castration-resistant prostate cancer (PCa) tissues. It is a specific molecular marker for prostate cancer and is considered an ideal target for its diagnosis and treatment. In recent years, PSMA-based diagnostic and therapeutic approaches for prostate cancer (RCC) have received FDA and EU approval, encouraging more RDC drugs to enter clinical research.

[0005] The main problem with currently marketed PSMA-targeted radioconjugates is their low absolute values ​​of tumor uptake and retention, resulting in insufficient area under the tumor uptake-time curve (AUC), leading to ineffective tumor treatment, high recurrence rates, and high radionuclide costs. While conjugated albumin binders can improve tumor uptake and retention, they sacrifice the inherent safety advantage of small-molecule radionuclides, namely low non-target organ uptake, and carry a high risk of bone marrow suppression and nephrotoxicity. Addressing the issues of insufficient tumor uptake and retention of PSMA inhibitor small molecules while retaining their excellent targeting properties, and improving the therapeutic window and efficacy while ensuring molecular tumor targeting and safety, remains a key challenge hindering the development of superior PSMA small-molecule radionuclides. Summary of the Invention

[0006] By transforming traditional PSMA nuclear drugs into nuclear drugs containing specific phosphonate structure linkers, this invention aims to solve the technical problem of how to maintain a certain degree of targeting (ensuring drug safety) while significantly improving the uptake and retention of nuclear drugs in tumor tissues (improving drug efficacy). The PSMA-targeted conjugates provided by this invention have higher tumor detection sensitivity after chelating diagnostic radionuclides and meet drug efficacy requirements after combining with therapeutic radionuclides. The radionuclide chelating portion of the conjugate can also be replaced with fluorescent probes or cytotoxic drugs, thereby being used for disease diagnosis and treatment.

[0007] SUMMARY OF THE INVENTION

[0008] In one aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. The compound of formula (I) is a PSMA-targeting compound having a phosphonate backbone, which is used for tumor detection after chelating a diagnostic nuclide, for radiotherapy after binding a therapeutic nuclide, and for disease diagnosis and treatment after replacing the nuclide chelating portion of the conjugate with a fluorescent probe or cytotoxic drug.

[0009] In another aspect, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof. The compound of formula (II) is used as an intermediate in the preparation of the compound of formula (I).

[0010] In another aspect, the present invention provides a chelate or radionuclide label comprising

[0011] (i) a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof; and

[0012] (ii) Radionuclides.

[0013] In another aspect, the present invention provides a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or the aforementioned chelate or radionuclide label, and a pharmaceutically acceptable carrier.

[0014] On the other hand, the present invention provides a compound of formula (I) or its pharmaceutically acceptable salt, stereoisomer or solvate, or the aforementioned chelate or radionuclide label, or the use of the aforementioned composition in the diagnosis or treatment of a disease. On the other hand, the present invention provides a compound of formula (I) or its pharmaceutically acceptable salt, stereoisomer or solvate, or the aforementioned chelate or radionuclide label, or the use of the aforementioned composition in the preparation of a medicament for the treatment of a disease, or in the preparation of a disease diagnostic reagent. The disease is a prostate disease, preferably benign prostatic hyperplasia or prostate cancer.

[0015] Detailed Description of the Invention

[0016] In one aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof,

[0017] in

[0018] X is selected from O, S or NH, preferably O;

[0019] Y is a C1-C4 alkylene group;

[0020] L1 is selected from a bond, a linker or is absent;

[0021] L2 is selected from a bond or a linker;

[0022] L3 is a linker;

[0023] Z is selected from O, S or NH, preferably O;

[0024] R1 is selected from hydrogen, C1-C6 alkyl, C1-C6 unsaturated hydrocarbon, hydroxyl, thiol, halogen, nitro, -CN or absent;

[0025] Ring A is selected from optionally substituted C5-C 10 Arylene or C5-C 10 heteroarylene;

[0026] One or two of R2, R3, and R5 are PSMA-targeting ligands, any one of R2, R3, and R5 is a payload, and the remaining R2, R3, and R5 are optional capping groups or are absent;

[0027] The effective load is selected from a drug molecule group, a chelator group, a labeling molecule group or an optical dye.

[0028] In some embodiments, the PSMA-targeting ligand R5 is selected from:

[0029] In some embodiments, L1, L2 or L3 are independently selected from a bond or -L a -(L b ) m -L c -(L d ) n -L e -L f -, where L a , L b , L c , L d , L e , L f Each occurrence is independently selected from a bond, -O-, -S-, -SS-, -S(=O)2-, -NH-, -N(CH3)-, -C(R a )(R b )-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NH-, -NHC(=O)-, -C(=O)-N(CH3)-, -N(CH3)-C(=O)-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2NH-, -NHCH2-, -CH2O-, -OCH2-, -CH=NO-, -C(CH3)=N-NH-, -C(CH3)=N-NH-C(=O)-, -NH-CH2-C(=CH-COOH)-, a peptide group containing 1 to 4 amino acids, a cyclohexylene group, a phenylene group, a heterocyclic group (e.g., piperazine-1,4-diyl) or where R a and R b Each occurrence is independently selected from H, methyl, ethyl, propyl, isopropyl, phenyl, -OH, -SH, -NH2, -NH(CH3) or -NH(CH3)2; or L1 is absent; wherein the subscripts m and n are independently selected from integers of 0, 1, 2, 3 or 4. In some embodiments, NH2 in L1, L2 or L3 is optionally further substituted with a chelating agent group selected from the chelating agent groups in the following embodiments or definitions.

[0030] In some embodiments, L1, L2 or L3 are independently selected from -NH-, -CH2-, -N(CH3)-, -C(=O)-, -C(=O)-PEP-, -NH-PEP-, or

[0031] Wherein the subscripts m and n are integers of 1-4; PEP represents a peptide group comprising 1 to 4 amino acids; M is a coordinating metal, preferably a radioactive or non-radioactive coordinating metal, more preferably a radioactive or non-radioactive lutetium, gallium, yttrium, or the like; "#" indicates the end closest to the phosphorus atom. Alternatively, L1 is absent. In some embodiments, the radioactive coordinating metal is selected from a radionuclide.

[0032] In some embodiments, L1 is selected from absent, or The subscripts m and n are integers from 1 to 4, respectively.

[0033] In some embodiments, L2 is selected from The subscripts m and n are integers from 1 to 4, respectively.

[0034] In some embodiments, L2 is selected from or Wherein M is a coordination metal, which is preferably a radioactive or non-radioactive coordination metal, more preferably radioactive or non-radioactive lutetium, gallium, yttrium, etc., and "#" represents the end close to the phosphorus atom.

[0035] In some embodiments, L3 is selected from -NH-, -CH2-, -N(CH3)-, -C(=O)-, C(=O)-PEP-, -NH-PEP-, or

[0036] Wherein the subscript n is an integer from 1 to 4, and PEP represents a peptide group containing 1 to 4 amino acids.

[0037] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein

[0038] X is O;

[0039] Y is a C1-C4 alkylene group;

[0040] L1 does not exist;

[0041] Z is O;

[0042] R1 is a C1-C4 alkyl group;

[0043] Ring A is an optionally substituted C5-C 10 Arylene or C5-C 10 Heteroarylene, preferably phenylene;

[0044] R2 does not exist or is a blocking group;

[0045] One of R3 and R5 is a PSMA-targeting ligand; the other is a payload; preferably, R3 is a payload and R5 is a PSMA-targeting ligand.

[0046] In some embodiments, Ring A is selected from optionally substituted 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene, 1,5-naphthylene, 1,6-naphthylene, 2,6-naphthylene, furanylene, thienylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene.

[0047] In some embodiments, "optionally substituted" in Ring A includes unsubstituted, or substituted with C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 The alkyl group is substituted with one or more substituents selected from alkoxy, hydroxy, amino, mercapto, halogen, nitro and -CN.

[0048] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof is selected from

[0049] In some embodiments, the labeling molecule group comprises 18 F. 123 I. 124 I. 125 I. 131 I and 211 At radiolabeled synthetic group.

[0050] In some embodiments, the synthetic group in the labeling molecule group is selected from:

[0051] Where X is 18 F. 123 I. 124 I. 125 I. 131 I and 211At, each R or R' is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and n is an integer between 0 and 12.

[0052] In some embodiments, the chelator group chelates an Al2O3 for diagnostic purposes. 18 F, 68 Ga, 64 Cu, 89 Zr, 86 Y, 99m Tc, 111 In or 44 Sc; or radionuclide therapy 67 Ga, 67 Cu, 89 Zr, 90 Y, 153 Sm, 161 Tb, 186 / 188 Re, 177 Lu, 212 Pb, 212 / 213 Bi, 225 Ac, 227Th or 47 Sc.

[0053] In some embodiments, the chelator group is selected from:

[0054]

[0055] or where R B is H, methyl or phenyl.

[0056] In some embodiments, the optical dye is selected from:

[0057] In some embodiments, the drug molecule group is selected from cytotoxic drugs, immunomodulators, antibiotics, protein degraders or molecular glues; preferably

[0058] In some embodiments, the capping group is selected from -L g -(L h ) n -L i -R e , where L g , L h, L i Each occurrence is independently selected from a bond, -O-, -S-, -C(R c )(R d )-, -NH-, -N(CH3)-, -C(=O)-, -CH2O- or -OCH2-, subscript n is an integer from 0 to 4, R c and R d Each occurrence is independently selected from H, methyl, ethyl, propyl, isopropyl, phenyl, -OH, -SH, -NH2, -NH(CH3) or -NH(CH3)2, R e Selected from methyl, ethyl, hydroxyl or mercapto.

[0059] In some embodiments, the compound of formula (I) is selected from:

[0060] or

[0061] In another aspect, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof,

[0062] in

[0063] X, Y, and Z have the same definitions as those described above for any compound of formula (I);

[0064] L1, L2, L3 have the definitions as in any of the preceding claims or do not exist;

[0065] G1, G2, and G3 are each independently selected from a hydroxyl protecting group, a carboxyl protecting group, an amino protecting group, an amide protecting group, an imine protecting group, a cyclic imide protecting group, a thiol protecting group, or a phosphorus hydroxyl protecting group.

[0066] In some embodiments, the hydroxy protecting group is selected from benzyl, 2,6-dichlorobenzyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, benzoyl, mesyl, tosylate, dimethoxytrityl (DMT), 9-phenylxanthin-9-yl (Pixyl), or 9-(p-methoxyphenyl)xanthin-9-yl (MOX);

[0067] The carboxyl protecting group is selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl-C 1-2alkyl, 2-adamantyl, 4-nitrobenzyl, 4-methoxybenzyl, 4-chlorobenzyl, phenacyl, benzyloxycarbonylhydrazide, tert-butyloxycarbonylhydrazide, and tritylhydrazide;

[0068] the amino protecting group is selected from 2-trimethylsilylethoxycarbonyl (Teoc), 1-methyl-1-(4-biphenylyl)ethoxycarbonyl (Bpoc), tert-butoxycarbonyl (BOC), allyloxycarbonyl (Alloc), 9-fluorenylmethoxycarbonyl (Fmoc) and benzyloxycarbonyl (Cbz);

[0069] the amide protecting group is selected from the group consisting of formyl, acetyl, trihaloacetyl, benzoyl, and nitrophenylacetyl;

[0070] Sulfonamide protecting groups are selected from 2-nitrobenzenesulfonyl; and imide and cyclic imide protecting groups such as phthalimido and dithiasuccinoyl;

[0071] The phosphorus hydroxy protecting group is selected from methyl, ethyl, benzyl (Bn), phenyl, isopropyl, tert-butyl, 4-methoxybenzyl, 4-chlorobenzyl, 2-chlorophenyl and 2-cyanoethyl.

[0072] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof is selected from

[0073] In another aspect, the present invention provides use of any one of the aforementioned compounds of formula (II) as an intermediate in the preparation of a compound of formula (I).

[0074] In another aspect, the present invention provides a chelate or radionuclide label comprising

[0075] (i) a compound of formula (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof; and

[0076] (ii) Radionuclides.

[0077] In some embodiments, the radionuclide is selected from: 18 F. 51 Cr, 67 Ga, 68 Ga, 111 In, 99m Tc, 186 Re、 188 Re、 139 La, 140 La, 175 Yb, 153 Sm, 166 Ho,86 Y. 88 Y. 90 Y. 149 Pm, 165 Dy, 169 Second, 177 Lu, 47 Sc, 142 Pr, 159 Gd, 212 Bi, 213 Bi, 72 As、 72 Se, 97 Such as 109 Pd, 105 Rh, 101m Rh, 119 Sb, 128 Ba, 123 I. 124 I. 131 I. 1197 Hg, 211 At 151 Eu, 153 Eu, 169 Eu, 201 Tl, 203 Pb, 212 Pb, 64 Cu, 67 Cu, 188 Re、 186 Re、 198 Au, 225 Ac, 227 Th and 199 Ag.

[0078] In another aspect, the present invention provides a composition comprising the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or the chelate or radionuclide label, and a pharmaceutically acceptable carrier.

[0079] In another aspect, the present invention provides a use of the aforementioned compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, the aforementioned chelate or radionuclide label, or the aforementioned composition in the diagnosis or treatment of a disease.

[0080] On the other hand, the present invention provides the use of the aforementioned compound of formula (I) or its pharmaceutically acceptable salt, stereoisomer or solvate, the aforementioned chelate or radionuclide label, or the aforementioned composition in the preparation of a drug for treating a disease, or in the preparation of a disease diagnostic reagent.

[0081] In some embodiments, the disease is a prostate disease, preferably prostate hyperplasia or prostate cancer.

[0082] definition

[0083] All publications and patents mentioned in this disclosure are hereby incorporated into the present disclosure in their entirety by reference. If the purposes or terms used in any publications and patents incorporated by reference conflict with the purposes or terms used in this disclosure, then the purposes and terms of this disclosure shall prevail.

[0084] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0085] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those commonly used in the art to which the claimed subject matter belongs. If there are multiple definitions for a term, the definition herein shall prevail.

[0086] Unless otherwise indicated, when any type of range is disclosed or claimed, it is intended to disclose or claim individually every possible value that the range may reasonably encompass, including any subranges encompassed therein. For example, the number of substituents is 1 to 5, indicating integers within the range, where 1-5 is understood to include 1, 2, 3, 4, 5, and also includes subranges of 1-4 and 1-3.

[0087] The description of the present disclosure should be interpreted in accordance with the laws and principles of chemical bonding.In some cases, it may be possible to remove a hydrogen atom in order to accommodate a substituent at a given position.

[0088] As used in this disclosure, words such as "include," "comprising," or "including" mean that the elements preceding the word include the elements listed after the word and their equivalents, without excluding unlisted elements. The terms "comprising" or "including" as used herein may be open, semi-closed, or closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0089] The term "pharmaceutically acceptable" as used herein means that the compound or composition is chemically and / or toxicologically compatible with the other ingredients constituting the formulation and / or with humans or mammals for the prevention or treatment of a disease or condition.

[0090] The term "subject" or "patient" as used in this application includes humans and mammals.

[0091] In the context of this application, the term "treatment" may also include prophylaxis, unless specifically stated to the contrary.

[0092] The term "solvate" as used herein refers to a complex formed by combining a compound of formula (I) or a pharmaceutically acceptable salt thereof and a solvent. It should be understood that any solvate of a compound of formula (I) used in the diagnosis or treatment of a disease or condition described herein, although potentially providing different properties (including pharmacokinetic properties), will yield the compound of formula (I) once absorbed into a subject, such that use of a compound of formula (I) encompasses the use of any solvate of the compound of formula (I).

[0093] The term "hydrate" refers to the above-mentioned term "solvate" in which the solvent is water.

[0094] It should be further understood that the compound of formula (I) or its pharmaceutically acceptable salt can be isolated in the form of a solvate, and therefore any such solvate is included within the scope of the present invention. For example, the compound of formula (I) or its pharmaceutically acceptable salt can exist in an unsolvated form as well as in a solvated form with a pharmaceutically acceptable solvent (such as water, ethanol, etc.).

[0095] The term "pharmaceutically acceptable salts" refers to relatively non-toxic addition salts of the compounds of the present disclosure. See, for example, SM Berge et al. "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19.

[0096] Suitable pharmaceutically acceptable salts of the disclosed compounds may be acid addition salts of compounds of the disclosed compounds having a nitrogen atom in a chain or ring and having sufficient basicity, such as acid addition salts formed with inorganic or organic acids.

[0097] Alternatively, another suitable pharmaceutically acceptable salt of a sufficiently acidic compound of the present invention is an alkali metal salt, an alkaline earth metal salt, or a salt with an organic base which provides a physiologically acceptable cation.

[0098] Those skilled in the art will also recognize that acid addition salts of the claimed compounds can be prepared by reacting the compounds with a suitable inorganic or organic acid by any of a variety of known methods. Alternatively, alkali metal and alkaline earth metal salts of the acidic compounds of the present disclosure can be prepared by reacting them with a suitable base by various known methods.

[0099] The present invention includes all possible salts of the disclosed compounds, either as a single salt or as any mixture of such salts in any ratio.

[0100] It should be understood that the term "compounds of the present disclosure" used in this application may include, depending on the context, the compound represented by formula (I), its pharmaceutically acceptable salts, its solvates, its pharmaceutically acceptable salt solvates, and mixtures thereof.

[0101] The compounds of the present disclosure may contain one or more asymmetric centers, depending on the position and properties of the various substituents desired. Asymmetric carbon atoms can exist in the (R) or (S) configuration, resulting in racemic mixtures in the case of one asymmetric center and diastereomeric mixtures in the case of multiple asymmetric centers. In some cases, asymmetry may also exist due to hindered rotation about a particular bond, such as where the central bond connects two substituted aromatic rings of a particular compound.

[0102] Preferred compounds are those that produce more desirable biological activity. Isolation, purification or partial purification of isomers and stereoisomers, or racemic mixtures or diastereomeric mixtures of the disclosed compounds are included within the scope of the present invention. Purification and separation of such substances can be achieved by standard techniques known in the art.

[0103] The term "optionally" is used herein to describe a situation that may or may not occur. For example, the term "optionally substituted" refers to a situation that is unsubstituted or has at least one non-hydrogen substituent that does not destroy the intended property possessed by the unsubstituted analog. For example, with respect to a pharmaceutical composition, the phrase "optionally, and a pharmaceutically acceptable excipient" as used herein means that a pharmaceutically acceptable excipient may or may not be present in the pharmaceutical composition.

[0104] In the present disclosure, unless otherwise specified, the number of "substituted" may be one or more; when it is multiple, it may be 2, 3 or 4. Moreover, when the number of "substituted" is multiple, the "substituted" may be the same or different.

[0105] In the present disclosure, the position of “substitution” can be any position unless otherwise specified.

[0106] In this disclosure, Indicates the connection position. “#” indicates the end closest to the phosphorus atom.

[0107] The term "alkyl" as used herein refers to a straight or branched alkane chain containing 1 to 10 carbon atoms. 10 Representative examples of alkyl include, but are not limited to, methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), and isobutyl (C4). 10Representative examples of alkyl groups include, but are not limited to, n-pentyl (C5), 3-pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). The term "lower alkyl" refers to a straight or branched chain alkyl group having 1 to 4 carbon atoms. "Substituted alkyl" refers to an alkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. The term "haloalkyl" refers to an alkyl group having one or more halogen substituents, including, but not limited to, groups such as -CH2Br, -CH2I, -CH2Cl, -CH2F, -CHF2, and -CF3.

[0108] The term "optionally substituted alkyl" as used herein means that the alkyl group may be unsubstituted or substituted. Substituted alkyl groups include, but are not limited to, groups selected from C 1-4 Alkyl, C 1-4 C substituted with one or more substituents selected from alkoxy, hydroxy, amino, mercapto, halogen, nitro and -CN 1-5 alkyl.

[0109] As used herein, the term "alkylene" refers to a divalent hydrocarbon group as described above for "alkyl," but with two points of attachment. For example, a methylene group is a -CH2- group and an ethylene group is a -CH2-CH2- group.

[0110] As used herein, the terms "alkoxy" and "alkylthio" refer to an alkyl group as described above attached via an oxygen bond (-O-) or a sulfur bond (-S-), respectively. The terms "substituted alkoxy" and "substituted alkylthio" refer to substituted alkyl groups attached via an oxygen bond or a sulfur bond, respectively. "Lower alkoxy" is a group OR where R is a lower alkyl group (an alkyl group containing 1 to 4 carbon atoms).

[0111] As used herein, the term "halogen" refers to fluorine, chlorine, iodine, or bromine.

[0112] The term "cycloalkyl" as used herein refers to a saturated cycloalkyl group derived by removing one hydrogen atom from a single carbon atom of a parent cycloalkane. 3-10 Cycloalkyl groups include, but are not limited to, groups such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, and the like. Cycloalkyl groups can be described by the number of carbon atoms in the ring. For example, a cycloalkyl group having 5-7 ring atoms can be referred to as a (C5-C7)cycloalkyl group. In certain embodiments, a cycloalkyl group can be a (C5-C7)cycloalkyl group. 10 )cycloalkyl, (C5-C8)cycloalkyl, (C5-C7)cycloalkyl, (C5-C6)cycloalkyl, and these may be referred to using alternative language as C5-C 10 Cycloalkyl, C5-C8 cycloalkyl, C5-C7 cycloalkyl, C5-C6 cycloalkyl or C5-C7 cycloalkyl.

[0113] The term "cycloalkylene" as used herein refers to a general term for a divalent group remaining after removing two hydrogen atoms from any position of a cycloalkyl carbon ring. Typical cycloalkylene groups include, but are not limited to, cyclopentylene, cyclohexylene, cycloheptylene, cyclooctylene, and the like.

[0114] As used herein, the term "heterocycloalkyl" and interchangeably "heterocyclyl" refers to a saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one, preferably 1 to 3, heteroatoms as ring members, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur, wherein each ring is preferably a 5- to 8-membered ring, preferably a 5- to 6-membered ring. Typical heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, dioxanyl, piperazinyl, pyrazinyl, morpholinyl, dioxanyl, and the like.

[0115] As used herein, the term "heterocycloalkylene" refers to a general term for a divalent group remaining after removing two hydrogen atoms from any position on the heterocycloalkyl ring. Typical heterocycloalkylene groups include, but are not limited to, tetrahydrofuranylene, tetrahydropyrrolylene, tetrahydrothiophenylene, tetrahydropyranylene, piperidinylene, tetrahydrothiopyranylene, dioxanylene, piperazinylene, 1,4-piperazinylene, pyrazinylene, morpholinylene, and dioxanylene.

[0116] The term "arylene" as used herein refers to a general term for a divalent group remaining after removing two hydrogen atoms from the carbon at any position of the aromatic nucleus of an aromatic hydrocarbon molecule, such as phenylene, naphthylene, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene, 1,5-naphthylene or 1,6-naphthylene or 2,6-naphthylene, etc.

[0117] As used herein, the term "optionally substituted arylene" includes unsubstituted arylene, as well as substituted arylene, for example, substituted by C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Arylene substituted with one or more substituents selected from the group consisting of alkoxy, hydroxy, amino, mercapto, halogen, nitro and -CN.

[0118] As used herein, the term "heteroaryl" refers to an arbitrarily substituted aryl group containing about 5 to about 10 skeleton ring atoms, one to three of which are heteroatoms independently selected from, but not limited to, oxygen, nitrogen, and sulfur, provided that the ring of the group does not contain two adjacent O or S atoms. In embodiments where two or more heteroatoms are present in the ring, the two or more heteroatoms may be identical to each other, or some or all of the two or more heteroatoms may be different from each other. The term heteroaryl includes optionally substituted fused or non-fused heteroaryls having at least one heteroatom. In addition, the term heteroaryl also includes fused and non-fused heteroaryls containing 5 to about 10 skeleton ring atoms. Heteroaryl groups may be bound to the parent molecule via carbon atoms or heteroatoms. Thus, for example, imidazole may be attached to the parent molecule via any of its carbon atoms (imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl) or its nitrogen atom (imidazol-1-yl or imidazol-3-yl). Similarly, the heteroaryl group may be further substituted by any or all of its carbon atoms and / or any or all of its heteroatoms. A fused heteroaryl group may comprise a fused ring of 2-4 aromatic heterocycles, and the other independent rings may be alicyclic, heterocyclic, aromatic, aromatic heterocyclic, or any combination thereof. Non-limiting examples of monocyclic heteroaryls include pyridyl; fused ring heteroaryls include benzimidazolyl, quinolinyl, acridinyl, and non-fused biheteroaryls include bipyridinyl.Other examples of heteroaryl groups include, but are not limited to, furanyl, thienyl, oxazolyl, acridinyl, phenazinyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzothiophenyl, benzoxadiazolyl, benzotriazolyl, imidazolyl, indolyl, isoxazolyl, isoquinolinyl, indolizinyl, isothiazolyl,

[0014] Examples of the present invention include oxadiazolyl, thiazolyl, triazinyl, thiazolyl, pyridyl, pyridazyl, pyrimidyl, pyrazinyl, pyrrolyl, pyrazolyl, purinyl, phthalazinyl, pteridinyl, quinolinyl, quinazolinyl, quinoxalinyl, triazolyl, tetrazolyl, thiazolyl, triazinyl, and thiadiazolyl, and oxides thereof, such as pyridyl-N-oxide.

[0119] The term "heteroarylene" as used herein refers to a general term for a divalent group remaining after removing two hydrogen atoms from any carbon position of the heteroaromatic nucleus of a heteroaryl molecule, such as furanylene, thienylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene or pyridazinylene. The term "optionally substituted heteroarylene" as used herein includes unsubstituted heteroarylene and substituted heteroarylene, such as C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Heteroarylene substituted with one or more substituents selected from alkoxy, hydroxy, amino, mercapto, halogen, nitro and -CN.

[0120] In the compounds provided herein, any atom not specifically limited to a particular isotope represents any stable isotope of that atom. Isotopic substitution, such as deuterium substitution, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is replaced by deuterium. As a non-limiting general example, deuterium ( 2 H) and tritium ( 3 Isotopes of hydrogen, such as H), can be used anywhere in the structure to achieve the desired result. Alternatively, isotopes of carbon, such as 13 C and 14 C.

[0121] In certain embodiments, the isotope is at least about 90, 95, or 99% or more isotopically enriched at any of the positions involved. In one non-limiting embodiment, deuterium is at least about 90, 95, or 99% enriched at the desired position.

[0122] In some non-limiting embodiments, the substitution of a deuterium atom for a hydrogen atom occurs in a 1 、R 2 、R 3 、R 5 、R a 、R b 、R c Or any other substituent group defined herein. In other non-limiting embodiments, R 1 、R 2 、R 3 、R 5 、R a 、R b 、R c At least one of the groups is deuterium-enriched. For example, when any group is, or contains, a substituent such as a methyl, ethyl, or methoxy group, the alkyl residue may be deuterated (e.g., CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3, etc.). In certain other embodiments, when two substituents are combined to form a ring, the unsubstituted carbon may be deuterated.

[0123] It is to be understood that as used in this disclosure, singular forms such as "a," "an," and "the" may include plural referents unless otherwise specified.

[0124] As used herein, the term "drug molecule group" refers to a group derived from a drug molecule. For example, the drug molecule has one or more of cytotoxicity, immunomodulatory function, protein degradation function, and antimicrobial function. For example, the drug molecule is a cytotoxic drug, an immunomodulator, an antibiotic, a protein degrader, or a molecular glue. In one embodiment, the drug molecule is a DNA crosslinker, a microtubule inhibitor, a DNA alkylating agent, a topoisomerase inhibitor, or a combination thereof. For example, the drug molecule is selected from vinca alkaloids, laulimalide, taxane, colchicine, tubulysin, Cryptophycin, Hemiasterlin, Cemadotin, Rhizoxin, Discodermolide, taccalonolide A or B or AF or AJ, taccalonolide AI-epoxide, CA-4, epothilone A and B, paclitaxel, docetaxel, doxorubicin, camptothecin, iSGD-1882, centanamycin, PNU-159682, uncialamycin, indolebenzodiazepine Dimer, β-amanitin, amatoxin (Amatoxin), thailanstatin (thailanstatin) or its derivatives or analogs, or its combination.Immunomodulator, for example, can be selected from: cytokine, chemokine, stem cell growth factor, lymphotoxin, hematopoietic factor, colony stimulating factor (CSF), interferon, erythropoietin, thrombopoietin, tumor necrosis factor (TNF), interleukin (IL), granulocyte colony stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), stem cell growth factor called "S1 factor", activator of costimulatory molecules (for example, OX40 agonist), immune checkpoint molecules (for example, PD-1, PD-L1, LAG-3, TIM-3, CEACAM or CTLA-4, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and / or TGFRβ inhibitor.

[0125] The term "chelating agent group" used herein refers to a group derived from a chelating agent molecule. The chelating agent can be a chelating agent capable of chelating metal nuclides or labeling medical nuclides, such as HYNIC, DTPA, DOTA, NOTA and their derivatives.

[0126] The term "labeling molecule group" as used herein refers to a group derived from a labeling molecule. The labeling molecule may be, for example, a fluorescent dye, quantum dots, biotin, or a radionuclide (e.g. 18 F. 51Cr, 67 Ga, 68 Ga, 111 In, 99m Tc, 186 Re、 188 Re、 139 La, 140 La, 175 Yb, 153 Sm, 166 Ho, 86 Y. 88 Y. 90 Y. 149 Pm, 165 Dy, 169 Second, 177 Lu, 47 Sc, 142 Pr, 159 Gd, 212 Bi, 213 Bi, 72 As、 72 Se, 97 Such as 109 Pd, 105 Rh, 101m Rh, 119 Sb, 128 Ba, 123 I. 124 I. 131 I. 197 Hg, 211 At 151 Eu, 153 Eu, 169 Eu, 201 Tl, 203 Pb, 212 Pb, 64 Cu, 67 Cu, 188 Re、 186 Re、 198 Au, 225 Ac, 227 Th and 199 Ag).

[0127] The term "capping group" as used herein refers to a low molecular weight group that does not readily undergo chemical transformation under typical synthetic reaction conditions. Capping groups include methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, and the like. BRIEF DESCRIPTION OF THE DRAWINGS

[0128] In order to more clearly illustrate the technical solutions of the embodiments of the present disclosure, the drawings of the embodiments will be briefly introduced below. Obviously, the drawings in the following description only relate to some embodiments of the present disclosure, and are not intended to limit the present invention.

[0129] Figure 1 shows the [ 68 Radioactive HPLC spectrum of Ga]Ga-PSMA-P2

[0130] Figure 2 shows the [ 177 Radioactive HPLC spectrum of Lu]Lu-PSMA-P2

[0131] Figure 3 shows [ 68 Ga]Ga-PSMA-P2 and [ 68 Uptake of [Ga]Ga-PSMA-617 in LNCaP cells and 22Rv1 cells (P values ​​calculated by student t-test)

[0132] Figure 4 shows a.[ 68 Ga]Ga-PSMA-P2 and [ 68 PET / CT contrast imaging of 180 min after injection of Ga]Ga-PSMA-617 in 22Rv1 mouse model. The maximum tumor standard uptake value (SUV max ) were 2.2 and 2.4 respectively; b. Statistical histogram of tumor uptake (P value calculated by student t-test), the difference was statistically significant

[0133] Figure 5 shows [ 68 Ga]Ga-PSMA-P2 and [ 68 PET / CT contrast imaging of Ga]Ga-PSMA-11 at 60 and 180 minutes after injection in the LNCaP mouse model

[0134] Figure 6 shows [ 177 Lu]Lu-PSMA-P2 and [ 177 PET / CT contrast imaging at early and late time points after Lu]Lu-PSMA-617 injection in the 22Rv1 mouse model

[0135] Figure 7 shows the injection of 22Rv1 mice [ 177 Lu]Lu-PSMA-P2 and [ 177 Changes in tumor volume within 30 days after Lu]Lu-PSMA-617 and saline control group (P values ​​calculated by student t-test)

[0136] Figure 8 shows [ 177 Lu]Lu-PSMA-P2 and [177 The integrated area under the tumor uptake-time curve (AUC) and dosimetry of Lu]Lu-PSMA-617, and the tumor-to-nontumor ratio (T / N) were calculated.

[0137] Figure 9 shows 99m Radioactive HPLC spectrum of Tc-PSMA-TR-4

[0138] Figure 10 shows 99m Tc-PSMA-TR-4 and 99m SPECT / CT contrast imaging of Tc-PSMA-I&S in LNCaP model (A. 99m Tc-PSMA-TR-4 and 99m Maximum intensity projection images of Tc-PSMA-I&S at 3 and 24 hours after administration in the LNCaP model; B. Comparison of tumor uptake)

[0139] Figure 11 shows 99m Tc-PSMA-TR-4 and 99m SPECT / CT contrast imaging of Tc-HYNIC-PSMA in the same LNCaP model. A. 99m Tc-PSMA-TR-4 and 99m Maximum intensity projection images of Tc-HYNIC-PSMA at 3 and 24 hours after administration in the LNCaP model; B. Comparison of tumor uptake)

[0140] Figure 12 shows the same patient 99m Tc-PSMA-TR-4 and 18 Comparison of F-FDG imaging (A. 99m SPECT maximum intensity projection image of Tc-PSMA-TR-4; B. 18 F-FDG PET maximum intensity projection image), arrows indicate bone metastases, 99m Tc-PSMA-TR-4 is superior to 18 F-FDG

[0141] Figure 13 shows 99m SPECT / CT images of Tc-PSMA-TR-4 (A. Plain scan image; B. fusion SPECT / CT image; solid arrows indicate the tumor, and from top to bottom, sacral metastasis, lymph node metastasis, and primary lesion are shown. Dashed arrows indicate the bladder. The black dashed arrow points to the bladder, and the red solid arrows point to the sacral metastasis, lymph node metastasis, and primary lesion, respectively. DETAILED DESCRIPTION

[0142] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiment is a module embodiment of the present invention, rather than all embodiments. The elements and features described in one embodiment of the present invention may be combined with the elements and features shown in one or more other embodiments. It should be noted that for the purpose of clarity, the representation and description of components and processes that are not related to the present invention and are known to those of ordinary skill in the art are omitted in the description. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative work are within the scope of protection of the present invention.

[0143] The starting materials of the embodiments are commercially available and / or can be prepared by a variety of methods known to those skilled in the art of organic synthesis. Those skilled in the art of organic synthesis will appropriately select reaction conditions (including solvent, reaction atmosphere, reaction temperature, duration of experiment and aftertreatment) in the following synthetic methods. Those skilled in the art of organic synthesis will appreciate that the functional groups present in each part of the molecule should be compatible with the proposed reagents and reactions.

[0144] Instrument Information

[0145] (1) Compound preparation and identification: High performance liquid chromatography (Waters), high performance liquid chromatography radioactivity detector (Eckert & Ziegler Group), high-resolution mass spectrometer (Orbitrap Fusion Lumos or Bruker Solarix XR), nuclear magnetic resonance (NMR) spectrometer (Bruker 400 / 500 / 600 MHz).

[0146] (2) Cell experiments: fluorescence confocal microscopy (Nikon A1R-si);

[0147] (3) Animal experiments: Small animal PET / CT (Mediso PET122S).

[0148] Reagent Information

[0149] (1) Synthetic reagents: Some synthetic intermediates were commissioned to CRO companies for preparation, and other reagents were purchased from Sigma-Aldrich (USA), Bidrich (China), Anage (China) and other companies.

[0150] (2) Nuclides: 68 GaCl3 is obtained by eluting with 0.6M hydrochloric acid 68 Ge- 68 Ga generator (iThemba LABS, South Africa). 177LuCl3 was dissolved in 0.1 M hydrochloric acid and purchased from ITG (Germany).

[0151] (4) Cell models: The PSMA-highly expressing human prostate cancer cell line LNCaP and the PSMA-moderately expressing human prostate cancer cell line 22Rv1 were purchased from commercial sources.

[0152] (5) Mouse model: NOD SCID mice (SPF grade) or NU / NU mice (SPF grade) were purchased from commercial channels and injected subcutaneously with LNCaP cells or 22Rv1 cells to construct PSMA high or medium expression tumor models.

[0153] Example 1 Preparation of PSMA-P2

[0154] Compound 1 (3.60 g, 18.4 mmol, 2.95 mL, 1.00 equiv.) was dissolved in DMF (50.0 mL), and HBTU (10.4 g, 27.53 mmol, 1.5 equiv.) and NMM (2.23 g, 22.0 mmol, 2.42 mL, 1.20 equiv.) were added to prepare a suspension. Finally, compound 1a (4.10 g, 12.85 mmol, 0.70 equiv.) was added to the reaction mixture, and the mixture was stirred at 25°C for 12 h. Citric acid solution was added to the reaction mixture to adjust the pH to 5. The mixture was then extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with H2O (50.0 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (FA conditions) to give compound 2 (2.90 g, 6.25 mmol, yield 34.1%, purity 99.3%) as a white solid. 1 H NMR confirmation.

[0155] Compound 2 (2.00 g, 4.34 mmol, 1.00 equiv.) was dissolved in DCM (20.0 mL), and TMSBr (665 mg, 4.34 mmol, 561 μL, 1.00 equiv.) was added, and the mixture was stirred at 25° C. for 12 h. Methanol (50.0 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure to obtain a residue. The residue was subjected to preparative HPLC (column: Kromasil Eternity XT 250*80mm*10um; mobile phase: [water(NH4HCO3)-ACN]); verified by LCMS and HPLC to obtain compound 3 (800 mg, 1.55 mmol, 35.80%, purity 99.4%, NH4HCO3) as a white solid. Compound 3 (800 mg, 1.55 mmol, yield 35.80%, purity 99.4%, NH4HCO3) was dissolved in 5.0 mL of water, 1N HCl was added, the pH was adjusted to 2, and the mixture was filtered. The filter cake was concentrated to obtain compound 3 (400 mg, free state) as a white solid.

[0156] Compound 3 (500 mg, 1.15 mmol, 1.00 equiv.) and compound 3a (223 mg, 1.15 mmol, 1.00 equiv.) were dissolved in DMF (2.00 mL), and DIEA (149 mg, 1.15 mmol, 200 μL, 1.00 equiv.) and Bop (559 mg, 1.26 mmol, 1.1 equiv.) were added and stirred at 25°C for 12 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm*10 um; mobile phase: [water (TFA)-ACN]) to obtain compound 4 (200 mg, 329 μmol; yield 28.6%, purity 100%). The product was analyzed by LCMS and 1 HNMR was confirmed.

[0157] Compound 4 (200 mg, 329 μmol, 1.00 equiv.) was dissolved in DCM (2.00 mL), and TFA (3.07 g, 26.9 mmol, 2.00 mL, 81.9 equiv.) was added and stirred at 25°C for 1 h. The reaction mixture was concentrated under reduced pressure to give compound 5 (200 mg, 300 μmol, yield 91.3%, purity 100%, TFA) as a white solid. LCMS (R t =0.870 min, MS calculated value: 552.2, MS found value: [M+H] + =553.2.), HPLC (R t =2.06min) and 1H NMR confirmation.

[0158] Peptide solid phase synthesis:

[0159] 1) Resin Preparation: Fmoc-Lys(Dde)-OH (0.01 mmol, 1.00 equiv., Sub: 0.50 mmol / g) and DIEA (0.04 mmol, 4.00 equiv.) dissolved in DCM (20.0 mL) were added to 2-CTC resin (0.01 mmol, 1.00 equiv.) and DIEA (0.04 mmol, 4.00 equiv.) at 20°C under N₂ conditions for 2.00 h. Methanol (0.02 mL) was added, and the mixture was stirred under N₂ conditions for an additional 30 min. The resin was washed with DMF (5.00 mL x 5).

[0160] 2) Deprotection: add 20% piperidine in DMF (5.00 mL), stir under N2 for 15.00 min, wash with DMF (5.00 mL*5), and filter to obtain a resin.

[0161] 3) Coupling: Obtain an H-Glu(OtBu)-OtBu solution. Add HCl (0.03 mmol, 3.00 equiv.), CDI (0.03 mmol, 3.00 equiv.), DMAP (0.03 mmol, 3.00 equiv.), and DIEA (0.03 mmol, 3.00 equiv.) to THF (5.00 mL) and stir at 20°C for 1 hour. Then, add the solution to the resin and stir at 20°C under N2 for 12 hours. The resin is then washed with DMF (5.00 mL x 5).

[0162] 4) Deprotection: Add 3% hydrazine hydroxide (5.00 mL) and stir under N2 for 15 min*2. Wash the resin with DMF (5.00 mL*5) and filter to obtain the resin.

[0163] 5) Coupling: A solution of DIEA (0.06 mmol, 6.00 equiv.) in Fmoc-2-Nal-OH (0.03 mmol, 3.00 equiv.) and HBTU (0.03 mmol, 2.85 equiv.) was added to DMF (5.00 mL) and stirred at 20°C under N2 for 1 hr. The resin was then washed with DMF (5.00 mL x 5).

[0164] 6) Deprotection: add 20% piperidine in DMF (5.00 mL), stir under N2 for 15 min, wash with DMF (5.00 mL*5), and filter to obtain a resin.

[0165] 7) Coupling: HATU (0.01 mmol, 1.42 equiv.) was added to the resin, and a solution of Int_5 (0.02 mmol, 1.50 equiv.) and DIEA (0.03 mmol, 3.00 equiv.) was added to DMF (5.00 mL). The mixture was stirred at 20°C under N2 for 45 min. The resin was then washed with DMF (5.00 mL x 5).

[0166] 8) Deprotection: add 20% piperidine in DMF (5.00 mL), stir under N2 for 15.0 min, wash with DMF (5.00 mL*5), and filter to obtain a resin.

[0167] 9) Coupling: HATU (0.01 mmol, 1.42 equiv.) was added to a solution of DOTA(tBu*4) (0.02 mmol, 1.50 equiv.) and DIEA (0.03 mmol, 3.00 equiv.) in DMF (5.00 mL), and the mixture was stirred at 20°C under N2 for 45 min. The resin was then washed with DMF (5.00 mL*5).

[0168] Peptide cleavage and purification:

[0169] 1) Wash the resin with methanol (5.00 mL x 3) and vacuum dry to yield 2.00 g of peptide resin. Then, add 1.00 mL of lysis buffer (92.5% TFA / 2.5% TIS / 2.5% H2O / 2.5% 3-MPR) to the flask containing the side-chain protected peptide resin and stir at 20°C for 2.00 h. Precipitate the peptide with cold tert-butyl methyl ether (5.00 mL) and centrifuge (3000 rpm, 3.0 min). Wash the peptide precipitate twice with tert-butyl methyl ether (5.00 mL). Dry the crude peptide in vacuum for 2.00 h to yield 0.02 g of crude peptide.

[0170] 2) The crude peptide was purified by pre-HPLC (A: 0.075% TFA in H2O, B: ACN) to obtain the final product PSMA-P2 (2.00 mg, 1.61 μmol, 16.1% yield, 98.1% purity, TFA) as a white solid. The final product was analyzed by LCMS (R t =0.99 min) and HPLC (R t =9.68min, MS calculated value: 1214.5, MS found value: [M+H] + =1215.7) for confirmation.

[0171] Example 2 Metal Complex [ 68 Synthesis of Ga]Ga-PSMA-P2

[0172] The radiochemical purity of the labeled product was determined by HPLC. HPLC conditions: C18 chromatographic column, flow rate: 1.0 mL / min, mobile phase: A = 0.1% TFA / H2O; B = 0.1% TFA / CH3CN, B phase gradient: 0-2 min, 3%, 2-10 min, rising from 3% to 60%, 10-10.5 min, falling from 60% to 3%, 10.5-11 min, 3%. After purification [ 68 The radiochemical purity of Ga]Ga-PSMA-P2 was 100% (R t =8.986min). See Figure 1 for the test results.

[0173] Example 3 Metal Complex [ 177 Synthesis of Lu]Lu-PSMA-P2

[0174] The radiochemical purity of the labeled product was determined by HPLC. HPLC conditions: C18 chromatographic column, flow rate: 1.0 mL / min, mobile phase: A = 0.1% TFA / H2O; B = 0.1% TFA / CH3CN, B phase gradient: 0-2 min, 3%, 2-10 min, rising from 3% to 60%, 10-10.5 min, falling from 60% to 3%, 10.5-11 min, 3%. After purification [ 177 The radiochemical purity of Lu]Lu-PSMA-P2 was 100% (R t =8.995min). See Figure 2 for the test results.

[0175] Example 4 68 Cellular uptake experiments of Ga-labeled compounds

[0176] LNCaP cells and 22Rv1 cells [ 68 Ga]Ga-PSMA-P2 and [ 68 The uptake of Ga]Ga-PSMA-617 is shown in Figure 3. 68 The uptake of Ga]Ga-PSMA-P2 in both cells was higher than that in [ 68 Ga]Ga-PSMA-617, the difference was statistically significant.

[0177] Example 5 68 PET / CT imaging of Ga-labeled compounds

[0178] [ 68 Ga]Ga-PSMA-P2 and [ 68 The distribution of Ga]Ga-PSMA-617 in the same 22Rv1 tumor-bearing mouse 180 min after drug injection is shown in Figure 4. 68Ga]Ga-PSMA-P2 showed significantly higher uptake at the tumor site.

[0179] [ 68 Ga]Ga-PSMA-P2 and [ 68 The distribution of Ga]Ga-PSMA-11 in the same LNCaP tumor-bearing mice at 60 min and 180 min after drug injection is shown in Figure 5 . 68 Ga]Ga-PSMA-P2 had significantly higher uptake at tumor sites and lower kidney enrichment.

[0180] Example 6 177 SPECT / CT imaging of Lu-labeled compounds

[0181] [ 177 Lu]Lu-PSMA-P2 and [ 177 The distribution of Lu]Lu-PSMA-617 in 22Rv1 tumor-bearing mice at early and late time points after drug injection is shown in Figure 6. 177 Lu]Lu-PSMA-P2 showed significantly higher uptake at the tumor site.

[0182] Example 7 177 Treatment of 22Rv1 mice with Lu-labeled compounds

[0183] 22Rv1 tumor-bearing mice were injected with 37MBq[ 177 Lu]Lu-PSMA-P2 and [ 177 The changes in tumor volume within 30 days after Lu]Lu-PSMA-617 and saline control groups are shown in Figure 7. The experimental results showed that [ 177 Lu]Lu-PSMA-P2 and [ 177 Lu]Lu-PSMA-617 had a certain degree of inhibitory effect on the growth of 22Rv1 tumors, especially within 10 days after administration. 177 Lu]Lu-PSMA-P2 had significantly better therapeutic effects in 22Rv1 tumor-bearing mice, maintaining a good inhibitory effect within 30 days and showing significant therapeutic effects.

[0184] Example 8 177 Tumor uptake-time curves of Lu-labeled compounds in 22Rv1 mice

[0185] [ 177 Lu]Lu-PSMA-P2 and [ 177 The uptake and retention of Lu]Lu-PSMA-617 in tumors are shown in Figure 8 using the integrated area under the tumor uptake-time curve AUC. 177The accumulation of Lu]Lu-PSMA-P2 in tumors was higher than that of [ 177 Lu]Lu-PSMA-617. The tumor-to-kidney ratio (T / N) and absorbed dose are shown in the table on the right side of Figure 8. 177 Lu]Lu-PSMA-P2 had a higher tumor-kidney ratio and a higher tumor absorbed dose.

[0186] Example 9 Synthesis of intermediates

[0187] Synthesis of intermediate RD0278-1

[0188] (1) Compound RD0278A (12 g, 61.2 mmol, 1 equivalent) was dissolved in DMF (180 mL), and HBTU (27.8 g, 73.4 mmol, 1.2 equivalent) and NMM (CAS No.: 109-02-4, 15.5 g, 153 mmol, 2.5 equivalent) were added. After 5 minutes, compound RD0278B (19.5 g, 61.2 mmol, 1 equivalent) was added and the mixture was allowed to react overnight at room temperature. After the reaction was complete as determined by HPLC, the DMF reaction system was concentrated to dryness under reduced pressure and purified by reverse phase preparative liquid chromatography to obtain compound RD0278C (8 g, light yellow solid, 28.5% yield, 90.32% purity).

[0189] (2) Compound RD0278C (8 g, 17.4 mmol, 1 eq) was dissolved in MeCN (160 mL), and LiBr (22.6 g, 261 mmol, 15 eq) was added. The mixture was heated to reflux and allowed to react overnight. After the reaction was complete as determined by HPLC, the reaction mixture was filtered, concentrated to dryness under reduced pressure, and purified by reverse phase preparative liquid chromatography to obtain compound RD0278D (3.6 g, light yellow solid, 47.9% yield, 96.14% purity).

[0190] (3) Compound RD0278D (3 g, 6.94 mmol, 1 equivalent) and compound E (3.16 g, 13.9 mol, 2 equivalents) were dissolved in DMF (30 mL), and then NMM (2.8 g, 27.8 mmol, 4 equivalents) and BOP (6.75 g, 15.3 mmol, 2.2 equivalents) were added. The reaction was allowed to proceed at room temperature for 3 hours. After the reaction was complete as determined by HPLC, the reaction system was directly concentrated and the solvent removed by vortexing. Compound RD0278F (1.8 g, 40.4% yield, 91.25% purity) was obtained by reverse phase preparative liquid chromatography.

[0191] (4) Compound RD0278F (1.6 g, 2.5 mmol, 1 equivalent) was dissolved in THF (32 mL). The nitrogen atmosphere was replaced, and then Pd / C (320 mg, 20% w / w) was added. The hydrogen atmosphere was replaced four times (hydrogen balloon), and the mixture was reacted at room temperature for 4 hours. After the reaction was complete as determined by HPLC, the Pd / C was removed by filtration through celite, and the crude product was concentrated under reduced pressure to dryness to obtain 1.22 g (yellow viscous product, 88.4% yield, 82.34% purity).

[0192] Synthesis of intermediate RD0278-2

[0193] (1) Compound 9 (2 g, 13 mmol, 1 equivalent) was added to DMF (80 mL), and compound 10 (2.85 g, 13.7 mmol, 1.05 equivalent) was added at room temperature. The mixture was reacted at room temperature for 3 hours. Compound 8 (1.5 g, 13 mmol, 1 equivalent) and DCC (5.52 g, 26.8 mmol, 2.05 equivalent) were then added, and the reaction was continued at room temperature for 5 hours.

[0194] (2) The reaction system was filtered and then concentrated under reduced pressure to remove DMF to obtain compound RD0278-2 as a light yellow solid powder (6.5 g).

[0195] Synthesis of intermediate Int.11

[0196] (1) Weigh 450 mg of chlororesin and place it in a peptide synthesis tube. Add 5 mL of DMF and 5 mL of DCM to the peptide synthesis tube and let it stand at room temperature for 30 minutes. Drain the solvent with an air pump and wash the resin three times with DMF.

[0197] (2) Weigh 614 mg of Fmoc-Ser(tBu)-OH into a 15 mL EP tube. Dissolve the mixture in 6 mL of DMF and shake thoroughly. Add 600 μL of DIPEA to the EP tube and transfer the mixture to a peptide synthesis tube. Transfer the peptide synthesis tube to a 27°C constant temperature shaker and shake overnight. Drain the solvent and wash the resin three times with DMF. Then, add a mixture of methanol and DMF in a ratio of 1:10 to block for 20 minutes. Drain the solvent and wash the resin three times with DMF. Add 15 mL of 20% piperidine / DMF reagent and react for 15 minutes. Drain the solvent and wash the resin three times with DMF to deprotect. Repeat three times.

[0198] (3) Weigh 536 mg of protected thioglycolic acid (CAS No.: 34914-36-8), 576 mg of HBTU, and 208 mg of HOAT and dissolve them in 12 mL of DMF. Finally, add 600 μL of DIPEA, shake well, and add to the synthesis tube. Purge nitrogen for 1 h, drain the solvent, and wash the resin three times with DMF.

[0199] (4) Wash with DCM / methanol and drain until the resin becomes powder. Transfer the dry resin to a 50 mL EP tube and weigh it. Prepare 10 mL of a 20% hexafluoroisopropanol / DCM solution of full protective cutting liquid, add it to the 50 mL EP tube containing the resin, place it in a constant temperature shaker and shake for 1.5 hours, then take it out and pour the cutting liquid into the peptide synthesis tube for filtration to obtain a clear cutting liquid containing the crude peptide. Pour the filtered cutting liquid into a 50 mL round-bottom flask, spin dry the DCM using a rotary evaporator to obtain the crude peptide MAS3, and weigh it for later use.

[0200] The synthesis of MAS3 (D-serine), MAE3 (D-glutamic acid), and MAD3 (D-aspartic acid) can be referred to the above steps.

[0201] Example 10 Synthesis of PSMA-TR-3

[0202] (1) Weigh 450 mg of chlororesin and place it in a peptide synthesis tube. Add 5 mL of DMF and 5 mL of DCM to the peptide synthesis tube and let it stand at room temperature for 30 minutes. Drain the solvent with an air pump and wash the resin three times with DMF.

[0203] (2) Weigh 920 mg of Fmoc-Lys(ivdde)-OH and place it in a 15 mL EP tube. Add 6 mL of DMF to the EP tube to dissolve it and shake it thoroughly. Then add 600 μL of DIEA to the EP tube and transfer the mixed solution to a peptide synthesis tube. Then transfer the peptide synthesis tube to a 27°C constant temperature shaker and shake overnight. Drain the solvent and wash the resin three times with DMF. Then add a mixture of methanol:DMF = 1:10 to block for 20 minutes, drain the solvent and wash the resin three times with DMF. Obtain intermediate Int.2

[0204] (3) Add 15 mL of 20% piperidine / DMF reagent and react for 15 minutes. Drain the solvent and wash the resin three times with DMF. Weigh 410 mg of carbonate (CAS No.: 74124-79-1) and dissolve it in 12 mL of DMF. Add 600 μL of DIEA, shake well and add it to the synthesis tube. Blow nitrogen for 1 hour. Drain the solvent and wash the resin three times with DMF. Weigh 474 mg of H-Glu(OtBu)-OtBu.HCl (CAS No.: 32677-94-4) and dissolve it in 12 mL of DMF. Add 600 μL of DIEA, shake well and add it to the synthesis tube. Blow nitrogen for 1 hour. Drain the solvent and wash the resin three times with DMF. Add 20 mL of 3% hydrazine hydrate / DMF to the synthesis tube. Transfer the peptide synthesis tube to a 33°C constant temperature shaker and shake for 15 minutes. Then remove it, drain the solvent and wash the resin three times with DMF. Obtain intermediate Int.3

[0205] (4) 700 mg of D-2-NAL (CAS No.: 138774-94-4), 576 mg of HATU, and 208 mg of HOAT were dissolved in 12 mL of DMF. Finally, 600 μL of DIEA was added. The mixture was shaken thoroughly and added to a synthesis tube. Nitrogen was purged for 1 h, the solvent was drained, and the resin was washed three times with DMF to obtain Intermediate Int. 4.

[0206] (5) Add 15 mL of 20% piperidine / DMF reagent and react for 15 min. Drain the solvent and wash the resin three times with DMF. Weigh 442 mg of the small molecule RD0278-1 and 304 mg of HATU into 12 mL of DMF. Add 280 μL of DIPEA, shake thoroughly, and add to the synthesis tube. Purge nitrogen for 1 h, drain the solvent, and wash the resin three times with DMF. Intermediate Int.5 is obtained.

[0207] (6) Add 15 mL of 20% piperidine / DMF reagent and react for 15 min. Drain the solvent and wash the resin three times with DMF. Weigh 340 mg of the small molecule RD0278-2, add 280 μL of DIEA, shake thoroughly, and add to the synthesis tube. Purge nitrogen for 1 h, drain the solvent, and wash the resin three times with DMF.

[0208] (7) Prepare 10 mL of conventional cutting solution (0.5 g phenol, 1 mL TIPS, 0.5 mL water, and TFA to volume). Pour the cutting solution into a 50 mL EP tube, place it in a constant temperature shaker (33°C) and shake for 2 hours, then take it out and blow the cutting solution to less than 5 mL with nitrogen at room temperature. Add 20 mL of ice ether to the 50 mL EP tube, shake the EP tube appropriately, place the EP tube in a centrifuge at 3500 rpm, and centrifuge for 3 minutes; after centrifugation, pour out the supernatant and centrifuge three times. Dry at room temperature. The crude peptide was separated by semi-preparative liquid chromatography and lyophilized to obtain the final product PSMA-TR-3. The final product was analyzed by LCMS and HPLC (R t =12.21min, MS actual value: [M+H] + =1132.30) for confirmation.

[0209] HPLC conditions: YMC-Pack ODS-A 12A 5 μM 4.6×250 mm column, flow rate: 1.0 mL / min, mobile phase: A = 0.1% TFA / H2O; B = 0.08% TFA / CH3CN, B phase gradient: 0-2 min, 5%, 2-22 min, increasing from 5% to 99%, 22-30 min, 99%.

[0210] Example 11 Synthesis of PSMA-TR-4

[0211] (1) The synthesis steps of intermediate Int.5 are described in detail above. 15 mL of 20% piperidine / DMF reagent was added to intermediate Int.5 and the reaction was carried out for 15 min. The solvent was drained and the resin was washed three times with DMF. 724 mg of Fmoc-Lys(Aloc)-OH (CAS No.: 146982-27-6), 576 mg of HATU, and 208 mg of HOAT were weighed and dissolved in 12 mL of DMF. Finally, 600 μL of DIPEA was added, shaken thoroughly, and added to the synthesis tube. Nitrogen was blown for 1 h, the solvent was drained, and the resin was washed three times with DMF. Intermediate Int.7 was obtained.

[0212] (8) Add 15 mL of 20% piperidine / DMF reagent and react for 15 min. Drain the solvent and wash the resin three times with DMF. Weigh 916 mg of DOTA and 212 mg of HOBT and dissolve them in 12 mL of DMF. Finally, add 300 μL of DIC. Shake well and add to the synthesis tube. Then transfer the peptide synthesis tube to a 27°C constant temperature shaker and shake overnight. Drain the solvent and wash the resin three times with DMF. Obtain Int.8

[0213] (9) Weigh 232 mg of tetrakistriphenylphosphine palladium and dissolve it in DMF:DCM = 1:1. Finally, add 248 μL of phenylsilane, shake thoroughly, and add it to the synthesis tube. Then transfer the peptide synthesis tube to a 27°C constant temperature shaker and react for 4 h. Drain the solvent and wash the resin three times with DMF. Add 10 mL of palladium washing reagent and react for 20 min. Drain the solvent and wash the resin three times with DMF.

[0214] (10) Weigh 611 mg of MAS3 and 114 mg of Oxyma, dissolve in 12 mL of DMF, and finally add 124 μL of DIC. Shake thoroughly and add to the synthesis tube. Then transfer the peptide synthesis tube to a 27°C constant temperature shaker and shake overnight. Drain the solvent and wash the resin three times with DMF to obtain intermediate Int.9.

[0215] (11) Prepare 10 mL of conventional cutting solution (0.5 g phenol, 1 mL TIPS, 0.5 mL water, 0.5 mL thioanisole, and TFA to volume). Pour the cutting solution into a 50 mL EP tube, place it in a constant temperature shaker (33°C) and shake for 3 hours, then take it out and blow the cutting solution with nitrogen gas to less than 5 mL at room temperature. Add 20 mL of ice ether to the 50 mL EP tube, shake the EP tube appropriately, place the EP tube in a centrifuge at 3500 rpm, and centrifuge for 3 minutes; after centrifugation, pour out the supernatant and centrifuge three times. Dry at room temperature. The crude peptide obtained was separated by semi-preparative liquid chromatography and lyophilized to obtain pure peptide PSMA-TR-4.

[0216] The final product was analyzed by LCMS and HPLC (R t =12.202 min, MS found: [M+2H] 2+ =840.20) for confirmation. HPLC conditions: YMC-Pack ODS-A 12A 5μM 4.6×250mm column, flow rate: 1.0 mL / min, mobile phase: A = 0.1% TFA / H2O; B = 0.08% TFA / CH3CN, phase B gradient: 5% from 0-2 min, 5% to 99% from 2-32 min, 99% from 32-40 min.

[0217] Example 12 Synthesis steps of PSMA-TR-5, PSMA-TR-6, and PSMA-TR-7

[0218] The synthesis steps of PSMA-TR-5, PSMA-TR-6, and PSMA-TR-7 are similar to those of PSMA-TR-4, and the synthesis steps of Int.11 are described above.

[0219] The final product of PSMA-TR-5 was analyzed by LCMS and HPLC (R t=12.240 min, MS found: [M+2H] 2+ =840.65) for confirmation. HPLC conditions: YMC-Pack ODS-A 12A 5μM 4.6×250mm column, flow rate: 1.0 mL / min, mobile phase: A = 0.1% TFA / H2O; B = 0.08% TFA / CH3CN, phase B gradient: 5% from 0-2 min, 5% to 99% from 2-32 min, 99% from 32-40 min.

[0220] The final product of PSMA-TR-6 was analyzed by LCMS and HPLC (R t =12.359 min, MS found: [M+2H] 2+ =903.05) for confirmation. HPLC conditions: YMC-Pack ODS-A 12A 5μM 4.6×250mm column, flow rate: 1.0 mL / min, mobile phase: A = 0.1% TFA / H2O; B = 0.08% TFA / CH3CN, phase B gradient: 5% from 0-2 min, 5% to 99% from 2-32 min, 99% from 32-40 min.

[0221] The final product of PSMA-TR-7 was analyzed by LCMS and HPLC (R t =12.339 min, MS found: [M+2H] 2+ =882.20) for confirmation. HPLC conditions: YMC-Pack ODS-A 12A 5μM 4.6×250mm column, flow rate: 1.0 mL / min, mobile phase: A = 0.1% TFA / H2O; B = 0.08% TFA / CH3CN, phase B gradient: 5% from 0-2 min, 5% to 99% from 2-32 min, 99% from 32-40 min.

[0222] Example 13 99m Tc radiolabeling

[0223] Preparation before the experiment:

[0224] Prepare 3mg / mL ascorbic acid (dissolved in 10mM hydrochloric acid)

[0225] Prepare 4 mg / mL of stannous chloride (dissolved in 3 mg / mL of ascorbic acid)

[0226] Prepare 0.5M sodium acetate. (Dissolve in water)

[0227] Prepare 50 mg / mL potassium sodium tartrate (dissolved in 0.5 M sodium acetate)

[0228] Marked section

[0229] 1: Use 5mL of normal saline to rinse the molybdenum-technetium generator

[0230] Second: Take 450 μL of eluent;

[0231] 3. Add 50 μL of ③, 20 μL of ④, and 10 μL of ② to 450 μL of eluent, which is called stock solution 1.

[0232] 4. Adjust the pH of stock solution 1 to 7.0 using 1M HCl or NaOH

[0233] Five: Add 20 μL of molecules to stock solution one;

[0234] 6. React at 90 degrees for 20 minutes.

[0235] 7. Use ethanol-water to activate Spark C18 cartridges (5 mL each)

[0236] 8. After the reaction solution was cooled to room temperature, the product was diluted with 1 mL of normal saline and purified by passing through a C-18 separation column, and finally passed through a 0.22 μm sterile filter membrane;

[0237] 9. Take an appropriate amount of sterile-filtered product preparation for quality control inspection. It can only be used after all items are qualified.

[0238] The radiochemical purity of the labeled product was determined by HPLC. HPLC conditions: C18 chromatographic column, flow rate: 1.0 mL / min, mobile phase: A = 0.1% TFA / H2O; B = 0.1% TFA / CH3CN, B phase gradient: 0-2 min, 10%, 2-10 min, rising from 10% to 60%, 10-12 min, 60%, 12-13 min, falling from 60% to 10%, 13-15 min, 10%. After purification 99m The radiochemical purity of Tc-PSMA-TR-4 was 95% (R t =8.34min). See Figure 9 for the test results.

[0239] Example 14 99m SPECT imaging of Tc-labeled compounds

[0240] Instrument information: Yongxin InliView Animal PET / SPECT / CT

[0241] 99m Tc-PSMA-TR-4 and 99mDistribution of Tc-PSMA-I&S (a phase II drug) in the same representative LNCaP tumor-bearing mouse at early (3 hours) and late (24 hours) time points after drug injection (left) and tumor SUV max The capture (right) is shown in Figure 10. 99m Tc-PSMA-TR-4 showed significantly higher uptake at the tumor site.

[0242] 99m Tc-PSMA-I&S (labeled precursor CAS No.: 2639475-07-1)

[0243] Example 15 99m SPECT imaging of Tc-labeled compounds

[0244] 99m Tc-PSMA-TR-4 and 99m Distribution of Tc-HYNIC-PSMA (an unapproved drug that has entered Phase III clinical trials, labeled precursor CAS No.: 2192215-74-8) in the same representative LNCaP tumor-bearing mouse at early time points (3 hours) and late time points (24 hours) after drug injection (left) and tumor SUV max Ingestion (right). The test results are summarized in Figure 11. 99m Tc-PSMA-TR-4 showed significantly higher uptake at the tumor site.

[0245] Example 16 In the same prostate cancer patient with multiple bone metastases 99m SPECT imaging of Tc-PSMA-TR-4 and 18 Comparison of F-FDG PET imaging

[0246] Prepared and quality-controlled 99m Tc-PSMA-TR-4 (0.1-0.15mCi / kg) was injected intravenously into the subject. After the subject rested quietly for 180 minutes, SPECT-CT was used to image the head and trunk. The scanning range was from the top of the head to the upper 1 / 3 of the thigh. Delayed scanning could be performed if necessary. The subject took a supine position and breathed calmly. The data was reconstructed by the OSEM method to obtain coronal, sagittal, and transverse SPECT and SPECT / CT fusion images. The test results are summarized in Figure 12. Instrument information: Single photon emission tomography device (Siemens Symbia Intevo Bold). Figure 12 shows the same patient 99m Tc-PSMA-TR-4 and 18 Comparison of F-FDG imaging (A. 99m SPECT maximum intensity projection image of Tc-PSMA-TR-4; B.18 F-FDG PET maximum intensity projection image), the arrow indicates the suspected metastatic lesion, which can be seen 99m Tc-PSMA-TR-4 is superior to 18 F-FDG.

[0247] Example 17 99m SPECT / CT imaging of Tc-PSMA-TR-4 in patients with oligometastatic prostate cancer

[0248] Prepared and quality-controlled 99m Tc-PSMA-TR-4 (0.1-0.15mCi / kg) was injected intravenously into the subjects. After the subjects rested quietly for 180 minutes, SPECT-CT was used to image the head and trunk. The scanning range was from the top of the head to the upper 1 / 3 of the thigh. Delayed scanning could be performed if necessary. The subjects took a supine position and breathed calmly. The data were reconstructed by the OSEM method to obtain coronal, sagittal, and transverse SPECT and SPECT / CT fusion images. Delayed imaging was performed at the 22nd hour, and the test results are summarized in Figure 13. Instrument information: Single photon emission tomography device (Siemens Symbia Intevo Bold). Figure 13 is 99m SPECT / CT images of Tc-PSMA-TR-4: A. Plain scan or 2D static scan; B. SPECT / CT fusion image after tomographic scan. Solid arrows indicate highly suspected tumor lesions, from top to bottom: sacral metastasis, lymph node metastasis, and primary lesion; dashed arrows indicate the bladder. This indicates that the drug can delay imaging, facilitate the excretion of highly radioactive urine, significantly reduce bladder radioactivity uptake, minimize its impact on the primary prostate cancer lesion and nearby metastases, and improve contrast and other detection performance.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, in, X is selected from O, S or NH, preferably O; Y is a C1-C4 alkylene group; L1 is selected from a bond, a linker or is absent; L2 is selected from a bond or a linker; L3 is a linker; Z is selected from O, S or NH, preferably O; R1 is selected from hydrogen, C1-C6 alkyl, C1-C6 unsaturated hydrocarbon, hydroxyl, thiol, halogen, nitro, -CN or absent; Ring A is selected from optionally substituted C5-C 10 Arylene or C5-C 10 heteroarylene; One or two of R2, R3, and R5 are ligands targeting prostate-specific membrane antigen (PSMA), any one of R2, R3, and R5 is a payload, and the remaining R2, R3, and R5 are optional capping groups or are absent; The effective load is selected from a drug molecule group, a chelator group, a labeling molecule group or an optical dye.

2. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein The PSMA-targeting ligand R5 is selected from:

3. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein L1, L2 or L3 are independently selected from a bond or -L a -(L b ) m -L c -(L d ) n -L e -L f -, where L a , L b , L c , L d , L e , L f Each occurrence is independently selected from a bond, -O-, -S-, -SS-, -S(=O)2-, -NH-, -N(CH3)-, -C(R a )(R b )-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NH-, -NHC(=O)-, -C(=O)-N(CH3)-, -N(CH3)-C(=O)-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2NH-, -NHCH2-, -CH2O-, -OCH2-, -CH=NO-, -C(CH3)=N-NH-, -C(CH3)=N-NH-C(=O)-, -NH-CH2-C(=CH-COOH)-, a peptide group containing 1 to 4 amino acids, a cyclohexylene group, a phenylene group, a heterocyclic group (e.g., piperazine-1,4-diyl) or where R a and R b Each occurrence is independently selected from H, methyl, ethyl, propyl, isopropyl, phenyl, -OH, -SH, -NH2, -NH(CH3) or -NH(CH3)2; or L1 is absent; wherein the subscripts m and n are each independently selected from an integer from 0 to 4.

4. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein L1, L2 or L3 are independently selected from -NH-, -CH2-, -N(CH3)-, -C(=O)-, -C(=O)-PEP-、-NH-PEP-、 or wherein the subscripts m and n are integers of 1-4, PEP represents a peptide group comprising 1 to 4 amino acids, M is a coordination metal, preferably a radioactive or non-radioactive coordination metal, more preferably radioactive or non-radioactive lutetium, gallium, or yttrium; "#" represents the end closest to the phosphorus atom; or L1 is absent; The NH2 in L1, L2 or L3 is optionally further substituted with a chelating agent group.

5. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein L1 is selected from the group consisting of: or The subscripts m and n are integers from 1 to 4, respectively.

6. A compound of formula (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein L2 is selected from or in, The subscripts m and n are integers from 1 to 4 respectively; M is a coordination metal, preferably a radioactive or non-radioactive coordination metal, more preferably radioactive or non-radioactive lutetium, gallium, or yttrium; "#" indicates the end close to the phosphorus atom.

7. A compound of formula (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein L3 is selected from -NH-, -CH2-, -N(CH3)-, -C(=O)-, -C(=O)-PEP-、-NH-PEP-、 or Wherein the subscript n is an integer from 1 to 4, and PEP represents a peptide group containing 1 to 4 amino acids.

8. A compound of formula (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, in, X is O; Y is a C1-C4 alkylene group; L1 does not exist; Z is O; R1 is a C1-C4 alkyl group; Ring A is selected from the group consisting of optionally substituted 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene, 1,5-naphthylene, 1,6-naphthylene, 2,6-naphthylene, furanylene, thienylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, and pyridazinylene; the substituents on Ring A are selected from the group consisting of C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 one or more of alkoxy, hydroxy, amino, thiol, halogen, nitro and -CN; R2 does not exist or is a blocking group; One of R3 and R5 is a PSMA-targeting ligand; the other is a payload; preferably, R3 is a payload and R5 is a PSMA-targeting ligand.

9. A compound of formula (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein the compound of formula (I) is selected from:

10. A compound of formula (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein The labeling molecule group comprises 18 F. 123 I. 124 I. 125 I. 131 I and 211 At radiolabeled synthetic group.

11. The compound of formula (I) according to claim 10 or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein The synthetic group in the labeling molecule group is selected from: Where X is 18 F. 123 I. 124 I. 125 I. 131 I and 211 At, each R or R' is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and n is an integer between 0 and 12.

12. A compound of formula (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein The chelating agent group chelates Al for diagnosis 18 F. 68 Ga, 64 Cu, 89 Zr, 86 Y. 99m Tc, 111 In or 44 Sc; or radionuclide therapy 67 Ga, 67 Cu, 89 Zr, 90 Y. 153 Sm, 161 Tb, 186 / 188 Re、 177 Lu, 212 Pb, 212 / 213 Bi, 225 Ac, 227 Th or 47 Sc.

13. The compound of formula (I) according to claim 12 or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein The chelating agent group is selected from: or where R B is H, methyl or phenyl.

14. A compound of formula (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein The optical dye is selected from:

15. A compound of formula (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein The drug molecule group is selected from cytotoxic drugs, immunomodulators, antibiotics, protein degraders or molecular glues; preferably 16. A compound of formula (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein The end-capping group is selected from -L g -(L h ) n -L i -R e , where L g , L h , L i Each occurrence is independently selected from a bond, -O-, -S-, -C(R c )(R d )-, -NH-, -N(CH3)-, -C(=O)-, -CH2O- or -OCH2-, subscript n is an integer from 0 to 4, R c and R d Each occurrence is independently selected from H, methyl, ethyl, propyl, isopropyl, phenyl, -OH, -SH, -NH2, -NH(CH3) or -NH(CH3)2, R e Selected from methyl, ethyl, hydroxyl or mercapto.

17. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein the compound of formula (I) is selected from 18. A compound of formula (II) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, in, X, Y, and Z have the same definitions as in any of the preceding claims; L1, L2, L3 have the definitions as in any of the preceding claims or do not exist; G1, G2, and G3 are each independently selected from a hydroxyl protecting group, a carboxyl protecting group, an amino protecting group, an amide protecting group, an imine protecting group, a cyclic imide protecting group, a thiol protecting group, or a phosphorus hydroxyl protecting group.

19. The compound of formula (II) according to claim 18 or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein: The hydroxy protecting group is selected from benzyl, 2,6-dichlorobenzyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, benzoyl, mesyl, tosylate, dimethoxytrityl (DMT), 9-phenylxanthine-9-yl (Pixyl) or 9-(p-methoxyphenyl)xanthine-9-yl (MOX); The carboxyl protecting group is selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl-C 1-2 alkyl, 2-adamantyl, 4-nitrobenzyl, 4-methoxybenzyl, 4-chlorobenzyl, phenacyl, benzyloxycarbonylhydrazide, tert-butyloxycarbonylhydrazide, and tritylhydrazide; the amino protecting group is selected from 2-trimethylsilylethoxycarbonyl (Teoc), 1-methyl-1-(4-biphenylyl)ethoxycarbonyl (Bpoc), tert-butoxycarbonyl (BOC), allyloxycarbonyl (Alloc), 9-fluorenylmethoxycarbonyl (Fmoc) and benzyloxycarbonyl (Cbz); the amide protecting group is selected from the group consisting of formyl, acetyl, trihaloacetyl, benzoyl, and nitrophenylacetyl; Sulfonamide protecting groups are selected from 2-nitrobenzenesulfonyl; and imide and cyclic imide protecting groups such as phthalimido and dithiasuccinoyl; The phosphorus hydroxy protecting group is selected from methyl, ethyl, benzyl (Bn), phenyl, isopropyl, tert-butyl, 4-methoxybenzyl, 4-chlorobenzyl, 2-chlorophenyl and 2-cyanoethyl.

20. The compound of formula (II) according to claim 18 or 19, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, selected from 21. Use of a compound of formula (II) according to any one of claims 18 to 20 in the preparation of a compound of formula (I) according to any one of claims 1 to 17.

22. A chelate or radionuclide label comprising (i) a compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof; and (ii) Radionuclides.

23. The chelate or radionuclide label according to claim 22, wherein the radionuclide is selected from: 18 F. 51 Cr, 67 Ga, 68 Ga, 111 In, 99m Tc, 186 Re、 188 Re、 139 La, 140 La, 175 Yb, 153 Sm, 166 Ho, 86 Y. 88 Y. 90 Y. 149 Pm, 165 Dy, 169 Second, 177 Lu, 47 Sc, 142 Pr, 159 Gd, 212 Bi, 213 Bi, 72 As、 72 Se, 97 Such as 109 Pd, 105 Rh, 101m Rh, 119 Sb, 128 Ba, 123 I. 124 I. 131 I. 197 Hg, 211 At 151 Eu, 153 Eu, 169 Eu, 201 Tl, 203 Pb, 212 Pb, 64 Cu, 67 Cu, 188 Re、 186 Re、 198 Au, 225 Ac, 227 Th and 199 Ag.

24. A composition comprising a compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or a chelate or radionuclide label according to any one of claims 22 to 23, and a pharmaceutically acceptable carrier.

25. Use of the compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, the chelate or radionuclide label according to any one of claims 22 to 23, or the composition according to claim 24 in the diagnosis or treatment of a disease.

26. Use of the compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, the chelate or radionuclide label according to any one of claims 22 to 23, or the composition according to claim 24 in the preparation of a medicament for treating a disease, or in the preparation of a disease diagnostic reagent.

27. The use according to claim 25 or 26, wherein the disease is associated with high expression of PSMA (the number of proteins on each cell is greater than 10 5 A) related disease, such as a prostate disease, preferably benign prostatic hyperplasia or prostate cancer.

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