New labeling targeting agent for diagnosing or treating prostate-specific membrane antigen expressing cancer

Abstract

The present invention discloses a new labeling targeting agent for diagnosing or treating prostate-specific membrane antigen (PSMA) expressing cancer, and specifically relates to a compound as represe

Description

Novel marker-targeted agents for the diagnosis or treatment of prostate-specific membrane antigen-expressing cancers Technical Field

[0001] The present invention relates to radiolabeled compounds for selective imaging or treatment of cancer, in particular prostate specific membrane antigen targeting compounds. Background Art

[0002] Prostate cancer is the second most common cancer among men worldwide and the sixth most common cancer among men in China. Over the past decade, the incidence of prostate cancer in China has rapidly increased, with an average annual growth rate of 12.07%. Older men are at higher risk of prostate cancer, and the risk increases with age. Prostate cancer, often described as a "silent killer," is difficult to detect in its early stages, with approximately two-thirds of patients already in the advanced stages by the time of diagnosis. Data indicate that at least 65% to 75% of prostate cancer patients develop bone metastases, leading to bone-related events such as bone pain, pathological fractures, limb mobility impairment, spinal cord compression, hypercalcemia, and even lower limb paralysis. Furthermore, patients with advanced prostate cancer may experience symptoms such as low mood, insomnia, depression, and general fatigue.

[0003] According to current guidelines, ultrasound-guided biopsy is recognized as the most common method for diagnosing prostate cancer. MRI is the standard imaging method for detecting suspected early-stage prostate cancer after negative pathology. Localizing suspected lesions using MRI to guide biopsy sampling improves diagnostic accuracy. However, even with MRI, omissions can still occur. Therefore, PET imaging, which provides additional cell biological information, has gained widespread attention.

[0004] The use of PET imaging based on choline and glucose metabolism for the diagnosis and staging of prostate cancer has been widely studied and discussed, but the results are not ideal. However, PET imaging using prostate-specific membrane antigen (PSMA) as a probe has gained increasing attention, adding new hope for improving the diagnosis and treatment of prostate cancer.

[0005] PSMA is a type II transmembrane protein composed of 19 intracellular amino acids, 24 transmembrane amino acids, and 707 extracellular amino acids. In normal tissue, PSMA expression and localization are associated with the cytoplasm and apical epithelial cells surrounding prostate ducts, and not with neuroendocrine or stromal cells. In dysplastic or cancerous tissue, PSMA translocates from the apical membrane to the luminal surface of the ducts, and higher PSMA expression is observed in tumors undergoing transformation to androgen-independent prostate cancer. Furthermore, PSMA is expressed in tumor tissues and neovascular tissues outside of prostate cancer, and PSMA expression has occasionally been detected in various cancer types during staging or restaging of prostate cancer patients using PSMA-PET. PSMA is composed of two monomers and three groups (intracellular, transmembrane, and extracellular amino acids). When a ligand (such as a small molecule antagonist or specific antibody) binds to PSMA, it undergoes endocytosis, where it is either retained in lysosomes or released into the cytoplasm. The following biological properties make PSMA an ideal target for molecular imaging of prostate cancer: (1) its expression in prostate cancer cells is 100 to 1000 times higher than that in normal cells; (2) its expression is higher in cancer cells at the advanced stage and those undergoing anti-androgen therapy. Some studies have shown that the expression of PSMA in cancer cells increases with the increase of tumor grade; (3) PSMA is composed of intracellular and extracellular groups. The external groups can be linked to ligands with different functions, while the internal groups contain functional factors for endocytosis reactions, which can initiate endocytosis reactions and intracellular biochemical circulation, thereby increasing the accumulation of radiotracers inside cells and improving imaging or therapeutic efficacy. These characteristics make PSMA a very promising biological target, especially in the development of small molecule radiopharmaceuticals (PSMA inhibitors). Such small molecule drugs usually have the characteristics of rapid elution from the blood and low uptake rate in surrounding normal tissues.

[0006] Since the 1980s, research on small molecule markers targeting intracellular or external groups of PSMA for nuclear medicine imaging has been underway. Currently, only one has been approved by the US FDA for clinical use. Furthermore, research on PSMA ligands has been intense. PSMA inhibitors are primarily classified into three categories: phospho-based (including phosphonates, phosphates, and aminophospho-based), thiol-based, and urea-based. 123 I. 99m Tc, 18 F. 111 In and 68 Ga can be used to label small molecule inhibitors of PSMA. 68 Ga-labeled Glu-NH-CO-NH-Lys(Ahx)-HBED-CC( 68Ga-PSMA-HBED-CC) was introduced to the public by Eder et al. in 2012 and has become the most popular PET imaging agent. 68 Ga-labeled PSMA ligand EuK-Subkff- 68 Ga-DOTAGA[ 68 Ga-PSMA Imaging & Therapy (I & T)] has also been introduced, because this small molecule ligand can also be used 177 Lu and 111 In is labeled, so it can be used as a drug for integrated diagnosis and treatment in clinical practice. 68 Ga as imaging agent, 111 In as a surgical guide marker, 177 Lu is widely used in clinical practice as a radiotherapy drug. 18 F labeling of PSMA ligands is the future trend of this type of drug development. 18 The yield of F is higher than that of 68 Ga is much larger and can accept a larger amount of inspection, and 18 F has better imaging performance and is more convenient for managing imaging dose. 18 There are few studies on F-labeled PSMA ligands, which require further basic and clinical trials to support.

[0007] Furthermore, in therapeutic applications of radiolabeled PSMA inhibitors, organs with physiological PSMA expression have proven to be dose-limiting, thereby minimizing the success rate of treatment. In particular, high renal and salivary gland uptake of radiolabeled PSMA inhibitor substances is significant, which can cause considerable side effects in the context of therapeutic applications. Attempts to improve the renal uptake of PSMA inhibitors have led to the development of PSMA-617, a drug that has been clinically tested in combination with 177 Lu or 225 Ac is a compound used in the in vivo radiotherapy of prostate cancer. However, reduction of salivary and lacrimal gland uptake has not been achieved and is still described as critical and dose-limiting in early clinical work. The accumulation of PSMA ligands in the salivary and lacrimal glands, which has been described in many papers, leads to considerable side effects. The salivary and lacrimal glands are severely and partially irreversibly damaged, especially when using 225Ac during α-therapy. Therefore, there is still a need for improved PSMA ligands that provide advantageous options for the detection, treatment, and management of PSMA-expressing cancers, particularly prostate cancer. Based on references, the present inventors designed and synthesized a series of novel PSMA marker inhibitors. Through PET imaging, they discovered new compounds that can be used as tracers and imaging agents in nuclear medicine and for the treatment of various conditions of PSMA-expressing cancers, particularly prostate cancer.

[0008] Summary of the Invention

[0009] The present invention aims to provide a compound that can be used as a novel marker targeting agent for diagnosing or treating cancers expressing prostate-specific membrane antigen (PSMA).

[0010] Another object of the present invention is to provide a complex comprising the above compound.

[0011] Another object of the present invention is to provide a pharmaceutical composition comprising the above-mentioned complex.

[0012] The present invention provides novel compounds that are useful and advantageous radiopharmaceuticals and can be used in nuclear medicine as tracers, imaging agents and for the treatment of various disease states in PSMA-expressing cancers, particularly prostate cancer.

[0013] The purpose of the present invention can be achieved through the following technical solutions:

[0014] The compound represented by general formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs,

[0015] in:

[0016] Z1, Z2 and Z3 are independently selected from -COOH, -SO2H, -SO3H, -OSO3H, -OPO3H2 and

[0017] X is C=OS=O C=NH

[0018] R2 is -CH3 or H;

[0019] u and w are independently 0, 1 or 2 (preferably u and w are not 0 at the same time); i is an integer from 1 to 3 (i.e., i is 1, 2 or 3); j is an integer from 3 to 5 (i.e., j is 3, 4 or 5);

[0020] R1 is selected from substituted or unsubstituted alkylaryl (-alkyl-aryl), aryl, alkylheteroaryl (-alkyl-heteroaryl) and heteroaryl;

[0021] Y1 and Y3 are each independently selected from substituted or unsubstituted aryl, alkylaryl (-alkyl-aryl), cycloalkyl, heterocycloalkyl, heteroaryl and alkylheteroaryl (-alkyl-heteroaryl);

[0022] Y2 is C=O, C=S or

[0023] g, k, e, s, and t are independently 0 or 1;

[0024] A is a nuclide, a nuclide with a linker arm, or a chelating agent capable of grabbing a nuclide.

[0025] As a preferred technical solution, R1 is selected from the residues of substituted or unsubstituted naphthyl, phenyl, biphenyl, indolyl and benzothiazolyl; further preferably, R1 is selected from the residues of substituted or unsubstituted naphthyl, alkyl-naphthyl, phenyl, benzyl, biphenyl, alkyl-biphenyl, indolyl, alkyl-indolyl, benzothiazolyl and alkyl-benzothiazolyl; further preferably, R1 is selected from

[0026] More preferably, R1 is

[0027] As a preferred technical solution, Y1 is

[0028] As a preferred technical solution, Y3 is selected from substituted or unsubstituted aryl, alkaryl, cycloalkyl, heterocycloalkyl, heteroaryl and alkylheteroaryl; preferably, Y3 is an aryl group; more preferably, Y3 is a substituted benzene ring;

[0029] More preferably, Y3 is Among them, R7, R8, R9 and R 10 R7, R8, R9 and R 10 R7, R8, R9 and R are independently alkyl or H. 10 For H.

[0030] As a preferred technical solution, at least one of Z1, Z2 and Z3 is -COOH, and R2 is H.

[0031] As a preferred technical solution, wherein i is preferably 2, j is preferably 4, and the compound has the structure shown in (Ia):

[0032] As a preferred technical solution, the nuclide is selected from 89 Zr, 44 Sc, 111 In, 99m Tc, 90 Y. 66 Ga, 67 Ga, 68 Ga, 177 Lu, 60 Cu, 6l Cu, 62 Cu, 64 Cu, 66 Cu, 67 Cu, 149 Tb, 152 Tb, 153 Sm, 155 Tb, 161 Tb, 153 Gd, 155 Gd, 157 Gd, 213 Bi, 225 Ac, 230 U. 223 Ra, 165 Second, 191 Radionuclides of Pt, Fe and radionuclides of Pb.

[0033] As a preferred technical solution, the nuclide with a connecting arm is selected from the following structures:

[0034] wherein Y4 and Y5 are independently H, alkyl, or optionally substituted or unsubstituted aryl, alkylaryl, heteroaryl, and alkylheteroaryl; wherein n is an integer from 0 to 5 (i.e., n is 0, 1, 2, 3, 4, or 5);

[0035] As a preferred technical solution, the chelating agent capable of capturing nuclides can selectively bind to the radioactive metal L, and its structure is selected from (1a), (1b) and (1c):

[0036] wherein R3, R4, R5 and R6 are independently selected from H, -CH2-COOH and -CH2-C(=O)-NH2, or wherein R3 and R5 form -(CH2) m - bridge, m is an integer from 1 to 3 (i.e., m is 1, 2 or 3), wherein m is preferably 2;

[0037] wherein r, v, and q are independently 0 or 1.

[0038] Further preferably, the chelating agent capable of capturing nuclides is selected from the following structures:

[0039] etc., but not limited to.

[0040] A complex comprising: (a) a radionuclide, and (b) the compound according to any one of claims 1 to 8, and a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof.

[0041] As a preferred technical solution, the radionuclide is selected from 89 Zr, 44 Sc, 111 In, 99m Tc, 90 Y. 66 Ga, 67 Ga, 68 Ga, 177 Lu, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 66 Cu, 67 Cu, 149 Tb, 152 Tb, 153 S m 、 155 Tb, 161 Tb, 153 Gd, 155 Gd, 157 Gd, 213 Bi, 225 Ac, 230 U. 223 Ra, 165 Second, 191 Radionuclides of Pt, Fe and radionuclides of Pb.

[0042] A pharmaceutical composition comprising the above compound or the above complex.

[0043] Use of the above-mentioned compound, complex or pharmaceutical composition in the following (1) or (2):

[0044] (1) preparing drugs for treating, ameliorating or preventing PSMA-expressing cancer and / or its metastases;

[0045] (2) Preparation of reagents for diagnosing PSMA-expressing cancer and / or its metastases.

[0046] The term "PSMA-expressing cancer and / or its metastases" as used within the meaning of the present invention relates to any cancer whose cancer cells express prostate-specific membrane antigen (PSMA) and its respective metastases. Preferably, the cancer (or cancer cell) that can be treated according to the present invention is selected from prostate cancer, conventional renal cell carcinoma, transitional cell carcinoma of the bladder, embryonal carcinoma of the testis, neuroendocrine cancer, colon cancer, brain tumors and breast cancer. In a particularly preferred aspect of the present invention, the PSMA-expressing cancer is prostate cancer or breast cancer, in particular prostate cancer.

[0047] As described above, the compound of the present invention or the compound contained in the complex has the following structure:

[0048] It will be appreciated that the compound or compounds contained in the complex may be in the form of anions or salts of the compounds of formula (I).

[0049] Therefore, the present invention also relates to salts of compounds of general formula (I) or compounds contained in the complex, in particular pharmaceutically acceptable salts. The present invention also relates to solvates of these compounds, including salts and active metabolites thereof, and, where appropriate, tautomers thereof, including prodrug preparations.

[0050] A "pharmaceutically acceptable salt" is a pharmaceutically acceptable organic or inorganic acid or base salt of a compound of the invention. Representative pharmaceutically acceptable salts include, for example, alkali metal salts, alkaline earth metal salts, ammonium salts, water-soluble and water-insoluble salts, such as acetates, carbonates, chlorides, gluconates, glutamates, lactates, laurates, malates, or tartrates.

[0051] The term "prodrug" refers to a precursor of a drug, which is a compound that, once administered to a patient, must undergo chemical transformation through metabolic processes and then become an active agent. Illustrative compound prodrugs according to formula (I) are esters and amides, preferably alkyl esters or fatty acid esters. The prodrug formulations herein include all substances formed by simple conversions, including enzymatic, metabolic, or hydrolysis, oxidation, or reduction in any other manner. Suitable prodrugs contain, for example, a substance of formula (I) that is connected to a substance (for example, tetraethylene glycol, saccharides, formic acid, or glucuronic acid) that improves dissolution through an enzymatically cleavable linker (for example, carbamate, phosphate, N-glycoside, or disulfide group). This prodrug of a compound according to the present invention can be administered to a patient, and this prodrug can be converted into a substance of formula (I) to obtain the desired pharmacological effect.

[0052] Some compounds of general formula (I) may be included in the form of stereoisomeric mixtures, such as racemic mixtures and / or mixtures of cis / trans isomers, or as single enantiomers, diastereomers and / or specific cis / trans isomers, including all possible mixtures thereof.

[0053] According to the present invention, all chiral C atoms should have the D configuration and / or the L configuration; combinations are also possible within one compound, i.e. some of the chiral C atoms may have the D configuration and others may have the L configuration. More preferably, the amino acid residues present in the compound have the L configuration.

[0054] The compounds obtained can optionally be separated into their enantiomers and / or diastereomers by known methods (e.g. Allinger, NL and Elliel ELin, Topics in Stereochemistry "Vol. 6, Wiley Interscience, 1971). One possible method for enantiomeric separation is to use chromatography.

[0055] Urea backbone:

[0056] Compound (I) comprises a urea building block (IA). In this urea building block (IA) of compound (I)

[0057] Z1, Z2 and Z3 are independently selected from -COOH, -SO2H, -SO3H, -OSO3H, -OPO3H2 and More preferably, at least one of Z1, Z2 and Z3 is -COOH, and more preferably, all of Z1, Z2 and Z3 are -COOH.

[0058] Building block (IA) may exist in any stereoisomeric form, however, preferably (IA) has the structure (IAa):

[0059] Therefore, it is preferred that the compounds of the present invention and the compounds contained in the complexes of the present invention have the following structure:

[0060] The integer i and the integer j are as described above.

[0061] Preferably, i is 2. Therefore, the present invention also relates to compounds of formula (I), preferably formula (Ia), in which i is 2, and to the compounds comprised in the complexes according to the invention.

[0062] Preferably, j is 4. Therefore, the present invention also relates to compounds of formula (I), preferably formula (Ia), and to the compounds comprised in the complexes according to the invention, in which j is 4.

[0063] R2 is preferably H.

[0064] X is preferably

[0065] Therefore, the urea building block (IAa) most preferably has the structure (IAa-1)

[0066] Residue R1 and building block (IB):

[0067] As described above, in this building block, R1 preferably comprises a residue selected from substituted or unsubstituted naphthyl, phenyl, biphenyl, indolyl and benzothiazolyl. Preferably, R1 is selected from substituted or unsubstituted naphthyl, alkyl-naphthyl, phenyl, benzyl, biphenyl, alkyl-biphenyl, indolyl, alkyl-indolyl, benzothiazolyl and alkyl-benzothiazolyl.

[0068] In the meaning of the present invention, the terms naphthyl, phenyl, biphenyl, indolyl and benzothiazolyl include groups further substituted by one or more than one suitable substituent. The term "substituted" as used in the context of the present invention preferably refers to a group substituted at any position by one or more than one substituent, preferably 1, 2, 3, 4, 5 or 6 substituents, more preferably 1, 2 or 3 substituents. If two or more substituents are present, each substituent may be identical or may be different from at least one other substituent. Preferably, the group is unsubstituted.

[0069] In the meaning of the present invention, the term "alkyl" relates to both unbranched and branched alkyl residues. The term also includes alkyl groups that are further substituted by one or more than one suitable substituent. The term "substituted alkyl" as used in the context of the present invention preferably refers to an alkyl group that is substituted at any position by one or more substituents, preferably 1, 2, 3, 4, 5 or 6 substituents, more preferably 1, 2 or 3 substituents.

[0070] More preferably, the residue R1 is selected from:

[0071] These groups may be appropriately substituted. Preferably, these groups are unsubstituted.

[0072] Most preferably, if R1 is present (i.e., e is 1), R1 is

[0073] Thus, building block (IB), if present, preferably has the following structure:

[0074] The term "aryl" as used in the context of the present invention refers to optionally substituted aryl groups, i.e. in particular optionally substituted 5-membered aromatic rings or 6-membered aromatic rings, and substituted or unsubstituted polycyclic aromatic groups (aryl groups), such as tricyclic aryl groups or bicyclic aryl groups. Examples of optionally substituted phenyl or naphthyl groups include. Polycyclic aromatic groups may also contain non-aromatic rings.

[0075] The term "heteroaryl" as used in the context of the present invention refers to optionally substituted heteroaryl groups, i.e. in particular optionally substituted 5-membered aromatic rings or 6-membered aromatic rings, and substituted or unsubstituted polycyclic aromatic groups, such as tricyclic or bicyclic aromatic groups, which contain one or more than one, e.g. 1 to 4, for example 1, 2, 3 or 4, heteroatoms in the ring system. If more than one heteroatom is present in the ring system, at least two of the heteroatoms present may be identical or different. Suitable heteroaryl groups are known to the skilled person. The following optionally substituted heteroaryl residues may be mentioned as non-limiting examples: benzodioxolanyl, pyrrolyl, furyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzimidazolyl, benzothienyl, methylenedioxyphenyl, naphthyridinyl, quinolyl, isoquinolyl, indolyl, benzofuranyl, purinyl, benzofuranyl, deazapurinyl, pyridazinyl and indolizinyl.

[0076] The term "alkylaryl" or "alkylheteroaryl" as used within the meaning of the present invention refers to a group in which the aryl or heteroaryl group is attached to the respective remainder of the building block via an alkyl group. Thus, in the case where R is, for example, a C backbone, "alkylaryl" in this case refers to an -alkyl-aryl group and "alkylheteroaryl" to an -alkyl-heteroalkyl group. In the case of Y, the aryl or heteroaryl group is attached to the carbonyl group via an alkyl group, i.e., in this case, "alkylaryl" refers to an -alkyl-aryl- group and "alkylheteroaryl" to an -alkyl-heteroaryl- group. In the case of Y, the aryl or heteroaryl group is attached to the NH group via an alkyl group, i.e., in this case, "alkylaryl" refers to an -alkyl-aryl- group and "alkylheteroaryl" to an -alkyl-heteroaryl- group.

[0077] In the context of the present invention, the term "cycloalkyl" refers to optionally substituted cycloalkyl residues, which may be monocyclic or polycyclic groups. As preferred examples of cycloalkyl residues, optionally substituted cyclohexyl may be mentioned.

[0078] The term "heterocycloalkyl" as used in the context of the present invention refers to optionally substituted cycloalkyl residues which have at least one heteroatom in the ring, such as O, N or S, whereby they may be monocyclic or polycyclic groups.

[0079] The term "substituted cycloalkyl residue" or "cycloheteroalkyl" as used in the context of the present invention refers to a cycloalkyl residue or a cycloheteroalkyl residue, wherein at least one H is substituted by a suitable substituent.

[0080] Preferably, Y1 is

[0081] Thus, building block (IC), if present (ie k is 1), preferably has the following structure:

[0082] Group Y2

[0083] As mentioned above, Y2 is preferably C=O, CSS, or

[0084] Radionucleotides

[0085] Depending on whether the compounds of the invention are used as radioimaging agents or radiopharmaceuticals, different radionuclides are complexed with chelating agents.

[0086] Illustrative radionuclides include, for example 89 Zr, 44 Sc, 111 In, 99m Tc, 90 Y. 66 Ga, 67 Ga, 68 Ga, 177 Lu, 60 Cu, 6l Cu, 62 Cu, 64 Cu, 66 Cu, 67 Cu, 149 Tb, 152 Tb, 153 Sm, 155 Tb, 161 Tb, 153 Gd, 155 Gd, 157 Gd, 213 Bi, 225 Ac, 230 U. 223 Ra, 165 Second, 191 Radionuclides such as Pt and Fe (e.g. 52 Fe and 59 Fe) and Pb radionuclides (e.g. 203 Pb and 212 Pb, 211 Pb, 213Pb, 214 Pb, 209 Pb, 198 Pb, 197 Pb).

[0087] The radionuclide Pb is more preferably 203 Pb and 212 Pb.

[0088] The radionuclide Cu is more preferably 64 Cu and 67 Cu.

[0089] Complexes of the compounds according to the invention may contain one or more than one radionuclide, preferably one radionuclide. These radionuclides are preferably suitable for use as radioimaging agents or as therapeutics for the treatment of proliferating cells, such as PSMA-expressing cancer cells, in particular PSMA-expressing prostate cancer cells. According to the invention, they are referred to as "metal complexes" or "radiopharmaceuticals."

[0090] A preferred imaging method is positron emission tomography (PET).

[0091] Implementation Plan (A)

[0092] According to a preferred embodiment of the present invention, s, t, u and w are 1. According to this embodiment, the compound of the present invention therefore has the following structure.

[0093] In this case, Y2 is most preferably c=s. Therefore, the compound of the present invention more preferably has the following structure.

[0094] As described above, Y3 is selected from substituted or unsubstituted aryl, alkaryl, cycloalkyl, heterocycloalkyl, heteroaryl and alkylheteroaryl. More preferably, Y3 is aryl, more preferably, Y3 comprises an optionally substituted phenyl ring, even more preferably Y3 is

[0095] Among them, R7, R8, R9 and R 10 R7, R8, R9 and R 10 are independently alkyl or H, more preferably R7, R8, R9 and R 10 For H.

[0096] Therefore, the compounds of the present invention preferably include the following structure:

[0097] With such compounds, the interaction with PSMA can be optimized.With the compounds according to the invention, improved tumor-non-target tissue accumulation and tissue values ​​can be achieved and an improved distribution pattern can be obtained in non-target tissues.

[0098] Furthermore, the integrators administered according to the present invention allow for stable binding of radionuclides that cannot be used to target PSMA-expressing tumors to actually known tracers.

[0099] In the case of embodiment A, as described above and below,

[0100] If A is a chelating agent capable of capturing nuclides, it is selected from (1a), (1b) and (1c).

[0101] In the case of embodiment A, as described above and below, the integer r is preferably 0. More preferably, A is a chelating agent selected from

[0102] But it’s not limited to this.

[0103] Therefore, the present invention also relates to compounds as described above and below and complexes comprising said compounds. The compounds of the present invention preferably include the following structure:

[0104] Wherein A is a chelating agent capable of capturing nuclides, which is selected from

[0105] But it’s not limited to this.

[0106] The structures of preferred compounds according to this embodiment are selected from ZT-006, ZT-007, ZT-008, ZT-018 and ZT-019 (see Table 1), with compound ZT-019 being more preferred.

[0107] The experimental results showed that these compounds showed high binding affinity to PSMA and were efficiently internalized.

[0108] Experimental plan (B)

[0109] According to another preferred embodiment of the present invention, s is 0 and t is 1, u and w are 1. According to this embodiment, the compound of the present invention thus has the structure

[0110] According to this embodiment, A has the structure

[0111] Or structure (1a), structure (1b), structure (1c).

[0112] But it’s not limited to this.

[0113] As described above, Y3 is selected from substituted or unsubstituted aryl, alkaryl, cycloalkyl, heterocycloalkyl, heteroaryl and alkylheteroaryl. More preferably, Y3 is substituted or unsubstituted aryl or heteroaryl, more preferably, Y3 comprises a substituted phenyl ring, and even more preferably Y3 is

[0114] Among them, R7, R8, R9 and R 10 are independently H or alkyl, most preferably H.

[0115] Y4 and Y5 are each independently selected from H, alkyl or optionally substituted or unsubstituted aryl, alkylaryl, heteroaryl and alkylheteroaryl, or in each case optionally substituted alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkanoyloxy, cycloalkyl, benzyloxy or aryl. More preferably, Y4 is H and Y5 is alkyl.

[0116] The integer n is preferably 1, 2, 3 or 4.

[0117] The present invention therefore also relates to compounds as described above and below and to complexes comprising said compounds, said compounds having the following structure:

[0118] wherein A has structure (1a) or structure (1b) or structure (1c). More preferably, in this case, Y2 is C=O.

[0119] As preferred groups A above and below, the following groups are mentioned:

[0120] More preferably, A is selected from

[0121] And, most preferably, A is

[0122] The preferred compound structures according to this embodiment are selected from ZT-001, ZT-002, ZT-003, ZT-011, ZT-012, ZT-013, ZT-014, ZT-015, ZT-016, ZT-017, ZT-020, ZT-021, ZT-022, ZT-023, ZT-024, More preferably, the structure of the compound is selected from the group consisting of ZT-021, ZT-025, ZT-028, ZT-031, ZT-035, ZT-037, ZT-038, ZT-039, ZT-040, ZT-041, ZT-042, ZT-044, ZT-045, ZT-046, ZT-047, ZT-048, ZT-049 and ZT-050.

[0123] It has been unexpectedly shown that these compounds display high binding affinity to PSMA and are efficiently internalized.

[0124] Implementation Plan (C)

[0125] According to a preferred embodiment of the present invention, s and t are 0, and u and w are 1. According to this embodiment, the compound of the present invention therefore has the following structure.

[0126] In this case, Y2 is most preferably Therefore, the compound of the present invention more preferably has the following structure:

[0127] With such compounds, the interaction with PSMA can be optimized.With the compounds according to the invention, improved tumor-non-target tissue accumulation and tissue values ​​can be achieved and an improved distribution pattern can be obtained in non-target tissues.

[0128] Furthermore, the integrators administered according to the present invention allow for stable binding of radionuclides that cannot be used to target PSMA-expressing tumors to actually known tracers.

[0129] In the case of embodiment A, as described above and below,

[0130] If A is a chelating agent, it is selected from (1a), (1b) and (1c).

[0131] In the case of embodiment A, as described above and below, the integer r is preferably 0. More preferably, A is a chelating agent selected from

[0132] As preferred groups A above and below, the following groups are also mentioned:

[0133] The structures of preferred compounds according to this embodiment are selected from ZT-004, ZT-005, ZT-009, ZT-010, ZT-032, ZT-033, ZT-034, ZT-036 and ZT-043 (see Table 1A), with compound ZT-033 being more preferred.

[0134] The experimental results showed that these compounds displayed high binding affinity to PSMA and were efficiently internalized.

[0135] Implementation Plan (D)

[0136] According to another preferred embodiment of the present invention, A is not

[0137] Preferably, according to this embodiment, A is selected from:

[0138] Surprisingly, it has been found that compounds of the present invention comprising these chelator building blocks form stable complexes with lead and / or copper radionuclides and possess favorable tumor targeting properties. The new compounds offer the possibility of fine-tuning the pharmacokinetic profile depending on the respective radionuclide used. Furthermore, these compounds allow for stable labeling with specific radionuclides.

[0139] Copper-binding compounds:

[0140] In case the compound is used as a copper-binding PSMA ligand, as described above, A is preferably selected from

[0141] Surprisingly, it has been found that these compounds can form stable and effective complexes with copper radionuclides. Therefore, the present invention also relates to compounds as described above or below, or complexes as described above or below, wherein A is

[0142] wherein the radionuclide is a copper radionuclide, more preferably 64 Cu and / or 67 Cu.

[0143] For example, the following copper-binding compounds should be mentioned, ZT-001, ZT-002, ZT-003, ZT-004, ZT-005, ZT-011, ZT-012, ZT-013, ZT-014 and ZT-015.

[0144] More preferably, in case a compound is used together with Cu as the radionuclide, the compound is selected from the group consisting of ZT-003, ZT-005, ZT-011 and ZT-012.

[0145] The most preferred is ZT-003.

[0146] Surprisingly, it was discovered that with these compounds, two unmet needs for PSMA targeting can be met: a) highly specific enrichment in tumors with favorable biodistribution properties, in particular significantly improved renal clearance; and b) the ability to use isotopes of both copper and lead metals, with radioisotopes being preferred.

[0147] Lead Binding Compounds:

[0148] In case the compound is used with, for example, lead as a radionuclide, as described above, A is preferably selected from

[0149] It was surprisingly found that with this composition, advantageous complexes with lead can be formed which show advantageous PSMA targeting properties.

[0150] Therefore, the present invention also relates to compounds as described above or below, or complexes as described above or below, wherein A is

[0151] wherein the radionuclide is lead, more preferably 203 Pb or 212 Pb.

[0152] For example, the following lead-binding compounds should be mentioned, ZT-006, ZT-007, ZT-008, ZT-009 and ZT-010, more preferably, the compounds are ZT-008 and ZT-010. And wherein the radionuclide is preferably a lead radionuclide, more preferably 203 Pb or 212 Pb.

[0153] Surprisingly, these compounds were found to exhibit high stability in human serum for 48 hours and to inhibit PSMA with high affinity.

[0154] Pharmaceutical composition:

[0155] As mentioned above, the present invention also relates to pharmaceutical compositions comprising a compound as described above or below, or a complex as described above or below. It should be understood that the pharmaceutical composition comprises a therapeutically effective amount of the compound and / or complex, respectively. The composition may further comprise at least one organic or inorganic solid or liquid and / or at least one pharmaceutically acceptable carrier.

[0156] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication, and with a reasonable benefit / risk.

[0157] "Patient" includes animals such as humans, monkeys, cows, horses, cats or dogs. Animals can be mammals, such as non-primates and primates (e.g., monkeys and humans). In one embodiment, the patient is a human.

[0158] Typically, the compound of formula (I) or its pharmaceutical composition can be administered orally or by a parenteral route, usually by injection or infusion.

[0159] "Parenteral administration" refers to modes of administration other than enteral and topical administration, generally injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0160] The dosage of the compounds according to the invention (referring to the amount of carrier molecules) is determined by the physician based on patient-specific parameters such as age, weight, sex, severity of the disease, etc. The dosage depends on the mode of administration: Typically, compounds for molecular imaging purposes are administered in tracer amounts, i.e., by using a total dose of 1 to 100 nanomoles per patient, with a preferred dose of 5 to 20 nanomoles per patient. For therapeutic applications (internal radiotherapy), higher doses are required to achieve the amount of radiation absorbed dose (gray) required to achieve a therapeutic effect. For therapeutic applications, the dosage is preferably 0.1 to 10 mmol / kg body weight, preferably 0.2 to 5 mmol / kg body weight, and most preferably 0.5 to 2 mmol / kg body weight. Depending on the type of administration, the drug is appropriately formulated, for example in the form of a solution or suspension, simple tablets or dragees, hard or soft gelatin capsules, suppositories, ovules, or an injectable formulation, which is prepared according to conventional galenic methods.

[0161] The compounds according to the invention can be formulated, where appropriate, with other active substances and excipients and carriers customary in pharmaceutical compositions, for example, depending on the preparation to be prepared, talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous and non-aqueous vehicles, fatty bodies of animal or vegetable origin, paraffin derivatives, glycols (especially polyethylene glycol), various plasticizers, dispersants or emulsifiers, pharmaceutically compatible gases (e.g. air, oxygen, carbon dioxide, etc.), preservatives.

[0162] To prepare liquid preparations, additives such as sodium chloride solution, ethanol, sorbitol, glycerol, olive oil, almond oil, propylene glycol or ethylene glycol may be used.

[0163] When solutions for infusion or injection are used, they are preferably aqueous solutions or suspensions, which may be prepared before use, for example from lyophilized formulations containing the active substance itself or with a carrier such as mannitol, lactose, glucose, albumin, etc. The ready-made solution is sterilized and, where appropriate, mixed with an excipient, for example, a preservative, stabilizer, emulsifier, solubilizer, buffer, and / or salt for regulating osmotic pressure. Sterilization can be achieved by aseptic filtration using a filter with a small pore size, in which case the composition can be lyophilized where appropriate. A small amount of antibiotic can also be added to ensure maintenance of the sterile state.

[0164] As used herein, the phrases "effective amount" or "therapeutically effective amount" refer to an amount of a compound, material, or composition comprising a compound of the invention, or other active ingredient, that is effective to produce some desired therapeutic effect in at least one cell subpopulation of a patient at a reasonable benefit / risk-ratio applicable to any medical treatment. A therapeutically effective amount with respect to the compositions of the invention refers to an amount of the therapeutic agent alone or in combination with other therapies that provides a therapeutic benefit in treating or preventing a disease. When used in conjunction with a compound of the invention, the term can include an amount that improves the overall treatment, reduces or avoids the symptoms or causes of a disease, or enhances the therapeutic efficacy of or synergizes with other therapeutic agents.

[0165] Furthermore, the present invention also relates to the compounds as described above or below, or the complexes as described above or below, or the pharmaceutical compositions, for treating, improving or preventing cell proliferative diseases or disorders, in particular prostate cancer and / or its metastases.

[0166] Furthermore, the present invention relates to a compound as described above or below, or a complex as described above or below, or a pharmaceutical composition for use in diagnosis.

[0167] Furthermore, the present invention relates to a compound as described above or below, or a pharmaceutical composition as described above or below, for use in the diagnosis of cancer, in particular prostate cancer and / or its metastases.

[0168] As used herein, the term "treatment" is intended to also include diagnosis, prophylaxis, prevention, therapy and cure.

[0169] The term "prevent" refers to preventing the onset, recurrence, or spread of a disease in a patient as a result of the administration of a prophylactic or therapeutic agent.

[0170] Preferably, the complex as described above or below, or the complex as described above or below, or pharmaceutical composition is used for in vivo imaging and radiotherapy. Suitable pharmaceutical compositions may contain radioactive imaging agents, or radiotherapeutic agents having a radionuclide as an element, i.e., radioiodine, or a radioactive metal chelate complex of a compound of formula (I) sufficient for imaging, and a pharmaceutically acceptable radioactive carrier. The radioactive carrier should be suitable for injection or aspiration, such as human serum albumin; aqueous buffer solutions, such as tris (hydroxymethyl) -aminomethane (and its salts), phosphates, citrates, bicarbonates, etc.; sterile water saline; and counterion solutions containing chloride and / or bicarbonate or normal plasma cations such as calcium, potassium, sodium and magnesium.

[0171] The concentration of the imaging agent or therapeutic agent in the radioactive carrier should be sufficient to provide a satisfactory image. For example, when using an aqueous solution, the dose is 0.1 mCi to 300 mCi. This wide range is due to the fact that α-emitting isotopes have very strong cytotoxic effects. Therefore, in the case of α-labeled PSMA-617, a low dose, such as 0.135 mCi per treatment cycle, is used. 225 Ac is used. For β-emitting radioisotopes such as 177 Lu, typically a dose of up to 216 millicuries is administered during a treatment cycle. These doses are determined by the skilled practitioner. However, the actual dose administered to the patient for imaging or therapeutic purposes is determined by the treating physician. The imaging or therapeutic agent should be administered to maintain its presence in the patient for approximately 1 hour to 10 days, although longer or shorter periods are acceptable. Therefore, convenient ampoules containing 1 mL to 10 mL of aqueous solution can be prepared.

[0172] Imaging can be performed in the normal manner, for example, by injecting a sufficient amount of the imaging composition to provide adequate imaging, followed by scanning with a suitable imaging machine or scanning machine, such as a tomography scanner or gamma camera. In certain embodiments, a method for imaging an area within a patient comprises the steps of: (i) administering to the patient a diagnostically effective amount of a compound complexed with a radionuclide; exposing the area of ​​the patient to a scanning device; and (ii) obtaining an image of the area of ​​the patient. In certain embodiments, the area imaged is the head or chest. In other embodiments, the compound or complex of formula (I) targets the PSMA protein.

[0173] Thus, in some embodiments, a method of imaging tissue, such as spleen tissue, kidney tissue, or PSMA-expressing tumor tissue, is provided, the method comprising contacting the tissue with a complex synthesized by contacting a radionuclide and a compound of formula (I).

[0174] The amount of a compound of the invention or a formulation containing a complex of the compound, or a salt, solvate, stereoisomer, or tautomer thereof, administered to a patient depends on several physiological factors, which are known to the physician and include the nature of the imaging to be performed, the target tissue to be imaged or treated, and the weight and medical history of the patient to be imaged or treated with the radiopharmaceutical.

[0175] According to another aspect, the present invention provides a method of treating a patient suffering from a cell proliferative disease or condition by administering to the patient a therapeutically effective amount of a complex as described above. In particular, the cell proliferative disease or condition treated or imaged using the compounds, pharmaceutical compositions or radiopharmaceuticals according to the present invention is cancer, for example, prostate cancer and / or prostate cancer metastases in, for example, the lung, liver, kidney, bone, brain, spinal cord, bladder, etc.

[0176] The compounds of the present invention can be synthesized, for example, in solution and in solid phase using, for example, standard peptide coupling procedures, such as Fmoc solid phase coupling procedures. Preferably, the chelating agent is coupled to the remainder of the molecule in the final coupling step, followed by a deprotection step and, in the case of solid phase chemistry, cleavage from the resin. However, other synthetic procedures are possible and are known to those skilled in the art. The preferred synthesis of the compounds of the present invention is described in detail in the Examples section.

[0177] For example, particularly preferred compounds of the present invention are shown in Table 1:

[0178] Table 1 shows the preferred compounds

[0179] Beneficial effects of the present invention:

[0180] The present inventors have discovered novel compounds that are useful and advantageous radiopharmaceuticals and can be used in nuclear medicine as tracers, imaging agents and for the treatment of various disease states in PSMA-expressing cancers, particularly prostate cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0181] Figure 1 shows the PET imaging of ZT-042.

[0182] Figure 2 shows the PET imaging of ZT-046.

[0183] FIG3 is a PET image of ZT-047.

[0184] Figure 4 shows the PET imaging of ZT-035.

[0185] FIG5 is a PET image of ZT-039. DETAILED DESCRIPTION

[0186] The present invention will be further described below with reference to the following examples. The following description is merely a preferred embodiment of the present invention and does not limit the present invention in any other form. Any person skilled in the art may utilize the above disclosed technical content to make equivalent embodiments with equivalent variations. Any modification or equivalent variation of the following examples made in accordance with the technical essence of the present invention without departing from the content of the present invention shall fall within the scope of protection of the present invention.

[0187] Example 1:

[0188] 1. Materials and Methods

[0189] All commercially available chemicals were of analytical grade and used without further purification. The in vitro experiments were performed three times, and at least three independent sets of data were obtained for each experiment.

[0190] 2. Synthesis of Chelating Agent

[0191] The chelating agent moiety was synthesized in high yield and characterized by LC-MS. The synthesis of the chelating agent bifunctional macrocyclic cycloamine analogue 4-[(1,4,8,11-tetraazacyclotetradecylamine-1-yl)-methyl]benzoic acid was described by Studer and Kaden (Studer M, and Kadan, T A One-step synthesis of mono-N-substituted azamacrocycles with acarboxylic group in the side-chain and their complexes with Cu 2+ and Ni 2+.Helvetica.1986;69:2081-2086), and cross-bridged glutaric acid was reported by Boswell et al. (Boswell CA, Regino CA, Baiduo KE et al. Chelating agent 4-carboxymethyl-11-(1,3-dicarboxypropyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-, Synthesis of a cross-bridged cyclam derivative for peptide conjugation and 64 Cu radiolabeling. Bioconjug Chem. 2008; 19: 1476-1484).

[0192] I. General Procedure: Synthesis of New PSMA Ligands

[0193] The PSMA binding motif was prepared by solid-phase synthesis on 2-chlorotrityl resin (2CT-resin). The preparation process is shown in the following flow chart:

[0194] Fmoc-Lys(Alloc)-OH was fixed on an equimolar amount of 2-chlorotrityl resin and N,N′-sulfonyldiimidazole was used to generate aminosulfonyl imidazole (2) of the glutamine moiety. Benzyloxycarbonyl protected lysine fixed on 2-chlorotrityl resin was added and the reaction was stirred for 20 hours to produce compound (3). The resin was filtered off and the benzyloxycarbonyl protecting group was cleaved to obtain (4). In order to obtain compounds ZT-001, ZT-016, ZT-020, ZT-023, ZT-026 and ZT-029, the corresponding chelating agent or 18 The F labeling group is coupled to the intermediate. 18 The PSMA coupled with the F labeling group is cleaved from the resin. Alternatively, Fmoc-2-indolylalanine is coupled to obtain (5). To obtain compounds ZT-002, ZT-004, ZT-007, ZT-009, ZT-021, ZT-024, ZT-027, and ZT-030, the corresponding chelating agent or 18 The F labeling group is coupled to the intermediate. Subsequently, the chelating agent or 18 Alternatively, trans-4-(Fmoc-aminomethyl)cyclohexanecarboxylic acid is coupled to obtain (6), and the corresponding chelating agent or 18F labeling groups were coupled to the compounds to obtain compounds ZT-003, ZT-005, ZT-008, ZT-010, ZT-011, ZT-012, ZT-013, ZT-014, ZT-015, ZT-017, ZT-018, ZT-019, ZT-022, ZT-025, ZT-028 and ZT-031. Subsequently, the residues were cleaved from the resin. 18 The F-labeled group was coupled to PSMA. The structure was confirmed by HPLC and MS-LC. The substance was separated by preparative HPLC using a water-acetonitrile gradient containing trifluoroacetic acid. To this end, the compound was purified using a gradient of acetonitrile in water with a volume fraction of 20% to 50% for 15 minutes. The purified compound was analyzed by analytical HPLC, wherein the compound was treated with acetonitrile in water with a volume fraction of 1‰ trifluoroacetic acid (HPLC gradient elution from 0% to 100% by volume of acetonitrile) for 5 minutes, using a 100×3 mm Monolith RP HPLC column and LC / MS analysis. The product fractions were combined and lyophilized.

[0195] The synthesis of ZT-034-ZT-039, ZT-049 and ZT-050 is shown in the following flow chart:

[0196] Fmoc-Lys(Alloc)-OH was fixed on an equimolar amount of 2-chlorotrityl resin. Then, triphosgene was used to generate the isocyanate (7) of the glutamyl moiety. Benzyloxycarbonyl protected lysine fixed on the 2-chlorotrityl resin was added and the reaction was stirred carefully for 16 hours to produce compound (8). The resin was filtered off and the allyloxycarbonyl protecting group was cleaved to obtain (9). Fmoc-2-naphthylalanine was coupled to obtain (10). Subsequently, trans-4-(Fmoc-aminomethyl)cyclohexanecarboxylic acid was coupled to obtain (11), and the corresponding 18 The F labeling group was coupled to the compound to obtain compounds ZT-034, ZT-035, ZT-036, ZT-037, ZT-038, ZT-039, ZT-049 and ZT-050. 18 The F-labeled group was coupled to PSMA. The structure was confirmed by HPLC and MS-LC. The substance was separated by preparative HPLC using a water-acetonitrile gradient containing trifluoroacetic acid. To this end, the compound was purified using a 20% to 50% acetonitrile in water gradient over 15 minutes. The purified compound was analyzed by analytical HPLC, where the compound was treated with acetonitrile in water (0% to 100%) containing trifluoroacetic acid for 5 minutes, using a 100×3 mm Monolith RPHPLC column and LC / MS analysis. The products were combined and stored in the freezer.

[0197] II. Ligands for Copper Isotope Imaging and Therapy

[0198] Description of ZT-001

[0199] The product was obtained by stirring the resin (compound 4) with 1.5 equivalents of CTPA-NHS-ester (4-[(1,4,8,11-tetraazacyclotetradec-1-yl)-methyl]benzoic acid) and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 1.68 minutes; ESI-MS (m / z) [M+H]: 672.34 [M+H] + .

[0200] Chemical structure of the chelating agent CTPA-NHS-ester, used in the synthesis of compounds ZT-001, ZT-002, and ZT-003.

[0201] Description of ZT-002

[0202] The product was obtained by stirring the resin (Compound 5) with 1.5 equivalents of CTPA-NHS-ester (4-[(1,4,8,11-tetraazacyclotetradec-1-yl)-methyl]benzoic acid) and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 2.39 minutes; ESI-MS (m / z): 858.42

[0203] [M+H] + .

[0204] Description of ZT-003

[0205] The product was obtained by stirring the resin (Compound 6) with 1.5 equivalents of CTPA-NHS-ester (4-[(1,4,8,11-tetraazacyclotetradec-1-yl)-methyl]benzoic acid) and 10 equivalents of DIPEA in 500 μL of dimethylformamide (DMF). The compound was purified as described above and the final product was analyzed by HPLC. HPLC retention time: 2.50 minutes; ESI-MS (m / z): 997.52 [M+H] + .

[0206] Description of ZT-004

[0207] The resin (compound 5) was prepared by mixing it with 1.5 equivalents of cross-linked TE2A chelator, 0.98×n 螯 合剂The product was obtained by stirring HBTU and 10 equivalents of DIPEA. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 2.38 minutes; ESI-MS (m / z): 938.45 [M+H] + .

[0208] Chemical structure of the chelating agent 8-carboxymethyl-crosslinking bridge-TE2A, used in the synthesis of compounds ZT-004 and ZT-005.

[0209] Description of ZT-005

[0210] The resin (compound 6) was prepared by mixing it with 1.5 equivalents of cross-linked TE2A chelator, 0.98×n 螯 合剂 The product was obtained by stirring HBTU and 10 equivalents of DIPEA. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 2.55 minutes; ESI-MS (m / z): 1077.62 [M+H] + .

[0211] Description of ZT-011

[0212] The product was obtained by stirring the resin (compound 6) with 1.5 equivalents of the cross-linked CTPA chelator and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 2.72 minutes; ESI-MS (m / z): 1023.56 [M+H] + .

[0213] The chemical structure of the chelating agent cross-linking bridge - CTPA. The NHS structure in the chelating agent cross-linking bridge - CTPA plays a catalytic role. NHS will fall off during the reaction and is used to synthesize the ZT-011 compound.

[0214] Description of ZT-012

[0215] The product was obtained by stirring the resin (compound 6) with 1.5 equivalents of 8-carboxymethyl-CTPA chelating agent and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 2.54 minutes; ESI-MS (m / z): 1055.55 [M+H] + .

[0216] The chemical structure of the chelating agent 8-carboxymethyl-CTPA. The NHS structure in 8-carboxymethyl-CTPA plays a catalytic role. NHS will fall off during the reaction and is used to synthesize the ZT-012 compound.

[0217] Description of ZT-013

[0218] The product was obtained by stirring the resin (compound 6) with 1.5 equivalents of 8-carboxymethyl-cross-linked-CTPA chelator and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 2.60 minutes; ESI-MS (m / z): 1081.56 [M+H] + .

[0219] The chemical structure of the chelating agent 8-carboxymethyl-cross-linked bridge-CTPA. The NHS structure in 8-carboxymethyl-cross-linked bridge-CTPA plays a catalytic role. NHS will fall off during the reaction and is used to synthesize the ZT-013 compound.

[0220] Description of ZT-014

[0221] The product was obtained by stirring the resin (Compound 6) with 1.5 equivalents of 8,11-bis(carboxymethyl)-CTPA chelator [CPTA = 4-[(1,4,8,11-tetraazacyclotetradec-1-yl)methyl]benzoic acid] and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC retention time: 2.60 minutes; ESI-MS (m / z): 1113.55 [M+H] + .

[0222] The chemical structure of the chelating agent 8,11-bis(carboxymethyl)-CTPA. The NHS structure in 8,11-bis(carboxymethyl)-CTPA plays a catalytic role. NHS will fall off during the reaction and is used to synthesize the ZT-014 compound.

[0223] Description of ZT-015

[0224] The product was obtained by stirring the resin (compound 6) with 1.5 equivalents of 8,11-bis(carboxymethyl)-CTPA chelator and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC retention time: 2.53 minutes; ESI-MS (m / z): 1171.56 [M+H] + .

[0225] The chemical structure of the chelating agent 4,8,11-tris(carboxymethyl)-CTPA. The NHS structure in 4,8,11-tris(carboxymethyl)-CTPA plays a catalytic role. NHS will fall off during the reaction and is used to synthesize the ZT-015 compound.

[0226] III. Lead isotopes for alpha therapy ( 203 Pb / 212 PSMA ligands of Pb)

[0227] Description of ZT-006

[0228] The product was obtained by stirring the resin (Compound 5) with 1.5 equivalents of p-SCN-Bn-TCMC chelating agent [TCMC = 1,4,7,10-tetraaza-1,4,7,10-tetrakis(2-carbamoylmethyl)cyclododecane] and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC retention time: 2.41 minutes; ESI-MS (m / z): 903.49 [M+H]. + .

[0229] Chemical structure of the chelating agent p-SCN-Bn-TCMC, used to synthesize compounds ZT-006, ZT-007, and ZT-008.

[0230] Description of ZT-008

[0231] The product was obtained by stirring the resin (compound 6) with 1.5 equivalents of p-SCN-Bn-TCMC chelating agent and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. ESI-MS (m / z): 1228.24 [M+H] + .

[0232] Description of ZT-009

[0233] The resin (compound 5) was mixed with 1.5 equivalents of 2-(4,7,10-tris(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetic acid, a monocarboxylic acid ester derivative of the chelating agent 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetamide (DO3AM), 0.98×n 螯合剂 The product was obtained by stirring HBTU and 10 equivalents of DIPEA. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 2.07 minutes; ESI-MS (m / z): 925.23 [M+H]+ .

[0234] Chemical structure of chelating agents

[0235] 2-(4,7,10-tris(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetic acid, a monocarboxylate derivative of the chelating agent 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetamide (DO3AM), is used to synthesize compounds ZT-009 and ZT-010.

[0236] Description of ZT-010

[0237] The resin (compound 6) was prepared by mixing it with 1.5 equivalents of DO3AM chelating agent, 0.98×n 螯合剂 The product was obtained by stirring HBTU and 10 equivalents of DIPEA. The compound was purified as described above and the final product was analyzed by HPIC. HPLC-retention time: 2.21 minutes; ESI-MS (m / z): 1064.35 [M+H] + .

[0238] IV. Chelating Agent Spacer Moieties that Enhance the Pharmacokinetic Properties of PSMA-617

[0239] Description of ZT-016

[0240] The product was obtained by stirring the resin (compound 4) with 1.5 equivalents of p-NHS-Bn-DOTA chelating agent and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 1.47 minutes; ESI-MS (m / z): 818.32 [M+H] + .

[0241] The chemical structure of p-NHIS ester-Bn-DOTA. The NHS structure in p-NHIS ester-Bn-DOTA plays a catalytic role. NHS will fall off during the reaction and is used to synthesize the chelating agents ZT-016 and ZT-017.

[0242] Description of ZT-017

[0243] The product was obtained by stirring the resin (compound 6) with 1.5 equivalents of p-NHS-Bn-DOTA integrator and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 2.36 minutes; ESI-MS (m / z): 1143.45 [M+H]+ .

[0244] Description of ZT-018

[0245] The product was obtained by stirring the resin (compound 6) with 1.5 equivalents of p-SCN-Bn-DOTA chelating agent and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 2.49 minutes; ESI-MS (m / z): 1174.49 [M+H] + .

[0246] Chemical structure of the chelating agent p-SCN-Bn-DOTA, used in the synthesis of the compound ZT-018.

[0247] Description of ZT-019

[0248] The product was obtained by stirring the resin (compound 6) with 1.5 equivalents of p-NCS-benzyl-DOTA-GA chelator and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC retention time: 2.50 minutes; ESI-MS (m / z): 1303.42 [M+H] + .

[0249] Chemical structure of the chelating agent p-NCS-benzyl-DOTA-GA, used in the synthesis of the compound ZT-019.

[0250] Synthesis of radiolabeled complexes

[0251] V.1 64 Radiochemical Synthesis of Cu-PSMA-Derivatives

[0252] The conjugate (1 mM in water, 5 μL, 5 nmol) was added to 400 μL of sodium acetate buffer (0.4 M in water, pH 5.0), 10 μL of an aqueous solution containing 20% ​​by mass of ascorbic acid, and 282 μL of [ 64 [Cu] CuCl2 in a mixture of 0.1 M HCl (200 MBq). The mixture was heated at 95°C for 5 minutes. The marker was controlled by radio-HPLC (0% to 100% aqueous MeCN gradient over 5 minutes on a Monolith column) at a flow rate of 2 mL / min and a retention time of 2.3 minutes.

[0253] This labeling results in a radiolabeling yield of >98% within 10 minutes. 64The specific radioactivity of Cu-PSMA-ZT-003 is about 40 megabecquerels / nanomol. 67 Cu marker.

[0254] V.2 203 / 212 Radiochemical Synthesis of Pb-PSMA-Ligand

[0255] 80 nanomoles of the conjugate (1 mM in water, 80 μL, 80 nanomoles) were added to 400 μl of sodium acetate buffer (0.4 M in water, pH 5.0), 10 μl of an aqueous solution containing 20% ​​by mass of ascorbic acid, and 140 μl of 203 The mixture was heated at 95°C for 5 minutes in a Pb-chloride solution (0.04 M HCl) with a specific radioactivity of approximately 102.6 TBq (Lantheus Medical Imaging, USA). The labeling was controlled by radio-HPLC.

[0256] V.3 68 Radiochemical Synthesis of Ga-PSMA-ZT-017 (ZT-016, ZT-018, ZT-019)

[0257] from 68 Elution in a Ge / Ga generator (iThemba LABS, South Africa) 68 Ga. The conjugate (1 mM in DMSO, 20 μL, 20 nmol) was added to 320 μL of sodium acetate buffer (0.4 M in water, pH 4 to 5), 10 μL of ascorbic acid (20% in water) and 400 MBq 68 The mixture was heated at 95° C. for 5 minutes and then purified by radio-HPLC (0% to 100% MeCN over 5 minutes, Monolith column) at a flow rate of 2 ml / min and a retention time of 2.4 minutes.

[0258] V.4 177 The radiochemical synthesis of Lu-PSMA-ZT-017 (ZT-016, ZT-018, ZT-019) is 177 Lu labeling, about 20 MBq was mixed with 200 μL of 0.4 M sodium acetate buffer (pH = 5) containing Chelex. 2 μL of 1 mM compound solution in 10% (v / v) DMSO aqueous solution, 2 μL of saturated ascorbic acid solution and 40 μL of [ 177 The Lu]LuCl3 solutions were mixed and heated to 95°C for 10 minutes. The labeling was checked by radio-HPLC (0% to 100% ACN in water over 5 minutes, Monolith column).

[0259] VI. Used for 18 F ligands for imaging and therapy

[0260] 18 The F-labeled ligand 4-(difluoro(18F)methyl)benzoic acid was used to synthesize compounds ZT-020, ZT-021, ZT-022, ZT-035, and ZT-042.

[0261] Description of ZT-020

[0262] The product was obtained by stirring the resin (compound 4) with 1.5 equivalents of 4-(difluoro(18-fluoro)methyl)benzoic acid, 1.5 equivalents of HATU, and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 15.60 minutes; ESI-MS (m / z): 527.13 [M+H] + .

[0263] Description of ZT-021

[0264] The product was obtained by stirring the resin (compound 5) with 1.5 equivalents of 4-(difluoro(18-fluoro)methyl)benzoic acid, 1.5 equivalents of HATU, and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 18.40 minutes; ESI-MS (m / z): 713.23 [M+H] + .

[0265] Description of ZT-022

[0266] The product was obtained by stirring the resin (Compound 6) with 1.5 equivalents of 4-(difluoro(18-fluoro)methyl)benzoic acid, 1.5 equivalents of HATU, and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 19.30 minutes; ESI-MS (m / z): 852.34 [M+H] + .

[0267] Description of ZT-035

[0268] The product was obtained by stirring the resin (Compound 11) with 1.5 equivalents of 4-(difluoro(18-fluoro)methyl)benzoic acid, 1.5 equivalents of HATU, and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 16.40 minutes; ESI-MS (m / z): 827.43 [M+H] + .

[0269] Description of ZT-042

[0270] The product was obtained by stirring the resin (Compound 9) with 1.5 equivalents of 4-(difluoro(18-fluoro)methyl)benzoic acid, 1.5 equivalents of HATU, and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 13.20 minutes; ESI-MS (m / z): 491.24 [M+H] + .

[0271] 18 The F-labeled ligand trifluoromethylphenyl-Tz-d-TCObenzoic acid (shown in the figure below) was used to synthesize compounds ZT-023, ZT-024, ZT-025, ZT-037, and ZT-044.

[0272] Description of ZT-023

[0273] The product was obtained by stirring the resin (compound 4) with 1.5 equivalents of trifluoromethylphenyl-Tz-d-TCObenzoic acid (n=1), 1.5 equivalents of HATU, and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 13.20 minutes; ESI-MS (m / z): 883.29 [M+H] + .

[0274] Description of ZT-024

[0275] The product was obtained by stirring the resin (compound 5) with 1.5 equivalents of trifluoromethylphenyl-Tz-d-TCObenzoic acid (n=1), 1.5 equivalents of HATU, and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 16.10 minutes; ESI-MS (m / z): 1069.37 [M+H] + .

[0276] Description of ZT-025

[0277] The product was obtained by stirring the resin (Compound 6) with 1.5 equivalents of trifluoromethylphenyl-Tz-d-TCObenzoic acid (n=3), 1.5 equivalents of HATU, and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 17.20 minutes; ESI-MS (m / z): 1282.45 [M+H] + .

[0278] Description of ZT-037

[0279] The product was obtained by stirring the resin (Compound 11) with 1.5 equivalents of trifluoromethylphenyl-Tz-d-TCObenzoic acid (n=1), 1.5 equivalents of HATU, and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 17.80 minutes; ESI-MS (m / z): 1183.56 [M+H] + .

[0280] Description of ZT-044

[0281] The product was obtained by stirring the resin (Compound 9) with 1.5 equivalents of trifluoromethylphenyl-Tz-d-TCObenzoic acid, 1.5 equivalents of HATU, and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 16.50 minutes; ESI-MS (m / z): 847.40 [M+H] + .

[0282] 18 The F-labeled ligand methyl-Tz-s-TCObenzoic acid (see the figure below) was used to synthesize compounds ZT-026, ZT-027, ZT-028, ZT-038, and ZT-045.

[0283] Description of ZT-026

[0284] The product was obtained by stirring the resin (compound 4) with 1.5 equivalents of methyl-Tz-s-TCObenzoic acid, 1.5 equivalents of HATU, and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 14.40 minutes; ESI-MS (m / z): 721.31 [M+H] + .

[0285] Description of ZT-027

[0286] The product was obtained by stirring the resin (compound 5) with 1.5 equivalents of methyl-Tz-s-TCObenzoic acid, 1.5 equivalents of HATU, and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 15.80 minutes; ESI-MS (m / z): 907.42 [M+H] + .

[0287] Description of ZT-028

[0288] The product was obtained by stirring the resin (compound 6) with 1.5 equivalents of methyl-Tz-s-TCObenzoic acid, 1.5 equivalents of HATU, and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 18.10 minutes; ESI-MS (m / z): 1046.36 [M+H] + .

[0289] Description of ZT-038

[0290] The product was obtained by stirring the resin (Compound 11) with 1.5 equivalents of methyl-Tz-s-TCObenzoic acid, 1.5 equivalents of HATU, and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 17.90 minutes; ESI-MS (m / z): 1021.44 [M+H] + .

[0291] Description of ZT-045

[0292] The product was obtained by stirring the resin (Compound 9) with 1.5 equivalents of methyl-Tz-s-TCObenzoic acid, 1.5 equivalents of HATU, and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 16.70 minutes; ESI-MS (m / z): 685.45 [M+H] + .

[0293] 18 The F-labeled ligand methyl-Tz-TCObenzoic acid (see the figure below) was used to synthesize compounds ZT-029, ZT-030, ZT-031, ZT-039, and ZT-046.

[0294] Description of ZT-029

[0295] The product was obtained by stirring the resin (compound 4) with 1.5 equivalents of methyl-Tz-TCObenzoic acid (n=3), 1.5 equivalents of HATU, and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 13.70 minutes; ESI-MS (m / z): 783.34 [M+H] + .

[0296] Description of ZT-030

[0297] The product was obtained by stirring the resin (compound 5) with 1.5 equivalents of methyl-Tz-TCObenzoic acid (n=3), 1.5 equivalents of HATU, and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 16.20 minutes; ESI-MS (m / z): 969.35 [M+H] + .

[0298] Description of ZT-031

[0299] The product was obtained by stirring the resin (compound 6) with 1.5 equivalents of methyl-Tz-TCObenzoic acid (n=3), 1.5 equivalents of HATU, and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 17.50 minutes; ESI-MS (m / z): 1108.54 [M+H] + .

[0300] Description of ZT-039

[0301] The product was obtained by stirring the resin (Compound 11) with 1.5 equivalents of methyl-Tz-TCObenzoic acid (n=1), 1.5 equivalents of HATU, and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 18.10 minutes; ESI-MS (m / z): 995.32 [M+H] + .

[0302] Description of ZT-046

[0303] The product was obtained by stirring the resin (Compound 9) with 1.5 equivalents of methyl-Tz-TCObenzoic acid (n=1), 1.5 equivalents of HATU, and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 17.30 minutes; ESI-MS (m / z): 659.35 [M+H] + .

[0304] 131 I-labeled ligand methyl-Tz-TCObenzoic acid, used to synthesize the compound ZT-049

[0305] Description of ZT-049

[0306] The product was obtained by stirring the resin (Compound 11) with 1.5 equivalents of methyl-Tz-TCObenzoic acid, 1.5 equivalents of HATU, and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 17.30 minutes; ESI-MS (m / z): 1108.40 [M+H] + .

[0307] 211 At-labeled ligand methyl-Tz-TCObenzoic acid, used to synthesize ZT-50 compounds

[0308] Description of ZT-050

[0309] The product was obtained by stirring the resin (Compound 11) with 1.5 equivalents of methyl-Tz-TCObenzoic acid, 1.5 equivalents of HATU, and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 16.30 minutes; ESI-MS (m / z): 1188.48 [M+H] + .

[0310] 18 F-labeled ligand HEPES was used to synthesize compounds ZT-032, ZT-033, ZT-034, and ZT-036.

[0311] Description of ZT-032

[0312] The product was obtained by stirring the resin (compound 4) with 1.5 equivalents of HEPES, 1.5 equivalents of HATU, and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 14.70 minutes; ESI-MS (m / z): 577.23 [M+H] + .

[0313] Description of ZT-033

[0314] The product was obtained by stirring the resin (compound 5) with 1.5 equivalents of HEPES, 1.5 equivalents of HATU, and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 15.60 minutes; ESI-MS (m / z): 763.35 [M+H] + .

[0315] Description of ZT-034

[0316] The product was obtained by stirring the resin (Compound 6) with 1.5 equivalents of HEPES, 1.5 equivalents of HATU, and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 17.40 minutes; ESI-MS (m / z): 874.52 [M+H] + .

[0317] Description of ZT-036

[0318] The product was obtained by stirring the resin (Compound 11) with 1.5 equivalents of HEPES, 1.5 equivalents of HATU, and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 18.30 minutes; ESI-MS (m / z): 849.03 [M+H] + .

[0319] Description of ZT-043

[0320] The product was obtained by stirring the resin (Compound 9) with 1.5 equivalents of HEPES, 1.5 equivalents of HATU, and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 15.10 minutes; ESI-MS (m / z): 513.22 [M+H] + .

[0321] 18F-labeled ligand methyl-Tz-oxo-TCObenzoic acid was used to synthesize the compound ZT-047.

[0322] Description of ZT-047

[0323] The product was obtained by stirring the resin (Compound 9) with 1.5 equivalents of HEPES, 1.5 equivalents of HATU, and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 17.60 minutes; ESI-MS (m / z): 805.43 [M+H] + .

[0324] 18 F-labeled ligand methyl-Tz-aza-TCObenzoic acid was used to synthesize the compound ZT-048.

[0325] Description of ZT-048

[0326] The product was obtained by stirring the resin (Compound 9) with 1.5 equivalents of HEPES, 1.5 equivalents of HATU, and 10 equivalents of DIPEA in 500 μL of DMF. The compound was purified as described above and the final product was analyzed by HPLC. HPLC-retention time: 18.10 minutes; ESI-MS (m / z): 830.56 [M+H] + .

[0327] VI. In vitro competitive binding assay and internalization rate

[0328] MultiScreen was washed with 100 μl PBS containing 1% BSA per well at room temperature. HTS -DV filter plate was incubated for 30 minutes. After removing the PBS / BSA solution, 1×10 5 C4-2 cells. Using 0.75 nM 68 Ga-labeled PSMA-HBED-CC dimer ( 68 Ga-PSMA-10)( M, Bauder-Wüst U, Leotta K, et al. A dimerized urea-based inhibitor of the prostate-specific membrane antigen for 68Ga-PET imaging of prostate cancer. EJNMMI research. 2012; 2: 23-23.) was used as a standard to determine the inhibitory potency of the synthesized compounds. All unlabeled compounds were dissolved in Opti-MEM at the following concentrations in a volume of 300 μL: 0nM, 0.5nM, 1nM, 2.5nM, 5nM, 10nM, 25nM, 50nM, 100nM, 500nM, 1000nM and 5000nM. Then, 3 μL of radiolabeled compound was added. 50 μL of this mixture was taken to obtain a 0.75nM concentration of radiolabeled ligand. After incubation at 37°C for 45 minutes, the cells were washed twice with PBS on a multi-screen vacuum manifold (Millipore, Billerica, MA) and the cell-bound radioactivity was measured using a gamma counter (Packard Cobra II, GMI, MN, USA). 68 Ga-labeled PSMA-HBED-CC dimer (e.g., IPSMA-11) was used as a reference to determine the inhibitory potency. K was calculated using a nonlinear regression algorithm (Graph Pad Prism 5.01 software). i The experiment was performed four times. For determination of specific internalization rate, 24-well plates were incubated with 0.1% poly-L-lysine in PBS for 20 min at room temperature and washed once with PBS. In the next step, 1 × 10 5 1 mL of RPMI medium was added to 100 C4-2 cells and cultured overnight. The conditions for each compound during the experiment were: incubation at 37°C or 4°C with or without receptor blocking by 2-(phosphonomethyl)glutaric acid (2-PMPA; Axxora) at a final concentration of 500 μM. Then, the cells were incubated with 250 μl of 30 nM labeled compound solution. The plate was incubated in a 37°C water bath or on ice at 4°C for 45 minutes. Then, the cells were washed three times with 1 mL of ice-cold PBS and incubated with glycine (50 mM in HCl, pH 2.8) for 5 minutes. After an additional washing step with 1 mL of ice-cold PBS, the cells were lysed with 0.5 mL of 0.3 M NaOH, collected and the radioactivity was measured in a gamma counter for 1 minute. The corresponding uptake under blocking conditions was subtracted to determine the amount of radioactivity bound to 10° cells (% IA / 10 6 Specific cellular uptake was determined as a percentage of the initial added radioactivity per 10 cells. All experiments were performed three times. The results are shown in Table 2. i The assay showed nanomolar binding affinity of the synthetic ligand to PSMA.

[0329] Table 2: Compound Ki and cell surface binding and internalization data

[0330] Data are mean ± SD (n = 3), nd = not determined

[0331] VII. In vivo PET imaging studies

[0332] Tumor-bearing nude mice were placed in an anesthesia box and pre-anesthetized with a 3% volume fraction of isoflurane-oxygen mixture for 5-10 minutes. The mice were placed on the scanning bed, their limbs were fixed with medical tape, and anesthesia was maintained with isoflurane-oxygen mixture. The position was adjusted so that it was in the center of the micro-PET scanner's field of view. A 1mL insulin syringe was used to draw up the saline-diluted 18 The radioactivity of the F-labeled target probe solution was measured and the measurement time was recorded. Following tail vein injection into tumor-bearing mice, the injection time was recorded. The residual radioactivity in the insulin syringe was then measured and the measurement time was recorded. Static scans were performed for 10 minutes at 30, 90, and 180 minutes after probe injection, using a 3D acquisition mode. Image reconstruction was performed using the 3D ordered subset expectation maximization (3D OSEM) algorithm. The results are shown in Figures 1, 2, 3, 4, and 5.

Claims

1. A compound represented by general formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs, in: Z1, Z2 and Z3 are independently selected from -COOH, -SO2H, -SO3H, -OSO3H, -OPO3H2 and X is C=O, S=O, C=NH、 R2 is -CH3 or H; u and w are independently 0, 1 or 2; i is an integer from 1 to 3; j is an integer from 3 to 5; R1 is selected from substituted or unsubstituted alkylaryl, aryl, alkylheteroaryl and heteroaryl; Y1 and Y3 are independently selected from substituted or unsubstituted aryl, alkylaryl, cycloalkyl, heterocycloalkyl, heteroaryl and alkylheteroaryl; Y2 is C=O, C=S or g, k, e, s and t are independently 0 or 1; A is a nuclide, a nuclide with a linker arm, or a chelating agent capable of grabbing a nuclide.

2. The compound according to claim 1, and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, characterized in that: R1 is selected from the residues of substituted or unsubstituted naphthyl, phenyl, biphenyl, indolyl and benzothiazolyl; preferably, R1 is selected from the residues of substituted or unsubstituted naphthyl, alkyl-naphthyl, phenyl, benzyl, biphenyl, alkyl-biphenyl, indolyl, alkyl-indolyl, benzothiazolyl and alkyl-benzothiazolyl; further preferably, R1 is selected from More preferably, R1 is 3. The compound according to claim 1, and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, characterized in that: Y1 is 4. The compound according to claim 1, and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, characterized in that: Y3 is selected from substituted or unsubstituted aryl, alkaryl, cycloalkyl, heterocycloalkyl, heteroaryl and alkylheteroaryl; preferably, Y3 is aryl; more preferably, Y3 is a substituted benzene ring; More preferably, Y3 is Among them, R7, R8, R9 and R 10 R7, R8, R9 and R 10 R7, R8, R9 and R 10 For H.

5. The compound according to claim 1, and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, characterized in that: The nuclide is selected from 89 Zr, 44 Sc, 111 In, 99m Tc, 90 Y. 66 Ga, 67 Ga, 68 Ga, 177 Lu, 60 Cu, 6l Cu, 62 Cu, 64 Cu, 66 Cu, 67 Cu, 149 Tb, 152 Tb, 153 Sm, 155 Tb, 161 Tb, 153 Gd, 155 Gd, 157 Gd, 213 Bi, 225 Ac, 230 U. 223 Ra, 165 2. 191 Radionuclides of Pt, Fe and radionuclides of Pb.

6. The compound according to claim 1, and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, characterized in that: The nuclide with the connecting arm is selected from the following structures: wherein Y4 and Y5 are independently H, alkyl or optionally substituted or unsubstituted aryl, alkylaryl, heteroaryl and alkylheteroaryl; and wherein n is an integer from 0 to 5.

7. The compound according to claim 1, and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, characterized in that: The structure of the chelating agent capable of grabbing nuclides is selected from (1a), (1b) and (1c): wherein R3, R4, R5 and R6 are independently selected from H, -CH2-COOH and -CH2-C(=O)-NH2, or wherein R3 and R5 form -(CH2) m - bridge, m is an integer from 1 to 3, wherein m is preferably 2; Where r, v and q are independently 0 or 1.

8. The compound according to claim 7, and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, characterized in that: The chelating agent capable of grabbing nuclides is selected from the following structures:

9. A complex, characterized in that The complex contains: (a) radionuclides, and (b) The compound according to any one of claims 1 to 8, and a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof.

10. The complex according to claim 9, characterized in that The radionuclide is selected from 89 Zr, 44 Sc, 111 In, 99m Tc, 90 Y. 66 Ga, 67 Ga, 68 Ga, 177 Lu, 60 Cu, 6l Cu, 62 Cu, 64 Cu, 66 Cu, 67 Cu, 149 Tb, 152 Tb, 153 Sm, 155 Tb, 161 Tb, 153 Gd, 155 Gd, 157 Gd, 213 Bi, 225 Ac, 230 U. 223 Ra, 165 2. 191 Radionuclides of Pt, Fe and radionuclides of Pb.

11. A pharmaceutical composition, wherein the pharmaceutical composition comprises the compound according to any one of claims 1 to 9 or the complex according to any one of claims 9 to 10.

12. Use of the compound according to any one of claims 1 to 9, the complex according to any one of claims 9 to 10, or the pharmaceutical composition according to claim 11 in the following (1) or (2): (1) Preparing drugs for treating, ameliorating or preventing PSMA-expressing cancer and / or its metastases; (2) Preparation of reagents for diagnosing PSMA-expressing cancer and / or its metastasis.

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