Preparation and application of prostate-specific membrane antigen small-molecule inhibitor and radionuclide complex of prostate-specific membrane antigen small-molecule inhibitor

Abstract

The invention relates to the field of nuclear medicine, in particular to a prostate specific membrane antigen small-molecule inhibitor and preparation and application of a radionuclide complex of the prostate specific membrane antigen small-molecule inhibitor. The prostate specific membrane antigen small-molecule inhibitor has a structure as shown in a general formula (I). The invention also provides a radionuclide complex containing radionuclide and the prostate specific membrane antigen small-molecule inhibitor. On the basis of a prostate specific membrane antigen small-molecule inhibitor, various medical radionuclides, such as a complex formed by 68Ga or 177Lu, are marked, and the complex can be respectively used for PSMA specific SPECT / CT (Single Photon Emission Computed Tomography / Computed Tomography), PET / CT (Positron Emission Tomography / Computed Tomography) imaging or prostate cancer treatment. The complex has the characteristics of high labeling rate, good stability, good tumor tissue targeting property and the like, provides a new idea for diagnosis and treatment integration of prostate cancer, and has a wide application prospect.

Description

Technical Field

[0001] This invention relates to the field of nuclear medicine, and more specifically, to the preparation and application of a small molecule inhibitor of prostate-specific membrane antigen and its radionuclide complex. Background Technology

[0002] In recent years, the incidence of prostate cancer in my country has increased significantly, becoming the fastest-growing type of malignant tumor.

[0003] Early imaging diagnosis and treatment of prostate cancer has become an urgent problem to be solved in China and around the world. Prostate cancer begins in the tissues surrounding the prostate and gradually metastasizes to other vital organs such as the lungs and bones as it grows. In the early stages, there are no obvious symptoms, but as the prostate cancer grows, it can cause problems such as urethral compression and urinary tract obstruction, and further metastasize to the spine or pelvis. For the diagnosis of prostate cancer, imaging diagnostic methods such as SPECT (single-photon emission computed tomography) and PET (positron emission tomography) are currently used. The principle is to use radioactive isotopes that emit gamma rays or positrons to label the peptides targeted by PSMA, thereby showing the presence and distribution of tumor cells in tomographic and three-dimensional images through the specific targeting distribution of prostate cancer. These imaging diagnostic methods have recently been greatly promoted due to the significant improvement in image quality brought about by the development of SPECT CT / MRI and PET CT / MRI, which combine CT or MRI. Currently, radiopharmaceuticals used for prostate cancer-specific imaging target PSMA ligands. These ligands bind to PSMA (prostate-specific membrane antigen), a protein specifically expressed in prostate cancer. PSMA is a type II transmembrane glycoprotein, also known as glutamate carboxypeptidase, and is a specific molecular marker for prostate cancer. Its expression level in tumor tissue is much higher than in normal tissue; it is overexpressed on the surface of almost all prostate cancer cells, with further increases in poorly differentiated, metastatic, and androgen-independent prostate cancer cells. In contrast, its expression level in normal tissues such as the kidneys, intestines, and brain is more than 1000 times lower. PSMA has become an effective target for the diagnosis and treatment of prostate cancer.

[0004] Currently, castration surgery, anti-androgen castration, and androgen receptor inhibitors are the mainstream treatment options for prostate cancer. Although these treatments are very effective in the initial stages, a large proportion of patients will develop castration-resistant prostate cancer (CRPC) or even metastatic castration-resistant prostate cancer (mCRPC).

[0005] mCRPC is a disease with limited treatment options and significant unmet medical needs, making PSMA-targeted radiopharmaceuticals a hot research topic in recent years. Representative ligands for PSMA are peptide derivatives such as Gluurea Lys (GUL) or Gluurea Cys (GUC). Therefore, by labeling radioisotopes with ligands containing such peptides, radiopharmaceuticals can be prepared for PET or SPECT imaging of prostate cancer or for the treatment of prostate cancer (MEder et al., Bioconjugate Chem 2012, 23:688-697).

[0006] Radionuclide-labeled small-molecule inhibitors targeting PSMA have demonstrated superior diagnostic and therapeutic properties in clinical practice. Ahmadzadehfar H et al. administered lutetium-177 (177Lu)-labeled PSMA-617 to 22 patients with metastatic castration-resistant prostate cancer (mCRPC), resulting in a decrease in prostate-specific antigen (PSA) in 79.1% of patients, with 41.6% experiencing a PSA decrease of more than 50%. (Ahmadzadehfar H et al. Oncotarget. 2016; 7:12477-88.) Kratochwil C et al. administered 177Lu-PSMA-617 to 30 mCRPC patients, resulting in a decrease in PSA in 70% of patients, with 43.3% experiencing a PSA decrease of more than 50%. Kratochwil C et al. also administered actinium-225 (225Ac)-labeled PSMA617 to two CRPC patients, both of whom achieved complete imaging response (CR) and their PSA levels returned to normal. (Kratochwil Cet al. Society of Nuclear Medicine. 2017.)

[0007] A series of clinical studies have been conducted on the use of PSMA-targeted radiopharmaceuticals to treat mCRPC patients. Although the preliminary clinical results of radiopharmaceuticals such as 177Lu-PSMA-617 and 177Lu-PSMA I&T are encouraging, some problems remain. For example, nearly 30% of patients do not respond to this treatment. One possible explanation is that its poor pharmacokinetics result in insufficient delivery of radiopharmaceuticals to the tumor lesions.

[0008] Therefore, a highly active and selective radiopharmaceutical targeting PSMA is a persistent hot topic in the treatment and diagnosis of mCRPC. The objective of this invention is to develop ligands that interact with PSMA and carry appropriate radionuclides, providing promising and novel targeting options for the detection, treatment, and management of prostate cancer. Summary of the Invention

[0009] This invention addresses the clinical accessibility issues of existing radionuclide-labeled small molecule inhibitors of prostate-specific membrane antigens by providing a small molecule inhibitor of prostate-specific membrane antigens. 68 Ga or 177 Lu complexes can be used for SPECT / CT imaging of target tissues and targeted tumor therapy, providing new ideas for the integrated diagnosis and treatment of prostate cancer.

[0010] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0011] A first aspect of the present invention provides a small molecule inhibitor of prostate-specific membrane antigen, having the structure shown in general formula (I):

[0012]

[0013] Where R is -L 1 -R 2 R 1 -L 2 -R 3 Or R is -L 2 -R 3 R 1 -L 1 -R 2 ;

[0014] Among them, L 1 L 2 It is a divalent linker -(L) p-; Each L is independently selected from the following group: chemical bond, CO, substituted or unsubstituted CH2, substituted or unsubstituted NH, S(O), S(O)2, -O-, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-10 heteroaryl, substituted or unsubstituted C0-C6 alkylaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted (-O-CH2-CH2-) t Substituted or unsubstituted (-CO-CH2-O-CH2-CH2-O-CH2-CH2-NH-) t The substitution refers to having one or more substituents selected from the group consisting of: deuterium, halogen, amino, hydroxyl, carboxyl, cyano, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 alkylthio, C1-C6 haloalkoxy, C3-C8 cycloalkyl, 3-8 heterocyclic, C6-C10 aryl, 5-10 heteroaryl, -NR 5 R 6 -ZC(O)-OR 7 -C(O)-Z-OR 7 -C(O)NR 5 R 6 -ZR 5 R 6 ;

[0015] Z is a chemical bond, -O-, -NH-, or C1-C3 alkylene;

[0016] R 5 R 6 and R 7 Each element is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, R 3 C6-C10 aryl, 5-10 heteroaryl, biphenyl, aniline, phenolic, halophenyl;

[0017] t is selected from 0, 1, 2, 3, 4, or 5;

[0018] p is an integer selected from 0 to 50;

[0019] R 2 It can be H or selected from the following structures:

[0020]

[0021] * is R 2 Connection site with L;

[0022] R 3H is a chelating agent selected from the following: 1,4,7,10-tetraazacyclododecane-N,N',N",N'",-tetraacetic acid (=DOTA), N,N"-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N"-diacetic acid (=HBED-CC), 1,4,7-triazacyclononane-1,4,7-triacetic acid (=NOTA), 2-(4,7-bis(carboxymethyl)-1,4,7-triazonane-1 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutaric acid (DOTAGA), 1,4,7-triazacyclononanephosphonic acid (TRAP), 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphonic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphonic acid] (NOPO), 3,6,9,15-tetraazacyclononane-1-[methyl(2-carboxyethyl)phosphonic acid](NOPO), Bicyclo[9.3.1.]pentadecanediol-1(15),11,13-trien-3,6,9-triacetic acid (=PCTA), N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutyryl}amino)pentyl]-N-hydroxysuccinamide (DFO), diethylenediaminepentaacetic acid (DTPA), trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DT) PA), 1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (O-Do3A), p-isocyanothiobenzyl-DTPA (SCN-Bz-DTPA), 1-(p-isocyanothiobenzyl)-3-methyl-DTPA (1B3M), 2-(p-isocyanothiobenzyl)-4-methyl-DTPA (1M3B), 1-(2)-methyl-4-isocyanobenzyl-DTPA (MX-DTPA);

[0023] R 4 Selected from -CO2H, -SO2H, -SO3H, -SO4H, -PO2H, PO3H, or PO4H2;

[0024] The additional condition is R 2 and R 3 They are not both H.

[0025] In another preferred embodiment, p is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

[0026] In another preferred embodiment, L 1 and L 2 Each is independently selected from: chemical bonds, -CO-(CH2) n -CO-, -CO-(CH2) n -NH-, -CH2-CO-;

[0027] n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11.

[0028] In another preferred embodiment, R is -L 2 -R 3 R 1 -L 1 -R 2 .

[0029] In another preferred embodiment, L 1 Selected from -CO-(CH2) n -CO-, -CO-(CH2) n -NH-, -CH2-CO-.

[0030] In another preferred embodiment, L 2 Selected from chemical bonds, -CO-(CH2) n -NH-.

[0031] In another preferred embodiment, R is H, R 1 For -(L) a -CH(NHR 3 )-(L) b -R 2 L is defined above; a and b are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, and the sum of a and b is less than p.

[0032] In another preferred embodiment, R 3 For DOTA.

[0033] In another preferred embodiment, R 4 It is -CO2H.

[0034] In another preferred example, n is 10 or 11.

[0035] In another preferred embodiment, the compound A, as shown in formula (I), is chelated with the radioactive metal nuclide (e.g., 68Ga or 177Lu), and the structure of compound A is shown in any of the following:

[0036]

[0037]

[0038]

[0039]

[0040]

[0041]

[0042]

[0043]

[0044] A second aspect of the invention provides the use of the compounds described in the first aspect of the invention for the preparation of radiolabeled compounds.

[0045] A third aspect of the present invention provides a metal complex comprising a radionuclide and the compound described in the first aspect of the present invention.

[0046] In another preferred embodiment, the radioactive metal nuclide is a radioactive metal nuclide that emits α, β or γ rays.

[0047] In another preferred embodiment, the radionuclide is 111 In、 90 Y、 68 Ga、 177 Lu、 99m Tc, 64 Cu、 153 Gd, 155 Gd, 157 Gd, 213 Bi、 225 Ac or Fe.

[0048] In another preferred embodiment, the radionuclide is 68 Ga or 177 Lu.

[0049] The fourth aspect of the present invention provides a method for preparing the metal complex described in the third aspect of the present invention, which is simple, efficient and easy to automate.

[0050] Specifically (taking M006 as an example), the preparation of M006 can use 3DASM01 and 3DASM02 as starting materials, and includes 5 steps:

[0051] Step 1: The starting material compounds 3DASM01 and 3DASM02 undergo a dehydration reaction to synthesize intermediate 1 solution;

[0052] Step 2: Intermediate 1 undergoes dehydration with 3DASM03 to form an amide bond, yielding intermediate 2;

[0053] Step 3: Remove the benzyl protecting group from intermediate 2 to obtain intermediate 3;

[0054] Step 4: Intermediate 3 undergoes dehydration with 3DASM04 to form an amide bond, yielding intermediate 4;

[0055] Step 5: Remove the tert-butyl protecting group from intermediate 4 to obtain M006;

[0056] The specific synthetic route information is as follows:

[0057]

[0058] Based on the method described above, various metal complexes of the present invention can be prepared by using other starting materials.

[0059] A fifth aspect of the present invention provides a pharmaceutical composition comprising (i) a compound described in the first aspect of the present invention, or a metal complex described in the third aspect of the present invention, or a pharmaceutically acceptable salt or ester thereof, and (ii) a pharmaceutically acceptable carrier.

[0060] The sixth aspect of the invention is the use of the compounds described in the first aspect of the invention, or the metal complexes described in the third aspect of the invention, in the preparation of pharmaceutical agents for imaging in patients, and pharmaceutical agents for diagnosing and / or treating prostate cancer and / or its metastases.

[0061] The present invention further provides a method for preparing the aforementioned radionuclide complex.

[0062] Specifically (taking 68Ga labeling as an example), the preparation method includes: eluting 68GaCl3 eluent from a 68Ge / 68Ga generator with HCl solution; adding sodium acetate solution to the 68GaCl3 eluent and shaking well; then adding the prostate-specific membrane antigen small molecule inhibitor of the present invention dissolved in pure water. The mixture is reacted at a certain temperature for an appropriate time. After diluting the reaction solution with sterile water for injection, it is purified by passing it through a C18 column, followed by eluting the C18 column with water. The product is then eluted from the C18 column with an ethanol / water (1 / 1, v / v) mixture. 68 Ga-labeled complexes.

[0063] Preferably, the dosage of the prostate-specific membrane antigen small molecule inhibitor is 5-15 nmol.

[0064] Preferably, the concentration of the HCl solution is 0.3-0.9M.

[0065] Preferably, the concentration of the sodium acetate solution is 1-5M.

[0066] Preferably, the reaction temperature is 90-110℃.

[0067] Preferably, the reaction time is 10-20 min.

[0068] Preferably, the reaction temperature is 100°C and the reaction time is 15 min.

[0069] The present invention also relates to pharmaceutically acceptable salts of compounds of general formula (I). The present invention also relates to solvates of compounds, including their salts and active metabolites, and, suitably, tautomers of these compounds according to general formula (I), comprising prodrug formulations.

[0070] "Pharmaceutically acceptable salt" is a pharmaceutically acceptable salt of an organic or inorganic acid or base of the compound of the present invention. Representative pharmaceutically acceptable salts include, for example, alkali metal salts, alkaline earth salts, ammonium salts, and water-soluble and water-insoluble salts such as acetates, carbonates, chlorides, gluconates, glutamates, lactates, laurates, malates, or tartrates.

[0071] "Prodrug" refers to a drug precursor, which is a compound that must undergo a chemical transformation by a metabolic process before becoming an active pharmacological agent when administered to a patient. Exemplary prodrugs according to formula (I) are esters and amides, preferably alkyl esters of fatty acid esters. The prodrug formulation herein comprises all substances formed by simple transformation by enzymes, metabolism, or any other means, including hydrolysis, oxidation, or reduction. Suitable prodrugs contain, for example, substances of general formula (I) bound to a solubility-improving substance (e.g., tetraethylene glycol, sugars, formic acid, or glucuronic acid, etc.) via an enzymatically cleavable linker (e.g., carbamate, phosphate, N-glucosidate, or sulfhydryl group). Such prodrugs of compounds according to the invention can be administered to a patient, and the prodrug can be converted into a substance of general formula (I) to achieve the desired pharmacological effect.

[0072] Some compounds of formula (I) may be contained in the form of racemates, their enantiomers, and optionally in the form of their non-corresponding isomers and all possible mixtures thereof.

[0073] According to the present invention, all chiral C atoms should have D- and / or L- configurations: combinations within a compound should also be possible, i.e., some chiral C atoms can be D- and others can be L- configurations.

[0074] The compounds according to the invention can be suitably formulated together with other active substances and excipients and carriers commonly used in pharmaceutical compositions, such as (depending on the formulation to be produced) talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous and non-aqueous carriers, fat bodies of animal or plant origin, paraffin derivatives, ethylene glycol (especially polyethylene glycol), various plasticizers, dispersants or emulsifiers, pharmaceutically compatible gases (e.g., air, oxygen, carbon monoxide, etc.), and preservatives.

[0075] To produce liquid formulations, additives such as sodium chloride solution, ethanol, sorbitol, glycerol, olive oil, almond oil, propylene glycol, or ethylene glycol can be used.

[0076] When solutions are used for infusion or injection, they are preferably aqueous solutions or suspensions that can be produced prior to use, for example, from lyophilized formulations containing such active substances or along with carriers, such as mannitol, lactose, glucose, albumin, etc. The sterilization is achieved by mixing the prepared solution with excipients, such as preservatives, stabilizers, emulsifiers, solubilizers, buffers, and / or salts for adjusting osmotic pressure. Sterilization can be achieved by aseptic filtration using a filter with a small pore size, which allows the composition to be appropriately lyophilized. Small amounts of antibiotics may also be added to ensure sterility is maintained.

[0077] In another preferred embodiment, the pharmaceutical composition may be a pharmaceutical composition for treating or diagnosing prostate cancer.

[0078] In another preferred embodiment, the pharmaceutical composition may be a pharmaceutical composition for imaging prostate cancer.

[0079] In another preferred embodiment, the prostate cancer is castration-resistant prostate cancer.

[0080] In another preferred embodiment, the prostate cancer is metastatic castration-resistant prostate cancer.

[0081] In another preferred embodiment, the prostate cancer is PSMA-positive prostate cancer.

[0082] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here.

[0083] The positive and progressive effects of the present invention after adopting the above technical solution are as follows:

[0084] (1) The small molecule inhibitor of prostate-specific membrane antigen provided by the present invention is stable in nature, has good imaging effect, and has high affinity and functional activity for PSMA. It can be used for preoperative imaging diagnosis and grading of PSMA-positive prostate cancer, as well as for the treatment of prostate cancer of various types and stages, achieving integrated diagnosis and treatment, and has broad application prospects.

[0085] (2) The preparation method of the prostate-specific membrane antigen small molecule inhibitor described in this invention is simple, efficient and easy to automate.

[0086] The specific embodiments of the present invention will now be described in further detail with reference to the accompanying drawings. Attached Figure Description

[0087] Figure 1 This is the HPLC chromatogram of M006 in Example 1 of the present invention.

[0088] Figure 2 This is the HPLC chromatogram of M001 in Example 2 of the present invention.

[0089] Figure 3 In Embodiment 5 of the present invention 68 HPLC chromatogram of Ga-M006 complex 0h.

[0090] Figure 4 In Embodiment 5 of the present invention 68 HPLC chromatogram of Ga-M006 complex after 1 h.

[0091] Figure 5 In Embodiment 5 of the present invention 68 HPLC chromatogram of Ga-M006 complex after 2 hours.

[0092] Figure 6 In Embodiment 5 of the present invention 68 HPLC chromatogram of Ga-M001 complex 0h.

[0093] Figure 7 In Embodiment 5 of the present invention 68 HPLC chromatogram of Ga-M001 complex after 1 hour.

[0094] Figure 8 In Embodiment 5 of the present invention 68 HPLC chromatogram of Ga-M001 complex after 2 hours.

[0095] Figure 9 In Embodiment 7 of the present invention 68 PET / MR images of the Ga-M006 complex in animals after 1.5 hours.

[0096] It should be noted that these accompanying drawings and textual descriptions are not intended to limit the scope of the invention in any way, but rather to illustrate the concept of the invention to those skilled in the art by referring to specific embodiments. Detailed Implementation

[0097] Through extensive and in-depth research, the inventors have developed a small molecule inhibitor of prostate-specific membrane antigen as described in formula (I). Specifically, a targeting portion Lys-Ureido-Glu specifically targeting prostate membrane antigen is attached to the core structure shown in formula (I), and a group with metal ion chelating function is introduced, thereby realizing a radionuclide. 68 Ga or 177The labeling method for Lu is simple, convenient, and rapid, with high labeling rate and good stability. The combination of the core structure, targeting portion, and chelating group in this invention achieves excellent targeting of prostate cancer tumor tissue, which can be used... 68 Ga markers are used for imaging diagnosis and can also be used... 177 The use of Lu markers for treatment provides a new approach to achieving integrated diagnosis and treatment of prostate cancer.

[0098] the term

[0099] In this document, unless otherwise specified, all abbreviations have their conventional meanings as understood by those skilled in the art.

[0100] "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group. For example, "C1-8 alkyl" refers to straight-chain alkyl and branched alkyl groups that include 1 to 8 (1, 2, 3, 4, 5, 6, 7, 8) carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, etc.

[0101] "Alkenyl" is a branched or straight-chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds that can occur at stable sites on the chain. Non-limiting examples include C2-C8 alkenyl groups (such as C2, C3, C4, C5, C6, C7, C8), C2-C6 alkenyl groups, and C2-C4 alkenyl groups. The specified ranges used herein represent alkenyl groups that can be considered as independent categories, having each value of the range as described herein, such as the alkyl portion. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, and butadienyl groups (including 1,2-butadienyl and 1,3-butadienyl). In one embodiment, the alkenyl group is optionally substituted, as described herein.

[0102] "Cycloalkyl" refers to a saturated or partially unsaturated cycloalkyl group having a monocyclic or polycyclic structure, including fused ring, bridged ring, and spirocyclic systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclogroups having at least one double bond). As used herein, C 3-8 Cycloalkyl groups have 3 to 8 cyclic carbon atoms (e.g., 3, 4, 5, 6, 7, or 8 cyclic carbon atoms). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and partially unsaturated groups such as cyclopentenyl and cyclohexenyl.

[0103] "Carbocyclic group," "carbocyclic group," "carbocyclic," or "cycloalkyl" is a saturated or partially unsaturated (i.e., non-aromatic) group containing all carbon ring atoms. A carbocyclic group typically comprises one ring of 3 to 7 carbon atoms or two fused rings each containing 3, 4, 5, 6, or 7 carbon atoms. A cycloalkyl substituent may have a substituted nitrogen or carbon atom as a side chain, or the substituted carbon atom of two substituents may have a cycloalkyl group linked as a spiroyl group. Examples of carbocyclic groups include cyclohexenyl, cyclohexyl, cyclopentenyl, cyclopentyl, cyclobutenyl, cyclobutyl, and cyclopropyl rings. In one embodiment, the carbocyclic group is optionally substituted as described herein. In one embodiment, a cycloalkyl group is a partially unsaturated (i.e., non-aromatic) group containing all carbon ring atoms. In another embodiment, a cycloalkyl group is a saturated group containing all carbon ring atoms.

[0104] A "heterocyclic group" is a saturated cyclic group. For example, it can have 1, 2, 3, or 4 heteroatoms independently selected from N, S, and O, with the remaining ring atoms being carbon atoms. In a representative embodiment, the heteroatom is nitrogen. Monocyclic heterocyclic alkyl groups typically have 3 to about 8 ring atoms or 4 to 6 ring atoms. Examples of heterocyclic alkyl groups include morpholino, piperazino, piperidino, and pyrrololino.

[0105] "Aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring that shares adjacent carbon atom pairs) group, a polycyclic (i.e., a ring with adjacent carbon atom pairs) group with a conjugated π-electron system, including but not limited to phenyl and naphthyl.

[0106] "Heteroaryl" refers to a heteroaryl system containing 1 to 4 heteroatoms, including nitrogen, oxygen and S. For example, 5-7-membered heteroaryl refers to a heteroaryl system containing 5-7 ring atoms, and 5-10-membered heteroaryl refers to a heteroaryl system containing 5-10 ring atoms, including but not limited to furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, indolyl, benzothiazolyl, etc.

[0107] "Alkoxy" is an alkyl group as defined above, consisting of a specified number of carbon atoms covalently bonded together by an oxygen bridge (-O-). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, 2-butoxy, tert-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexyloxy, 2-hexyloxy, 3-hexyloxy, and 3-methylpentoxy. Similarly, "alkylthio" or "thioalkyl" groups are alkyl groups as defined above, consisting of a specified number of carbon atoms covalently bonded together by a sulfur bridge (-S-). In one embodiment, the alkoxy group may optionally be substituted, as described herein.

[0108] "Substitution" refers to the replacement of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent is the substituent described accordingly above, or the substituent appearing in the various examples. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents may be the same or different at each position. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are stable or chemically feasible combinations. Such substituents include, but are not limited to: halogens, hydroxyl groups, carboxyl groups (-COOH), C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C8 cycloalkyl groups, 3- to 12-membered heterocyclic groups, aryl groups, heteroaryl groups, C1-C8 aldehyde groups, C2-C10 acyl groups, C2-C10 ester groups, amino groups, C1-C6 alkoxy groups, C1-C10 sulfonyl groups, etc.

[0109] In this document, the terms "metal complex", "complex", and "coordination compound" are used interchangeably and all refer to the structure formed by chelating the compound of the first aspect of this invention with a radioactive metal nuclide.

[0110] As used in this article, unless otherwise specified, solvents or solutions are added by pouring directly or adding at a constant rate.

[0111] As used in this article, the term "room temperature" generally refers to 4-30°C, preferably 20±5°C.

[0112] As used in this article, the "slow addition" method includes, but is not limited to: adding drop by drop, adding slowly along the container wall, etc.

[0113] The term "pharmaceutical excipients" refers to the excipients and additives used in the production of pharmaceuticals and the dispensing of prescriptions. It includes all substances contained in pharmaceutical preparations, excluding the active ingredient. See the Pharmacopoeia of the People's Republic of China (2020 edition) or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009) for details.

[0114] Lys represents L-lysine

[0115] Ureido represents the structure of urea.

[0116] Glu represents L-glutamic acid

[0117] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0118] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to one skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the inventive methods. The preferred embodiments and materials described herein are for illustrative purposes only.

[0119] General methods and reagents

[0120] All solvents used in this invention are of analytical grade and contain approximately 0.1% water.

[0121] All test methods in this invention are general methods, and the test parameters are as follows:

[0122] The high-performance liquid chromatography (HPLC) method of this invention:

[0123] Test method:

[0124] Column: SunFire C18 5µm 4.6x150mm

[0125] Column temperature: 25℃

[0126] Flow rate: 1.000 ml / min

[0127] Mobile phase:

[0128] A: 0.03% TFA in H2O

[0129] B: 0.03% TFA in ACN

[0130] gradient:

[0131] Time (min) Mobile phase A (%V / V) Mobile phase B (% V / V) 0.01 90 10 13.00 5 95 16.00 5 95

[0132] The present invention provides a liquid chromatography-mass spectrometry (LCMS) method:

[0133] Chromatographic column: Waters SunFire C18 50*4.6mm 5um 2.000ml / min 2.6min

[0134] Column temperature: 40℃

[0135] Gradient: 5% B hold for 0.2min, increase to 95% B within 1.40min, hold at 95% B for 0.9min, then back to 5% B within 0.01min

[0136] A: 0.03% TFA in H2O

[0137] B: 0.03% TFA in ACN

[0138] The present invention provides a method for nuclear magnetic resonance (H-NMR) analysis:

[0139] Test method:

[0140] Spectrometer: Avance

[0141] Solvent: DMSO-d6

[0142] Number of scans: 8

[0143] Spectral frequency: 400MHz

[0144] Scan time: 50s

[0145] The F-NMR method of this invention:

[0146] Test method:

[0147] Spectrometer: Avance

[0148] Solvent: DMSO-d6

[0149] Number of scans: 32

[0150] Spectral frequency: 377MHz

[0151] Scan time: 70s

[0152] The present invention provides a radio-high performance liquid chromatography (Radio-HPLC) method:

[0153] Test method:

[0154] Column: C18, 3μm, 150×4.6mm; Flow rate: 1.000ml / min

[0155] Mobile phase:

[0156] A: 0.03% TFA in Water

[0157] B: 0.03% TFA in ACN

[0158] gradient:

[0159] time min ％A ％B 0.0 90 10 13.0 5 95 16.0 5 95 16.1 90 10 20.0 90 10

[0160] Example 1: Preparation of the inhibitor M006

[0161]

[0162] Dissolve 3.2g of 3DASM01 in 30mL of DMF, add 4.13g of 3DASM02, 2.88g of EDCI, 2.03g of HOBt, and 6.45g of DIEA, stir at 30℃ for 16h, then dilute with 50mL of water, extract three times with 150mL of EA each time, combine the organic layers, concentrate and purify to obtain 4.1g of intermediate 1; dissolve 500mg of 3DASM03 in 10mL of DCM, add one drop of DMF, stir well, then slowly add 132mg of (COCl)2, stir at room temperature for 1h, then concentrate under vacuum to obtain 648mg of acyl chloride compound, add 500mg of intermediate 1 and 481mg of DIEA. In Cs₂CO₃, a total of 8 mL of solution was obtained. The mixture was stirred at 80 °C for 16 h. After the reaction was complete, the solution was filtered, diluted with 30 mL, and extracted three times with EA (80 mL each time). The organic layers were combined, dried, filtered, concentrated, and purified to obtain 510 mg of intermediate 2. 510 mg of intermediate 2 was dissolved in methanol, and 35 mg of Pd / C (10% w / w) was added at room temperature. The mixture was then stirred at room temperature for 0.3 h under H₂. After the reaction was complete, the mixture was filtered and concentrated to obtain 450 mg of intermediate 3. 450 mg of intermediate 3, 191 mg of 3DASMO₄, and 331 mg of TCFH were dissolved in 20 mL of ACN, and 193 mg of... NMI was added, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the mixture was concentrated and purified to obtain 300 mg of intermediate 4. 300 mg of intermediate 4 was dissolved in TFA / DCM (10 mL / 10 mL), and the mixture was stirred at room temperature for 36 hours. After the reaction was completed, the mixture was concentrated, and then purified by preparative HPLC to obtain 65.9 g of white solid final product M006 sample with a purity of 95.03% (214 nm). Its HPLC chromatogram is shown below. Figure 1 As shown. LCMS(ESI): RT 1.443 min; m / z 638.8 [M+2H] 2+ 1276.0 [M+H] +. 1H NMR (400MHz, DMSO-d6) δ12.49(s,4H),10.77(s,1H),9.41(s,1H),8.70(s,1H),8.40(d,J=8.4Hz,1H),7.98(d, J=7.5Hz,1H),7.80-7.64(m,2H),7.53(d,J=8.3Hz,2H),7.39(d,J=8.2Hz,2H),7.33(d,J=7.2Hz,1H),7.20-7.0 7(m,1H),6.83(s,1H),6.33(dd,J=12.7,8.3Hz,2H),4.15-3.99(m,2H),3.58(s,13H),3.20-2.92(m,15H),2.3 6-2.19(m,5H),2.03(t,J=7.3Hz,2H),1.92(dt,J=13.8,7.2Hz,1H),1.82-1.58(m,4H),1.58-1.15(m,19H).19F NMR(376.5MHz,DMSO-d6)δ-134.23.

[0163] Example 2: Preparation of inhibitor M001

[0164] Dissolve 1.70 g of 3DAO1 in 20 mL of DCM, then add 454 mg of (COCl)2 and one drop of dry DMF. Mix thoroughly at room temperature for 10 minutes under nitrogen protection. Concentrate the solution, add 1 g of 3DAO2 dissolved in dry THF and 1.44 g of K2CO3, stir at room temperature for 16 h under nitrogen protection, filter the reaction solution, dilute with 30 mL of water, and extract three times with EA, 100 mL each time. Dry the organic layer with Na2SO4, then filter, concentrate, and purify with H2O / ACN reverse phase to obtain 1.23 g of intermediate 1. Dissolve 1.23 g of intermediate 1 in 18 mL of DCM, then add 3 mL of TFA, and stir at 0 °C for 0.5 h. Concentrate, dilute with 30 mL of NaHCO3, and extract three times with EA, 80 mL each time. The organic layer was dried with Na₂SO₄, then filtered, concentrated, and purified by reverse-phase H₂O / ACN to obtain 1.08 g of intermediate 2. 400 mg of intermediate 2 was dissolved in 20 mL of DMF, and then 365.6 mg of 3DAO₃, 136.3 mg of EDCI, 100 mg of HOBt, and 143.4 mg of 4-Methylmorpholine were added. The mixture was then stirred at room temperature for 16 h. The reaction solution was then diluted with 30 mL of water and extracted three times with 80 mL of EA each time. The organic layer was dried with Na₂SO₄, then filtered, concentrated, and purified by reverse-phase H₂O / ACN to obtain 0.56 g of intermediate 3. 0.56 g of intermediate 3 was dissolved in 10 mL of DCM, and then 10 mL of TFA and 301.6 mg of Et₃SiH were added. The mixture was then stirred at 35 °C. o Stirred at C for 16 h. After concentration, the reaction solution was purified by preparative HPLC using an H2O / CAN mobile phase system containing 0.1% TFA to obtain 59 mg of white solid M001 with a purity of 95.41% (254 nm). Its HPLC chromatogram is shown below. Figure 2shown. LCMS (ESI): RT 4.01min; m / z 796.3[M+2H]2+, 1591.1[M+H]+. 1H NMR (400MHz, DMSO-d6) δ10.22(s,1H),9.83(s,1H),9.18(s,1H),8.72(s,1H),8.37(d,J=7.9Hz,1H),8.24(s, 1H),8.16-8.05(m,3H),7.90(s,1H),7.66(d,J=6.9Hz,1H),7.51(s,2H),7.33(dd,J=23.9,6.0Hz,3H),7.13-7 0.02 (m, 1H), 6.80 (s, 1H), 4.16–4.15 (m, 5H), 3.50 (d, J = 47.3 Hz, 6H), 3.18–2.86 (m, 17H), 2.72 (d, J = 14.8 Hz, 2H), 2.56 (d, J = 17.7 Hz, 3H), 2.29–2.15 (m, 11H), 2.04–1.90 (m, 4H), 1.83–1.67 (m, 6H), 1.38–1.23 (m, 18H). 19F NMR (376.5 MHz, DMSO-d6) δ -132.98. The reaction process is as follows:

[0165]

[0166]

[0167] Example 3: In vitro binding force test of the compound with PSMA protein

[0168] The Biacore 8K (Cytiva) instrument was used to detect ligand binding of Sinobiological PSMA protein. The NTA chip capture method was employed. First, the NTA chip was activated for 60 seconds with 0.5 mM NiCl2 at a flow rate of 10 μL / min. Then, Human PSMA protein was captured on the NTA chip: the Human PSMA protein was diluted to 20 μg / mL with running buffer (10 mM PBS, pH 7.4, 137 mM NaCl, 2.7 mM KCl, 0.05% P2O, 1% DMSO), and coupled at a flow rate of 5 μL / min for 30 seconds. The analyte was then used as the analytical agent, and the mixture was analyzed with running buffer (10 mM PBS, pH 7.4, 137 mM NaCl, 2.7 mM KCl, 0.05% P2O, 1% DMSO). DMSO was used to dilute the M006 and M001 samples obtained in Examples 1 and 2, along with the positive reference PSMA-617, to the desired concentration gradient. Multiple cycles of kinetic analysis were performed, with each cycle consisting of 180 seconds of injection followed by 180 seconds of dissociation before proceeding to the next cycle. This yielded kinetic data on the affinity between the analyte and Human PSMA protein. The final data were then analyzed using Biacore Insight Evaluation Software (V 2.0.15.12933) in a 1:1 kinetic model.

[0169] The Biacore results are shown in the table below: KD represents the binding affinity of the compound to the PSMA protein, as measured by Biacore. The results indicate that M006 exhibits an affinity comparable to or better than PSMA-617, with an affinity five times that of PSMA-617.

[0170]

[0171] PSMA-617

[0172]

[0173]

[0174] Example 4: AlphaLisa method IC 50 Measurement

[0175] The compounds M006, M001, and positive reference PSMA-617 obtained in Examples 1 and 2 were diluted to six appropriate concentrations using buffer solutions (1X PBS, 0.1% BSA, 0.05% P20), with 5 μL added to each well.

[0176] Dilute PSMA protein (Recombinant Human PSMA / FOLH1 Protein) to 10 nM, adding 5 μL to each well. Then add 5 μL of biotin-probe and 5 μL of Streptavidin Donor Beads: Histidine acceptor beads (1:100) to each well and incubate at room temperature for 120 minutes. Detect fluorescence signals at 680 nm and 570 nm (AlphaScreen) using a microplate reader, and provide the IC50 values ​​for each compound. 50 As shown in the table below.

[0177] The results showed that compound M006 exhibited a lower IC50 value compared to PSMA-617. 50 value.

[0178] Compound numbering <![CDATA[IC 50 on PSMA binding(nM)]]> PSMA-617 3.5 M006 2.8 M001 2289.0

[0179] Example 5: 68 Ga-M006 and 68 Preparation and stability study of Ga-M001 complex

[0180] from 68 Ge / 68 The Ga generator was rinsed with 0.6M HCl solution. 68 GaCl3 eluent, to 2 mL 68 Add 350 μL of 3M sodium acetate solution to the GaCl3 eluent and shake well. Then add 10 μL of pure water to dissolve M006 and M001 (10 nmol) obtained in Examples 1 and 2, respectively. React the mixture at 100 °C for 15 min. Dilute the reaction solution with sterile water for injection (2 mL) and purify by passing through a C18 column. Elute the C18 column with 2 mL of water. Elute the product from the C18 column with 2 mL of ethanol / water (1 / 1, v / v) mixture to obtain the standardized product. 68 Ga-M006 and 68 Ga-M001 complex. The total radioactivity before labeling and the radioactivity of the labeled and purified product were determined using a gamma counter, and the calculated labeling yields were 18.2% (M006) and 35.0% (M001), respectively. Radioactivity was monitored by online HPLC at 0 h, 1 h, and 2 h after labeling. 68 Ga-M006 and 68 The radiochemical purity of Ga-M001 was determined, and samples were obtained at different times. 68 The radiochemical purity of Ga-M006 was 97.55% (0h), 97.83% (1h), and 97.92% (2h), yielding... 68The radiochemical purity of Ga-M001 was 91.58% (0h), 91.56% (1h), and 91.60% (2h), indicating that the labeling... 68 Ga-M006 and 68 The Ga-M001 complex is stable for at least 2 hours, and its HPLC chromatogram is shown below. Figures 3 to 8 As shown.

[0181] Example 6: Cell uptake and endocytosis experiment

[0182] Logarithmic growth phase LNCaP cells (Nanjing Kebai Biotechnology Co., Ltd.) were prepared into a cell suspension, and the cell density was adjusted to 1×10⁻⁶. 5 Seed 1 mL / well of the medium into 24-well cell culture plates. Incubate at 37°C for 48 hours. Observe the cells under a microscope to ensure cell adhesion. Replace the serum-free 1640 medium (2 mL / well) 3 hours before the experiment, and then incubate in a CO2 incubator for 2 hours.

[0183] Remove the culture medium and add 10 nM of the solution used in Example 5. 68 Ga-M006 and 68 Ga-M001 was used to record total radioactivity. After adding the sample, the 24-well plate was gently shaken and incubated at 37°C for 45 min. After incubation, the supernatant was removed, and the cells were washed three times with PBS (pre-cooled at 2-8°C). 1 mL of 1M glycine hydrochloride buffer was added to each well, and the plate was incubated at 2-8°C for 10 min. The wells were washed twice with PBS (pre-cooled at 2-8°C), and all glycine hydrochloride buffer and PBS washing solution were collected. Total radioactivity was detected using a gamma counter. 0.5 mL of 1M NaOH solution was added to each well and the plate was incubated at room temperature for 10 min to fully lyse the cells. The cells were washed with PBS until the washing solution was free of radioactivity. The 1M NaOH and PBS washing solution were collected, and total radioactivity was detected using a gamma counter. Calculations were performed. 68 Ga-M006 and 68 The results of Ga-M001 cell uptake and endocytosis are shown in the table below.

[0184] The results show that 68 Ga-M001 can be effectively taken up and internalized into prostate cancer cells.

[0185] Labeled compounds <![CDATA[Cell uptake % IA / 10 6 cell]]> <![CDATA[Percentage of intracellular uptake % IA / 10 6 cell]]> <![CDATA[ 68 Ga-M001]]> 17.9 12.0 <![CDATA[ 68 Ga-M006]]> 11.9 5.9

[0186] Example 7: 68 PET / MR Imaging Experiments of Ga-labeled Inhibitors in Animals

[0187] B-NDG mice with human prostate cancer LNCaP cells implanted in the right upper limb axilla; the tumor diameter was approximately 100 mm. 3The result obtained by injecting 5 MBq via the tail vein in Example 5 68 Ga-M006 was anesthetized and fixed with isoflurane for 1.5 hours before PET / MR imaging. Pmod software was used to process the data and calculate the %ID / g (percentage of radioactive material per gram of tissue relative to the total injected dose) for organs such as the brain, heart, liver, lungs, kidneys, muscles, spleen (if radioactive distribution was observed), bones, and tumors. The results are shown in the table below. Figure 9 The results showed that axillary tumor tissue was significantly taken up within 1.5 hours and could be metabolized through multiple pathways, including the liver and kidneys.

[0188] organ %ID / g(1.5h) liver 7.7 kidney 10.2 joint 3.4 bone 2.7 muscle 2.4 tumor 9.0

[0189] Example 8: 177 Tissue distribution experiment of Lu-labeled inhibitors in animals

[0190] B-NDG mice with human prostate cancer LNCaP cells implanted in the right upper limb axilla; the tumor diameter was approximately 100 mm. 3 100 μCi was injected via the tail vein. 177 Animals were sacrificed at 0.5h, 4h, 24h, 72h, and 120h after administration of Lu-M006. Blood plasma, urine, brain, salivary glands, thyroid gland, heart, lungs, liver, stomach, small intestine, large intestine, spleen, pancreas, adrenal glands, kidneys, bladder, testes, prostate, bone, bone marrow, muscle, fat, and tumors were collected. Radioactivity %ID / g (the percentage of radioactivity in each gram of tissue relative to the total injected dose) was determined using a gamma counter. The results are shown in the table below. The results show... 177 Lu-M006 still showed high specific uptake on PSMA-expressing tumors after 120 hours.

[0191]

[0192] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some changes or modifications to the above-described technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes, and modifications made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt or ester thereof: in, R is -L 1 -R 2 R 1 -L 2 -R 3 Or R is -L 2 -R 3 R 1 -L 1 -R 2 ; Among them, L 1 L 2 It is a divalent linker -(L) p -; Each L is independently selected from the following group: chemical bond, CO, substituted or unsubstituted CH2, substituted or unsubstituted NH, S(O), S(O)2, -O-, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-10 heteroaryl, substituted or unsubstituted C0-C6 alkylaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted (-O-CH2-CH2-) t Substituted or unsubstituted (-CO-CH2-O-CH2-CH2-O-CH2-CH2-NH-) t The substitution refers to having one or more substituents selected from the group consisting of: deuterium, halogen, amino, hydroxyl, carboxyl, cyano, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 alkylthio, C1-C6 haloalkoxy, C3-C8 cycloalkyl, 3-8 heterocyclic, C6-C10 aryl, 5-10 heteroaryl, -NR 5 R 6 -ZC(O)-OR 7 -C(O)-Z-OR 7 -C(O)NR 5 R 6 -ZR 5 R 6 ; Z is a chemical bond, -O-, -NH-, or C1-C3 alkylene; R 5 R 6 and R 7 Each element is independently selected from: hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, R 3 C6-C10 aryl, 5-10 heteroaryl, biphenyl, aniline, phenolic, halophenyl; t is selected from 0, 1, 2, 3, 4, or 5; p is an integer selected from 0 to 50; R 2 It can be H or selected from the following structures: * is R 2 Connection site with L; R 3 H is a chelating agent selected from the following: 1,4,7,10-tetraazacyclododecane-N,N',N",N'",-tetraacetic acid (=DOTA), N,N"-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N"-diacetic acid (=HBED-CC), 1,4,7-triazacyclononane-1,4,7-triacetic acid (=NOTA), 2-(4,7-bis(carboxymethyl)-1,4,7-triazonane-1 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutaric acid (DOTAGA), 1,4,7-triazacyclononanephosphonic acid (TRAP), 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphonic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphonic acid] (NOPO), 3,6,9,15-tetraazacyclononane-1-[methyl(2-carboxyethyl)phosphonic acid](NOPO), Bicyclo[9.3.1.]pentadecanediol-1(15),11,13-trien-3,6,9-triacetic acid (=PCTA), N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutyryl}amino)pentyl]-N-hydroxysuccinamide (DFO), diethylenediaminepentaacetic acid (DTPA), trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DT) PA), 1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (O-Do3A), p-isocyanothiobenzyl-DTPA (SCN-Bz-DTPA), 1-(p-isocyanothiobenzyl)-3-methyl-DTPA (1B3M), 2-(p-isocyanothiobenzyl)-4-methyl-DTPA (1M3B), 1-(2)-methyl-4-isocyanobenzyl-DTPA (MX-DTPA); R 4 Selected from -CO2H, -SO2H, -SO3H, -SO4H, -PO2H, PO3H, or PO4H2; The additional condition is R 2 and R 3 They are not both H.

2. The compound according to claim 1, characterized in that, L 1 and L 2 Each is independently selected from the following group: chemical bond, -CO-(CH2) n -CO-, -CO-(CH2) n -NH-, -CH2-CO-; Preferably, L 1 Selected from -CO-(CH2) n -CO-, -CO-(CH2) n -NH-, -CH2-CO-; Preferably, L 2 Selected from chemical bonds, -CO-(CH2) n -NH-; n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11.

3. The compound according to claim 1, characterized in that, R 3 For DOTA.

4. The compound according to claim 1, characterized in that, R 4 It is -CO2H.

5. The compound according to claim 1, characterized in that, n is 10 or 11.

6. The compound according to any one of claims 1 to 4, characterized in that, The compounds are selected from the group consisting of:

7. Use of the compound according to any one of claims 1 to 6 for the preparation of radiolabeled compounds.

8. A metal complex, characterized in that, The metal complex comprises: a radionuclide, and a compound according to any one of claims 1 to 5.

9. The metal complex according to claim 7, characterized in that, The radioactive nuclide is 111 In、 90 Y、 68 Ga、 177 Lu、 99m Tc, 64 Cu、 153 Gd, 155 Gd, 157 Gd, 213 Bi、 225 Ac or Fe.

10. A pharmaceutical composition comprising (i) a compound according to any one of claims 1 to 6, or a metal complex according to claim 8 or 9, or a pharmaceutically acceptable salt or ester thereof, and (ii) a pharmaceutically acceptable carrier.

11. Use of the compound of any one of claims 1 to 6 or the metal complex of claim 8 or 9 in the preparation of a pharmaceutical agent for imaging in a patient.

12. Use of the compound of any one of claims 1 to 6 or the metal complex of claim 8 or 9 in the preparation of a medicament for the diagnosis or treatment of prostate cancer and / or its metastases.

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