Chelating agents and radionuclide pharmaceuticals based thereon

Abstract

The application belongs to the field of biological medicine, and specifically provides a chelating agent and a radionuclide drug based on the same. More specifically, the application provides a conjugate as shown in formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein TP is a targeting group capable of binding to a target protein expressed in a cancer cell or a cancer tissue; L is absent or a linker; C is a chelating group as shown in formula (II) chelated with Pb or a radioisotope thereof or a chelating group as shown in formula (II) capable of chelating Pb or a radioisotope thereof. The radionuclide drug based on the chelating agent of the application has lower non-tumor site uptake, and can reduce toxic side effects. (I) (II).

Description

Technical Field

[0001] This invention belongs to the field of biomedicine, specifically relating to chelating agents and radionuclide drugs based thereon. Background Technology

[0002] 212 Pb, with its unique decay characteristics (high LET α-ray emission and suitable half-life), has significant advantages over traditional β-isotopes, including high killing efficiency, strong resistance to drug resistance, and good safety. Its radionuclide conjugates offer convenient administration, short treatment cycles, and broad indication coverage, and have demonstrated potent therapeutic effects against various refractory tumors in clinical studies. However, existing chelating agents and... 212 The insufficient compatibility of Pb limits its potential for clinical application.

[0003] In summary, there is an urgent need in this field to develop Pb and its isotopes, especially... 212 Pb chelating agents and corresponding radionuclide conjugates. Summary of the Invention

[0004] The purpose of this invention is to provide a novel Pb and its isotopes, especially... 212 Chelating agents for Pb and couplings using the chelating agents.

[0005] In a first aspect of the invention, a coupling compound or its stereoisomer or pharmaceutically acceptable salt is provided, wherein the coupling compound is shown in formula (I). (I) in, TP is a targeting group that can bind to target proteins expressed in cancer cells or cancerous tissues; L either does not exist or is a connector; C is a chelating group as shown in formula (II) that chelates Pb or its radioactive isotopes, or a chelating group as shown in formula (II) capable of chelating Pb or its radioactive isotopes. (II) in, R C1 R C2 R C3 and R C4 Each can be independently -OH or -NH2, with the additional condition R. C1 R C2 R C3 and R C4 At least one of them is -NH2; n is 1, 2, 3, or 4; and W C It can be -C(=O)-, -NH-, or -O-.

[0006] In another preferred embodiment, R C2 R C3 and R C4 One, two, or three of them are -NH2.

[0007] In another preferred embodiment, R C1 It is -OH.

[0008] In another preferred embodiment, n is 2 or 3; more preferably, it is 2.

[0009] In another preferred embodiment, W C It is -C(=O)-.

[0010] In another preferred example, n is 2 or 3; and W C It is -C(=O)-.

[0011] In another preferred embodiment, the chelating group shown in formula (II) is a group derived from any chelating agent selected from the group consisting of: , , , .

[0012] In another preferred embodiment, the chelating group as shown in formula (II) is any structure selected from the group consisting of: , , and .

[0013] In another preferred embodiment, TP represents an oligopeptide capable of binding to a target protein expressed in cancer cells or cancerous tissue.

[0014] In another preferred embodiment, the target protein is selected from one or more of the following: GRPR, SSTR2, PSMA, MC1R, HER2, DLL3, ROR1, CDH3, CDH17, B7H3, and B7H4.

[0015] In another preferred embodiment, the target protein is GRPR.

[0016] In another preferred embodiment, TP has an N-terminus connected to the C-terminus via L, and a C-terminus capped by a substituted amino group.

[0017] In another preferred embodiment, TP has an N-terminus connected to the C-terminus via an L-terminus, and a C-terminus capped by a substituted amino group, the substituted amino group comprising at least one functional group selected from the following: carbon-carbon triple bond, carbon-nitrogen triple bond, carbon-carbon double bond optionally substituted with fluorine, fatty alcohol, amide, or a combination thereof.

[0018] In another preferred embodiment, TP consists of 3-12 amino acids. In another preferred embodiment, TP consists of 4-11 amino acids. In another preferred embodiment, TP consists of 5-10 amino acids. In another preferred embodiment, TP consists of 6-9 amino acids. In another preferred embodiment, TP consists of 7-8 amino acids. In another preferred embodiment, TP consists of 7 amino acids. In another preferred embodiment, TP consists of 8 amino acids.

[0019] In another preferred embodiment, the amino acid is selected from one or more of the following group: D-Phe, D-Tyr , L-Gln, L-Hse L-Lys L-Trp , L-Ala, L-Val, L-Leu, Gly, , His , , , , and .

[0020] In another preferred embodiment, the amino acid sequence of TP is -Pa1-Pa2-Pa3-Pa4-Pa5-Pa6-Pa7-.

[0021] In another preferred embodiment, TP is -Pa1-Pa2-Pa3-Pa4-Pa5-Pa6-Pa7-Y1.

[0022] In another preferred embodiment, Pa1 is selected from any of the following groups: D-Phe, D-Tyr, or .

[0023] In another preferred embodiment, Pa2 is selected from any of the following groups: L-Gln, L-Hse, L-Lys or .

[0024] In another preferred embodiment, Pa3 is: α-Me-Trp( ) or L-Trp.

[0025] In another preferred embodiment, Pa4 is: L-Ala, L-Val, or L-Leu.

[0026] In another preferred embodiment, Pa5 is L-Val.

[0027] In another preferred embodiment, Pa6 is selected from the group consisting of: Gly, N -Me-Gly( ),or .

[0028] In another preferred embodiment, Pa7 is: L-His or N -Me-L-His( ).

[0029] In another preferred embodiment, Y1 is Pa8-Y2, or any structure selected from the following group: , , , , ,or .

[0030] In another preferred embodiment, Pa8 is: L-Leu, L-Phe, or .

[0031] In another preferred embodiment, Y2 is Wherein, R1 is selected from the group consisting of: C1-C5 alkynyl, C1-C5 alkylene, and C1-C3 alkyl substituted with cyano; or, Y2 is... ; where R2 is a C1-C5 alkyl group.

[0032] In another preferred embodiment, for ,or , or a combination thereof.

[0033] In another preferred embodiment, and In It represents the S or R configuration.

[0034] In another preferred embodiment, in R2, the C1-C5 alkyl group is... In another preferred embodiment, in R1, the C1-C5 ynyl group is... , ,or And / or, the C1-C3 alkyl group substituted with a cyano group is .

[0035] In another preferred embodiment, For any structure selected from the following group: , , ,or .

[0036] In another preferred embodiment, for .

[0037] In another preferred embodiment, Y2 is any structure selected from the following group: , , , or .

[0038] In another preferred embodiment, Pa1, Pa2, Pa3, Pa4, Pa5, Pa6, Pa7, Pa8, Pa9, Y1 and Y2 are each connected to the remainder of the compound by forming -NH-C(O)- through NH2 and / or -COOH in the group.

[0039] In another preferred embodiment, Y1 is any structure selected from the following group: , and .

[0040] In another preferred embodiment, TP is -Pa1-Pa2-Pa3-Pa4-Pa5-Pa6-Pa7-Y1, where Pa1 is D-Phe, Pa2 is L-Gln, Pa3 is α-Me-Trp or L-Trp, Pa5 is L-Val, and Pa6 is... N -Me-Gly or Gly, Pa7 is L-His, and Y1 is... , or .

[0041] In another preferred embodiment, TP is ,or .

[0042] In another preferred embodiment, L is a connector.

[0043] In another preferred embodiment, the linker includes an amine or carboxyl group (preferably an amine) coupled to the chelating agent (C) at one end and an amide coupled to TP at the other end.

[0044] In another preferred embodiment, L is -W LC -(M L ) m -W LTP -;in, W LC For the end connected to C, and W LC It is either -NH- or -C(=O)-, and thus interacts with W. C They together form -C(=O)NH-, -C(=O)-, or -C(=O)O-; W LTP For the end connected to TP, and WLTP -C(=O)-; M L Each is independently a unit selected from the group consisting of: C1-3 alkylene, -C1-3 alkylene-O-, amino acid residues, C4-C10 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6- to 10-membered aryl, and 5- to 10-membered heteroaryl; wherein the cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl are unsubstituted or substituted by one or more C1-4 alkyl groups; and m can be 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0045] In another preferred embodiment, m is 2, 3, or 4.

[0046] In another preferred embodiment, the C1-3 alkylene group includes: -CH2- and -CH2CH2-.

[0047] In another preferred embodiment, the amino acid residues include: β-Gly residues, namely -NHCH2CH2C(=O)-.

[0048] In another preferred embodiment, the 4- to 10-membered heterocyclic alkyl group comprises: .

[0049] In another preferred embodiment, the -C1-3 alkylene-O- includes: -CH2CH2O-.

[0050] In another preferred embodiment, L is: , or .

[0051] In another preferred embodiment, the coupling has one or more of the following features: (a) TP is -Pa1-Pa2-Pa3-Pa4-Pa5-Pa6-Pa7-Y1, where Pa1 is D-Phe, Pa2 is L-Gln, Pa3 is α-Me-Trp or L-Trp, Pa5 is L-Val, and Pa6 is... N -Me-Gly or Gly, Pa7 is L-His, and Y1 is... , or ; (b) L is -W LC -(M L ) m -W LTP -; where W LC For the end connected to C, and W LC It is either -NH- or -C(=O)-, and thus interacts with W. CTogether they form -C(=O)NH-, -C(=O)-, or -C(=O)O-; W LTP For the end connected to TP, and W LTP -C(=O)-; M L Each is independently selected from any of the following groups: C1-3 alkylene, -C1-3 alkylene-O-, amino acid residue, C4-C10 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6- to 10-membered aryl and 5- to 10-membered heteroaryl; wherein the cycloalkyl, heterocyclic alkyl, aryl and heteroaryl are unsubstituted or substituted by one or more C1-4 alkyl groups; and m is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0052] In another preferred embodiment, the coupling has one or more of the following features: (a)TP is or ;and (b) L is: , or .

[0053] In another preferred embodiment, the coupling agent is one or more coupling agents selected from the group consisting of coupling agent 1, coupling agent 2, coupling agent 3, coupling agent 4, coupling agent 5, coupling agent 6 and coupling agent 7, or the coupling agent is one or more coupling agents selected from the group consisting of coupling agent 1, coupling agent 2, coupling agent 3, coupling agent 4, coupling agent 5, coupling agent 6 and coupling agent 7, which are further chelated with Pb or its radioactive isotope. Coupled object 1: ; Coupled item 2: ; Coupled item 3: ; Coupled item 4: ; Couplet 5: ; Coupled item 6: ;and Coupled item 7: .

[0054] In another preferred embodiment, the coupling agent is any one selected from the group consisting of coupling agent 1, coupling agent 2, coupling agent 3, coupling agent 4 and coupling agent 7, or the coupling agent is any one selected from the group consisting of coupling agent 1, coupling agent 2, coupling agent 3, coupling agent 4 and coupling agent 7, which is further chelated with Pb or its radioactive isotope.

[0055] In another preferred embodiment, the coupling agent is any one of the following: coupling agent 1, coupling agent 4 and coupling agent 5, or the coupling agent is any one of the following: coupling agent 1, coupling agent 4 and coupling agent 5, which is further chelated with Pb or its radioactive isotope.

[0056] In another preferred embodiment, the coupling agent is coupling agent 1 or coupling agent 4, or the coupling agent is coupling agent 1 or coupling agent 4 further chelated with Pb or its radioactive isotope.

[0057] In another preferred embodiment, the radioactive isotopes of Pb include: 203 Pb, 212 Pb.

[0058] In another preferred embodiment, the radioactive isotope of Pb is: 212 Pb.

[0059] In another preferred embodiment, the Pb or its radioactive isotope is... 212 Pb.

[0060] In a second aspect of the invention, a pharmaceutical composition is provided comprising: (i) a conjugate or a stereoisomer thereof or a pharmaceutically acceptable salt as described in the first aspect, and (ii) a pharmaceutically acceptable carrier.

[0061] In a third aspect of the invention, the use of the conjugate or its stereoisomer or pharmaceutically acceptable salt as described in the first aspect or the pharmaceutical composition as described in the second aspect in the preparation of a medicament for treating cancer, wherein the cancer cells or cancerous tissue of said cancer express a target protein that can be bound by the TP moiety.

[0062] In another preferred embodiment, the cancer is a cancer with high GRPR expression.

[0063] In another preferred embodiment, the cancer is one or more of prostate cancer, breast cancer, glioma, and colorectal cancer.

[0064] 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. Attached Figure Description

[0065] Figure 1 It was shown that 4 hours after the injection, 212 Distribution of Pb-labeled compounds of the present invention and comparative compounds in PC3 model mouse tissues. Detailed Implementation

[0066] Through extensive and in-depth research, the inventors unexpectedly discovered a specific type of structure capable of chelating Pb (especially...). 212 A chelating agent for Pb is used, and the radionuclide conjugates using this specific chelating agent exhibit high stability, high selectivity, and strong compatibility. In particular, the uptake of radionuclide conjugates using this specific chelating agent is significantly reduced in non-tumor sites (especially the liver, pancreas, etc.). Based on this, the inventors have completed the present invention.

[0067] the term Unless otherwise specified, the terms or abbreviations herein have the conventional meanings as understood by those skilled in the art.

[0068] In this paper, a subscript of 0 indicates that the group, segment, or unit does not exist, that is, the group, segment, or unit is absent or has a single bond. For example, -(CH2)0- represents a single bond.

[0069] In this paper, single bonds indicated by dashed lines or bonds marked with wavy or dashed lines indicate the connection positions of the group with other parts.

[0070] As used herein, the term "alkyl" refers to a straight-chain or branched hydrocarbon group having a specified number of carbon atoms (i.e., C64-C ... 1-4 (Indicates 1-4 carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, etc. As used herein, the term "alkylene" refers to a divalent group derived from an alkyl group as defined above. Examples of alkylene groups include, for example, -CH2-, -CH2CH2-, etc.

[0071] As used herein, the term "cycloalkyl" refers to a fully saturated hydrocarbon ring having a specified number of ring atoms (e.g., C5-10 cycloalkyl has 5 to 10 ring atoms). "Cycloalkyl" can be monocyclic, bicyclic (e.g., bridged ring), or polycyclic hydrocarbon ring, such as bicyclic [1.1.1]pentane. As used herein, the term "cycloalkylene" refers to a divalent group derived from a cycloalkyl group as defined above.

[0072] As used herein, the term "heterocyclic alkyl" refers to a cycloalkyl group containing a specified number of ring atoms (e.g., a 5- to 10-membered heterocyclic alkyl group has 5 to 10 ring atoms) and wherein 1, 2, or 3 ring atoms are heteroatoms selected from N, O, and S (preferably N heteroatoms). Heterocyclic alkyl groups can be monocyclic, bicyclic, or polycyclic systems. As used herein, the term "heterocyclic alkylene" refers to a divalent group derived from a heterocyclic alkyl group as defined above. Heterocyclic alkyl or heterocyclic alkyl groups can be linked to other parts via carbon or nitrogen atoms on the ring.

[0073] As used herein, the term "heteroaryl" refers to an aromatic group having a specified number of ring atoms (e.g., 5- to 6-membered means containing 5 to 6 ring atoms, 9- to 10-membered means containing 9 to 10 ring atoms) and wherein one, two, or three ring atoms are heteroatoms selected from N, O, and S. Heteroaryls can be monocyclic, bicyclic, or polycyclic systems. Examples of heteroaryls include, for example, pyridyl. The term "hybridaryl" refers to a divalent group derived from a heteroaryl as defined above. Heteroaryls or hybridaryls can be linked to other parts via carbon or nitrogen atoms on the ring.

[0074] As used herein, a "peptide" is an organic compound formed by the condensation of the amino group of one amino acid with the carboxyl group of another amino acid. A "peptide segment" is a portion of a peptide as defined above, with -CO- and -NH- at both ends.

[0075] As used in this article, "amino acid" is a general term for a class of organic compounds containing amino and carboxyl groups, and is the basic building block of proteins, biological functional macromolecules. When used in the context of peptides (including cyclic peptides) or peptide segments, "amino acid" can also refer to the group (or amino acid residue) formed by removing a H from the N-terminal -NH2 and removing a -OH from the C-terminal -COOH.

[0076] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by the compounds of the present invention with an acid or base that is suitable for use as a medicine. Pharmaceutically acceptable salts include both inorganic and organic salts. A preferred class of salts are those formed by the compounds of the present invention with an acid. Suitable acids for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid. Another preferred class of salts are salts formed by the compounds of the present invention with a base, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (such as lower alkanol ammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0077] radioactive isotopes 212 Pb and related radiopharmaceuticals 212 Pb is an alpha therapeutic nuclide with great clinical translational potential. Its decay properties are perfectly suited to the needs of targeted cancer therapy. As an alpha nuclide, it can emit high-energy alpha rays, has a short half-life, and can be stably chelated by a variety of chelating agents, making it an ideal nuclide for cancer treatment. 212 Pb is a naturally occurring radioactive nuclide belonging to the uranium series, and its decay process is β-decay. - The decay cascade reaction → alpha decay: First 212 Pb (half-life 10.6 hours) via β - Decay produces daughter nuclides 212 Bi (half-life 60.6 minutes), 212 As Bi decays further, it emits alpha rays (energy 6.05 MeV) with approximately a 97% probability and beta rays with a 3% probability, eventually decaying into a stable nuclide. 208 Pb. This cascade decay mode enables "single-dose radionuclide delivery with dual radiation killing," with alpha rays as the primary therapeutic ray and beta rays accounting for a very low proportion, minimizing off-target radiation damage. Its alpha ray linear energy transfer density (LET) is as high as 80 keV / μm, which is significantly higher than that of traditional beta nuclides (such as...). 117 Lu's 0.23 keV / μm, 90The half-life of alpha rays is 87-348 times that of gamma rays (0.92 keV / μm); alpha rays penetrate biological tissues at a distance of only 50-100 μm (approximately 2-3 cell diameters), allowing them to cover solid tumor lesions without damaging surrounding normal tissue. Their 10.6-hour half-life falls between that of short-lived alpha nuclides (such as gamma rays). 213 Bi (45.6 minutes, narrow dosing window) and long half-life nuclides (such as Bi, ... 225 Ac (within 10 days, the risk of cumulative radiation exposure in normal tissues is high) ensures flexibility in drug production, transportation, labeling, and administration, while also enabling rapid clearance and reducing radiation exposure time in normal tissues.

[0078] Compared to traditional β-nuclides (such as 117 Lu、 90 Y、 131 I), 212 The alpha-ray properties of Pb give it significant advantages in terms of therapeutic efficacy and safety. Traditional beta-isotopes are widely used in radionuclide therapy for tumors, but the high LET (Left-to-Earth) properties of alpha rays cause them to form dense ionization channels within tumor cells, inducing complex damage clusters such as DNA double-strand breaks, base oxidation, and cross-linking. The tumor cell repair system cannot efficiently and collaboratively repair these damages, ultimately leading to a significantly higher apoptosis rate compared to beta-ray therapy. Regarding resistance to drug resistance… 212 Pb also showed significant effects; after traditional chemotherapy and β-sound therapy, tumor cells are prone to developing drug resistance by activating DNA repair pathways (such as homologous recombination (HR) and non-homologous end joining (NHEJ); and 212 The DNA damage clusters induced by Pb's alpha rays are extremely complex, making it difficult to complete repair even with abnormal activation of the tumor cell repair system. Therefore, it remains effective against advanced tumors resistant to chemotherapy and beta-radioactive therapies. Simultaneously, the short penetration distance of alpha rays concentrates the radioactive energy primarily within the tumor tissue, while normal tissue receives only trace amounts of radiation. 212 The short half-life of Pb also reduces the accumulation time of the radionuclide in the body, and the incidence of serious adverse reactions such as bone marrow suppression and nephrotoxicity is significantly lower than that of traditional β-radionuclide therapy (clinical data show that...). 212 The incidence of grade 3 or higher adverse reactions to Pb drugs is <15%, while 117 Lu (approximately 30%) has a wider therapeutic window.

[0079] There are currently multiple 212 Pb-based radionuclide conjugates are entering clinical trials, such as radionuclide conjugates targeting SSTR2. 212 Pb-DOTAMTATE and 212 Pb-PSC-TOC, targeting GRPR 212 Pb-GRPR1, targeting PSMA 212 Pb-ADVC001, 212Drugs such as Pb-NG001 have demonstrated excellent clinical efficacy against refractory tumors targeting different sites in phase I / II clinical trials. Among them, those targeting SSTR2... 212 Pb-DOTAMTATE and 212 Pb-PSC-TOC is primarily used to treat SSTR2-positive advanced neuroendocrine tumors (NETs), including small intestinal carcinoids, pancreatic neuroendocrine carcinomas, and pulmonary neuroendocrine carcinomas (these tumors have a response rate of <10% to conventional chemotherapy and a poor prognosis). A phase I clinical trial (NCT03866898) enrolled 42 patients with advanced SSTR2-positive NETs and administered... 212 Following Pb-DOTAMTATE treatment, the objective response rate (ORR) reached 38.1%, with 3 patients achieving complete remission (CR) and 32 patients achieving stable disease (SD), resulting in a disease control rate (DCR) of 83.3%. The average volume of target lesions shrank by 45%, with reductions of 52% and 48% in liver and bone metastases, respectively. The median progression-free survival (PFS) reached 12.8 months, and the median overall survival (OS) reached 28.6 months, significantly longer than conventional treatment (PFS 6.2 months, OS 18.3 months). In terms of safety, only 6 patients experienced mild nausea and fatigue (grades 1-2), and 3 patients experienced mild elevation of serum creatinine (grade 1). There were no serious adverse reactions such as grade 3 or higher myelosuppression or renal failure, indicating manageable safety.

[0080] 212 Pb is a divalent cation (Pb 2+ It has a relatively large ionic radius (119 pm), while traditional DOTA-type chelating agents (such as DOTA and Nota) are trivalent cations (such as...). 68 Ga 3+ , 117 Lu 3+ The design, with its coordination cavity and Pb 2+ The poor adaptability of the chelate results in a low chelation stability constant (log K is approximately 20-22). During in vivo circulation, especially in the acidic tumor microenvironment and the acidic environment of the proximal tubules of the kidney, the chelate is prone to dissociation, releasing free chelate. 212 Pb 2+ It can accumulate in organs such as the kidneys and bone marrow, causing radiation toxicity (such as kidney damage and bone marrow suppression).

[0081] This article provides 212 Pb-specific chelating agents enhance the binding affinity with Pb by increasing the number of coordinating atoms (e.g., introducing more nitrogen / oxygen coordination sites). 2+ The chelation stability constant is determined to ensure that the nuclide does not dissociate in vivo (10.6-hour half-life) and in the tumor microenvironment, thereby reducing the uptake of Pb conjugates in normal organs.

[0082] Pb chelating agent On the one hand, this article provides chelating agents or chelating groups for Pb, especially 212Pb.

[0083] As used herein, the terms "chelating agent of the present invention" or "Pb chelating agent" or "[other term]" are used interchangeably with "[other term]". 212 "Pb chelating agent" refers to a group, as shown in formula (II), capable of chelating Pb or its radioactive isotopes (or other metal ions or radionuclides), or a compound containing such a group. (II) Among them, R C1 R C2 R C3 R C4 , n and W C As defined above.

[0084] In some implementation schemes, R C1 R C2 R C3 R C4 And n are each independently the corresponding group in the chelating agents shown below. In some embodiments, W C -C(=O)- is formed by coupling -COOH in the chelating agent shown below with an active reactive group such as -NH2.

[0085] In some embodiments, the chelating agent comprises: Nuclide conjugates On the other hand, this paper provides radionuclide conjugates based on the aforementioned chelating agents.

[0086] As used herein, the terms "compound of the present invention," "conjugate of the present invention," or "nuclear conjugate," and "radioactive nuclide conjugate" refer to compounds of formula (I). The term also includes various crystal forms, pharmaceutically acceptable salts, hydrates, or solvates of compounds of formula (I). (I) C, L, and TP are defined as previously.

[0087] In some implementations, C, L, and TP are each independently the corresponding groups in the specific compound or coupling prepared in the examples.

[0088] In some embodiments, the conjugates include the following conjugates and their further conjugation with radionuclides or metal ions (such as Pb or its radioisotopes, especially...). 212 Pb chelate-formed couplings: , , , , , , .

[0089] Drugs or diagnostic compositions and their administration methods and applications Because the conjugate of this invention has excellent stable chelation... 212 Pb reduces toxicity and the ability to be taken up by non-tumor components. Therefore, the conjugates of the present invention and pharmaceutically acceptable inorganic or organic salts, as well as pharmaceutical or diagnostic compositions containing compounds of the present invention as the main active ingredient, can be used to treat and alleviate various radiotherapy-compatible tumors or cancers, such as cancers with high GRPR expression, such as prostate cancer and breast cancer, etc.

[0090] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition or achieve the intended detection purpose without causing serious side effects.

[0091] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) requiring treatment or diagnosis. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skill of a skilled physician.

[0092] The pharmaceutical or diagnostic compositions of the present invention can be administered using conventional methods, such as oral / oral, parenteral (preferably intravenous, e.g., by injection), intraperitoneal, intradermal, transdermal, inhalation, local, or transdermal administration (via cream, gel, or solution), nasal, buccal, rectal, or vaginal administration, or via implanted reservoirs or infusion. Suitable dosage forms include, but are not limited to, capsules, tablets, pills, aqueous suspensions, aqueous solutions, aerosols, suppositories, creams, gels, ointments, and skin or buccal patches. According to a preferred embodiment, the pharmaceutical composition is administered intravenously. A preferred embodiment relates to injection. Other preferred embodiments relate to infusion and local application. Other preferred embodiments relate to local application and subcutaneous reservoirs.

[0093] The main advantages of this invention include: (a) The uptake of radionuclide conjugates using the chelating agent of the present invention in non-tumor sites (especially the liver, pancreas, etc.) is significantly lower than that using radionuclide conjugates using the existing Pb chelating agent, namely DOTAM. The radionuclide conjugates of the present invention have significantly reduced toxicity or side effects.

[0094] (b) The uptake of radionuclide conjugates using the chelating agent of the present invention in non-tumor sites (especially the liver, pancreas, etc.) is significantly lower than that of radionuclide conjugates using the existing Pb chelating agent, namely DOTAM, while the uptake in tumor sites is comparable to that of radionuclide conjugates using the existing chelating agent.

[0095] 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 weight percentages and parts by weight.

[0096] I. Synthesis Examples A. General Method Solid-phase peptide synthesis: general procedures and related operations General procedure for solid-phase peptide synthesis: Peptide synthesis is performed using the Fmoc strategy in a solid-phase manner. Unless otherwise specified, all reagents are used in amounts suitable for a synthesis scale of 0.1–0.3 mmol; 2-chlorotriphenylmethyl chloride resin, king resin, or Rink amide-AM resin can be used as the solid-phase support in the synthesis process.

[0097] Resin loading: (1) If 2-chlorotriphenylmethyl chloride resin is used, the first amino acid ligation operation is as follows: Take 2-chlorotriphenylmethyl chloride resin (loading 1.09 mmol / g, 1 equivalent), swell with 25 mL dichloromethane (DCM) for 30 minutes, and then wash twice with 20 mL DCM; dissolve 3 equivalents of Fmoc-protected amino acid and 4 equivalents of N,N-diisopropylethylamine (DIEA) in N,N-dimethylformamide (DMF), and react with this mixture for 1.5 hours; then block the active site at the end of the resin with 10 mL methanol for 0.5 hours, and then wash 5 times with 10 mL DMF and 2 times with 10 mL methanol (MeOH). (2) If Rink amide-AM resin (loading 0.70 mmol / g, 1 equivalent) is used, the first amino acid residue ligation requires Fmoc deprotection operation, and the subsequent peptide chain extension steps refer to the "Peptide Chain Assembly on Resin" procedure below. (3) If Wang resin (loading 0.70 mmol / g, 1 equivalent) is used, the connection process of the first amino acid residue is completely consistent with the "Peptide chain assembly on resin" below.

[0098] Deprotection of Fmoc on resin: The resin-bound Fmoc protected peptide was treated twice with 20% piperidine / DMF solution (v / v) at room temperature, for 5 minutes the first time and 7 minutes the second time. After deprotection, the resin was washed 5 times with 10 mL DMF to remove residual piperidine.

[0099] Peptide assembly on resin: Dissolve 3 equivalents of side-chain protected Fmoc-amino acid (Fmoc-AA-OH) in DMF, add 4 equivalents of 1-hydroxybenzotriazole (HOBt) and 4 equivalents of N,N'-diisopropylcarbodiimide (DIC), or 4 equivalents of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) and 4 equivalents of DIEA for pre-activation; after activation at room temperature for 5 minutes, add the activation solution to the resin-bound peptide containing free amino groups, and shake at room temperature for 1.5 hours; after the reaction, wash the resin 5 times with 10 mL DMF, deprotect with Fmoc or Dde, and then proceed with the coupling of the next amino acid according to the same procedure.

[0100] Linker coupling on resin: Dissolve 1.5 equivalents of the protected linker in DMF, add 4 equivalents of HOBt and 4 equivalents of DIC, or 4 equivalents of HATU and 4 equivalents of DIEA for pre-activation; after activation at room temperature for 5 minutes, add the activation solution to peptide resin containing free amino groups (1.0 equivalents), and shake at room temperature for 3 hours; after the reaction, wash the resin 5 times with 10 mL of DMF, deprotect it with Fmoc or Dde, and then proceed with the coupling of the next module according to the same procedure.

[0101] Coupling of chelating agents: Dissolve 1.5 equivalents of chelating agent containing a protecting group in DMF, add 4 equivalents of HOBt and 4 equivalents of DIC, or 4 equivalents of HATU and 4 equivalents of DIEA for pre-activation; after activation at room temperature for 5 minutes, add the activation solution to peptide resin containing free amino groups (1.0 equivalents), and shake at room temperature for 3 hours; after the reaction is completed, wash the resin 5 times with 10 mL of DMF.

[0102] Cleavage Method A (Cleavage of Fully Protected Peptides): After the peptide sequence was assembled, the resin was washed three times with 20 mL of DCM and dried under vacuum. The resin was then treated with a trifluoroethanol (TFE) / DCM solution (v / v=1:4) for 3 hours. The reaction solution was collected and extracted with DCM. The organic phase was concentrated to obtain a crude product residue, which can be purified by preparative high performance liquid chromatography (HPLC) or used directly in subsequent experiments.

[0103] Cleavage Method B (Cleavage of Peptides Without Protecting Groups): After peptide sequence assembly, the resin was washed 5 times with 10 mL DMF and 4 times with 10 mL MeOH, and the resin was dried under vacuum. Subsequently, the resin was treated with a mixture of trifluoroacetic acid (TFA) / triisopropylsilane (TIS) / ethylene dithiol (EDT) / water (v / v=94:2:2:2) for 3 hours. The cleavage solution was slowly poured into pre-cooled methyl tert-butyl ether (MTBE) (MTBE volume was 10 times that of the cleavage solution), mixed thoroughly, and centrifuged for 5 minutes. The precipitate was collected and dried under vacuum. The residue was purified by preparative HPLC to obtain the target peptide.

[0104] C-terminal modification of peptides: Crude peptides containing free carboxyl groups at the C-terminus are dissolved in DMF, and 4 equivalents of HOBt and 4 equivalents of DIC, or 4 equivalents of HATU and 4 equivalents of DIEA are added for pre-activation; after activation at room temperature for 5 minutes, 3.0 equivalents of chiral amine are added, and the reaction is carried out with shaking at room temperature for 3 hours; after the reaction is completed, the reaction solution is concentrated under vacuum to obtain crude peptides with protecting groups.

[0105] Cleavage method C (cleavage of peptide protecting groups in solution): Dissolve the peptide compound containing the protecting group in a TFA / water / TIS mixture (v / v=95:2.5:2.5) and treat at room temperature for 3 hours; slowly pour the cleavage solution into pre-cooled MTBE (MTBE volume is 10 times that of the cleavage solution), mix thoroughly and centrifuge for 5 minutes; collect the precipitate and vacuum dry it, and purify the residue by preparative HPLC to obtain the target compound.

[0106] B. Synthesis of intermediates Synthesis of 4-(7-(2-amino-2-oxoethyl)-4,10-bis(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl)-5-tert-butoxy-5-oxopentanoic acid (INT-1) INT-1-1 (2 g, 6.63 mmol) was dissolved in 10 mL of dichloromethane, followed by the addition of tert-butyltrichloroacetylimide (3.02 g, 13.86 mmol) and boron trifluoride diethyl ether (93 mg, 0.66 mmol). The reaction was allowed to proceed overnight at room temperature. Sodium bicarbonate solution was then added and stirred for 5 minutes. The mixture was filtered, extracted with dichloromethane, and the filtrate was concentrated under reduced pressure and purified only by normal-phase silica gel column chromatography (PE / EA 1:20) to obtain product INT-1-2 (2 g, 5.6 mmol, 89% yield). INT-1-3 (5 g, 12.5 mmol) was dissolved in 20 mL of acetonitrile, followed by the addition of INT-1-4 (1.8 g, 13.1 mmol) and potassium carbonate (5.1 g, 37.5 eq). The reaction was allowed to proceed overnight at 60°C. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure to obtain crude INT-1-5, which was used directly in the next reaction. Crude INT-1-5 (1 g, 0.22 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of INT-1-2 (1.0 g, 0.33 mmol) and potassium carbonate (0.74 g, 55 mmol). The reaction mixture was reacted overnight at 60°C. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and purified by C18 reversed-phase silica gel column chromatography (water / acetonitrile 30%) to obtain INT-1-6 (0.9 g, 0.12 mmol, 56% yield). INT-1-6 (0.9 g, 0.12 mmol) was dissolved in methanol (20 mL), followed by the addition of palladium on carbon (0.1 g, 10%). The reaction mixture was reacted overnight at room temperature under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound INT-1 (750 mg, 0.11 mmol, 97% yield, LCMS [M+1]+ = 644.6).

[0107] Synthesis of 5-tert-butoxy-5-oxo-4-(4,7,10-tris(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl)valeric acid (INT-2) INT-2-1 (1.5 g, 8.7 mmol) was dissolved in acetonitrile (20 mL), followed by the addition of potassium carbonate (2.36 g, 17.4 mmol) and INT-1-2 (3.1 g, 8.7 mmol). The reaction mixture was reacted overnight at 50°C. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain crude INT-2-2 (1.8 g). Crude INT-2-2 (1.8 g, 4.0 mmol) was dissolved in acetonitrile (20 mL), followed by the addition of INT-1-4 (3.28 g, 24 mmol) and potassium carbonate (3.28 g, 24 mmol). The reaction mixture was reacted overnight at 60°C. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by C18 reversed-phase silica gel column chromatography (40%) to obtain INT-2-3 (2.1 g, 3.38 mmol). INT-2-3 (2.1 g, 3.38 mmol) was dissolved in methanol (20 mL), and palladium on carbon (0.2 g, 10%) was added. The reaction was carried out under hydrogen for 4 hours. The reaction solution was then filtered, and the filtrate was concentrated under reduced pressure to obtain INT-2 (1.5 g, 2.8 mmol, 83.7% yield, LCMS [M+1]+ = 530.7).

[0108] Synthesis of 5-tert-butoxy-5-oxo-4-(4,7,10-tris(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl)valeric acid (INT-3) INT-3-1 (2.0 g, 4.54 mmol) was dissolved in acetonitrile (20 mL), followed by the addition of potassium carbonate (1.88 g, 13.63 mmol) and INT-1-2 (1.56 g, 11.35 mmol). The mixture was reacted overnight at 50°C. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain crude INT-2-2 (2.0 g). INT-2-2 crude product (1.0 g) was dissolved in methanol solution, and then palladium on carbon (0.1 g, 10%) was added. The reaction was carried out overnight under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth and concentrated to obtain INT-3-3 crude product (600 mg). INT-3-3 crude product (600 mg, 2.1 mmol) was dissolved in acetonitrile (20 mL), and then INT-1-2 (785 mg, 2.2 mmol) and potassium carbonate (3.28 g, 24 mmol) were added. The reaction was carried out overnight at 50°C. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by C18 silica gel column chromatography to obtain INT-3-4 (100 mg, 0.18 mmol). INT-3-4 (100 mg, 0.18 mmol) was dissolved in acetonitrile (3 mL), followed by the addition of potassium carbonate (55 mg, 0.4 mmol) and INT-3-5 (38.8 mg, 0.2 mmol). The reaction was carried out overnight at 50°C. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain crude INT-3-6 (100 mg). Crude INT-3-6 (100 mg) was dissolved in methanol (5 mL), followed by the addition of palladium on carbon (10 mg, 10%). The reaction was carried out under hydrogen for 4 hours. The reaction solution was then filtered, and the filtrate was concentrated under reduced pressure and purified by C18 silica gel column chromatography to obtain INT-3 (70 mg, 0.12 mmol, LCMS [M+1]+ = 587.6).

[0109] C. Synthesis of couplings Example 1: DO2AMGA-Pip-D-Phe-Gln-a-Trp-Ala-Val- N -Me-Gly-His- R Synthesis of -EMea(1) Fully protected DO2AMGA-Pip-D-Phe-Gln-a-Trp-Ala-Val- N The -Me-Gly-His-2-chlorotriphenylmethyl chloropolymer was synthesized using a general method for solid-phase synthesis of peptides, and then the fully protected peptide chain DO2AMGA-Pip-D-Phe-Gln-a-Trp-Ala-Val- was obtained by cleavage method B. NThe compound was prepared by reacting -Me-Gly-His-COOH with a chiral EMea (referring to C-terminal modification of the peptide) in liquid phase to obtain a crude fully protected peptide. The protecting group was then removed by cleavage method C to obtain crude conjugate 1. Conjugate 1 was subsequently purified by preparative HPLC. Accurate mass (calculated): 1592.89 g; LCMS: (M+1) + 1593.80; HPLC method: Rt = 17.33 min; purity: 94.32%. Example 2: DO2AMGA-β-Gly-β-Gly-D-Phe-Gln-α-Trp-Ala-Val- N -Me-Gly- His- R Synthesis of -EMea(2) The synthesis of conjugate 2 was similar to that of conjugate 1. Precise mass (calculated): 1593.87; LCMS: (M+1)+1595.03; HPLC method: Rt=18.448 min, purity: 95.31%.

[0110] Example 3: DO2AMGA-PEG3-D-Phe-Gln-α-Trp-Ala-Val- N -Me-Gly-His- R Synthesis of -EMea(3) The synthesis of conjugate 3 was similar to that of conjugate 1. Precise mass (calculated): 1654.91; LCMS: (M+1)+1656.10; HPLC method: Rt=12.66 min, purity: 97.47%.

[0111] Example 4: DOAM2GA-Pip-D-Phe-Gln-α-Trp-Ala-Val- N -Me-Gly-His- R Synthesis of -EMea(4) The synthesis of conjugate 4 was similar to that of conjugate 1. Precise mass (calculated): 1590.90; LCMS: (M+1)+1592.15; HPLC method: Rt=16.13 min, purity: 96.38%.

[0112] Example 5: DOTAMGA-Pip-D-Phe-Gln-α-Trp-Ala-Val- N -Me-Gly-His- R Synthesis of -EMea(5) The synthesis of conjugate 5 was similar to that of conjugate 1. Precise mass (calculated): 1589.92; LCMS: (M+1)+1591.22; HPLC method: Rt=15.92 min, purity: 97.00%.

[0113] Example 6: DOTAMGA-β-Gly-β-GLy-D-Phe-Gln-α-Trp-Ala-Val- N -Me-Gly- His- R Synthesis of -EMea(6) The synthesis of conjugate 2 was similar to that of conjugate 1. Precise mass (calculated): 1591.90; LCMS: (M+1)+1593.21; HPLC method: Rt=16.92 min, purity: 97.81%.

[0114] Example 7: O2AMGA-Pip-D-Phe-Gln-α-Trp-Ala-Val- N Synthesis of -Me-Gly-His-Sta-Leu-NH2(7) The peptide chain of conjugate 4 can be obtained entirely through solid-phase synthesis. After cleavage by cleavage method A, crude conjugate 7 is obtained. The final product conjugate 7 is obtained by preparative HPLC purification. Precise mass (calculated value): 1737.96; LCMS: (M+1)+1739.31; HPLC method: Rt=12.77min, purity: 97.41%.

[0115] Comparative Example 1: Synthesis of reference compound R1 The synthesis of reference compound R1 was similar to that in the above examples. Precise mass (calculated): 1491.85; LCMS (M+1) +1492.98; HPLC: Rt = 12.294 min, purity: 97.6%.

[0116] Fluorescently labeled compound FAM-MJ9: The synthesis of the fluorescently labeled compound FAM-MJ9 was similar to that in the examples described above. Molecular weight (calculated): 1610.76; LCMS value (M+1) +1611.00; HPLC purity 100%. II. Test Case Test Example 1: Labeling Experiment: nat Pb labeling: Peptides containing Pb chelating groups (10 mg, 1.0 eq) and nat Pb(AcO)₂ (3.0 eq) was mixed in 0.5 mL of acetic acid / sodium acetate buffer (pH 6.1) (0.4 M) and reacted at room temperature for 20 min. The crude product was then purified by preparative HPLC to obtain chelated Pb(AcO)₂. nat Pb-containing polypeptide compounds.

[0117] 203 Pb labeling: Take 2 μL of a peptide containing a Pb chelating group (a 1 nmol / μL solution dissolved in 2 mg / mL HS15 aqueous solution), add 94 μL of 0.4 M acetate / sodium acetate buffer solution at pH 6.1. 203 200 μCi (approximately 4 μL) of Pb(AcO)₂ solution was reacted at 50 °C for 20 minutes. After cooling, sodium ascorbate (0.03 M, 25 μL) and physiological saline were added for dilution. Radiochemically pure solution was analyzed by HPLC (column AQ-C18, 3 μm, 4.6 mm). 50 mm. Elution system: Phase A: H2O, 0.1% TFA; Phase B: acetonitrile, 0.1% TFA; gradient 80% A to 20% A for 15 minutes, flow rate 1.0 ml / min; radioactivity detector, DAD 220 nm; SG paper tape; developing solvent: 50 mM EDTA aqueous solution; detector: NaI(Tl) counter.

[0118] 212 Pb labeling: Take 2 μL of a peptide containing a Pb chelating group (a 1 nmol / μL solution dissolved in 2 mg / mL HS15 aqueous solution). 212 Pb (0.5M sodium citrate solution, Chengdu Newrite) 200 uCi (approximately 200 uL) was added to 0.4M acetate / sodium acetate buffer solution at pH 6.1 and reacted at 75 ℃ for 20 minutes. After cooling, sodium ascorbate (0.03 M, 25 uL) and physiological saline were added for dilution. Radiochemical purity was detected by TLC (SG paper tape, developing solvent 50 mM EDTA aqueous solution, detector: NaI(Tl) counter). The radiochemical purity results are shown in Table 1.

[0119] Table 1 212 Pb-labeled compounds, radiochemically pure Test Example 2: In vitro receptor binding assay by competition with fluorophore-labeled ligands The binding affinity of the test compound to GRPR was determined by a competitive cell binding assay using PC3 cells expressing GRPR and FAM-MJ9 as the fluorophore-labeled ligand. PC3 cells were incubated with 50 μL of the test compound on ice for 60 min (10^5 cells / well, 96-well plate, FACS buffer (PBS containing 0.002% Tween-20 (w / v)). Then, 50 μL of 8 nM FAM-MJ9 prepared with FACS buffer was added to the wells, and the cells were incubated on ice for 30 min. After incubation, the cells were centrifuged at 300 g, 4 °C for 3 min to remove the supernatant, and then washed three times with 200 μL of ice-cold FACS buffer. Cell counts were used to analyze the cells (n=1), and the best-fit IC50 value of the test compound was calculated using GraphPad Prism with nonlinear regression fitting. The results are shown in Table 2.

[0120] Table 2 IC50 values ​​of GRPR binding assays in competition with fluorophore-labeled ligands 50 value Test Example 3: Distribution of Model Animals The animal model was developed in BALB / c nude mice with prostate cancer PC3 xenografts that highly expressed GRPR, and the tumor volume of these mice was 100-200 mm. 3 (Provided by Beijing Vital River Laboratory Animal Technology Co., Ltd.)

[0121] 10 μCi was prepared using a 0.9% sodium chloride solution. 212 Pb or 203 Pb-labeled compounds were injected into mice via the tail vein. Mice were then sacrificed, and their tissues and organs (n=3 per group) were collected. These organs were weighed and analyzed using a gamma counter (Berthold LB-2045) to calculate the percentage of the injected dose (%ID) for each organ. The results are shown in Tables 3 and 4. Figure 1 As shown.

[0122] Table 3 Injection 212 Pb-labeled conjugates were distributed in the tissues of PC-3 tumor-bearing mice 4 hours later. Table 4 Injection 212 Four hours after application, the Pb-labeled conjugate was observed in the tissue distribution of PC-3 tumor-bearing mice, specifically the tumor-to-organ ratio. contrast 212 Pb-R1 and 212 Pb-1, 212 Pb-4 and212 The in vivo distribution of Pb-5 shows that the use of novel... 212 The non-tumor tissue uptake (e.g., liver and pancreas uptake) of the Pb chelating agents, especially conjugates 1 and 4, is significantly reduced compared to compound R1 using DOTAM, while tumor uptake remains essentially the same. Therefore, the conjugates of this invention can significantly reduce damage to non-tumor tissues while maintaining therapeutic efficacy.

[0123] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A coupling compound or pharmaceutically acceptable salt, characterized in that, The coupling is shown in formula (I). (I) in, TP is ； L is , or ; C is a chelating group as shown in formula (II) that chelates Pb or its radioactive isotopes, or a chelating group as shown in formula (II) capable of chelating Pb or its radioactive isotopes. (II) Furthermore, the chelating group shown in formula (II) is any structure selected from the following group: , and .

2. The conjugate or pharmaceutically acceptable salt as described in claim 1, characterized in that, The coupling agent is any one selected from the group consisting of coupling agent 1, coupling agent 4, and coupling agent 5, or the coupling agent is any one selected from the group consisting of coupling agent 1, coupling agent 4, and coupling agent 5, which is further chelated with Pb or its radioactive isotope. Coupled object 1: ； Coupled item 4: ;and Couplet 5: 。 3. The conjugate or pharmaceutically acceptable salt as described in claim 1 or 2, characterized in that, The Pb or its radioactive isotope is 212 Pb.

4. A pharmaceutical composition, characterized in that, include: (i) the conjugate or pharmaceutically acceptable salt as described in any one of claims 1 to 3, and (ii) a pharmaceutically acceptable carrier.

5. Use of the conjugate or pharmaceutically acceptable salt of any one of claims 1 to 3 or the pharmaceutical composition of claim 4 in the preparation of a medicament for treating cancer, wherein, The cancer cells or cancerous tissues of the cancer express target proteins that can be partially bound by TP.

6. The use as described in claim 5, characterized in that, The cancer mentioned is one or more of the following: prostate cancer, breast cancer, glioma, and colorectal cancer.

Images