A targeted c-MET nuclide probe, its preparation method and application

Abstract

This invention provides a c-MET-targeting nuclide probe, its preparation method, and its applications, relating to the field of nuclide probe technology. The c-MET-targeting nuclide probe comprises a compound of formula I labeled with a radionuclide. The c-MET-targeting nuclide probe of this invention can be used as a diagnostic and therapeutic agent in human or animal lesions with high c-MET protein expression, particularly as a tumor imaging agent and a radionuclide therapeutic drug.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of nuclide probe, and in particular to a c-MET-targeted nuclide probe and a preparation method and application thereof. BACKGROUND

[0002] c-MET (hepatocyte growth factor receptor, HGFR) is a tyrosine kinase receptor, and overexpression or abnormal activation thereof is closely related to the occurrence, development and prognosis of various tumors. In non-small cell lung cancer (NSCLC), about 3%~20% of NSCLC patients have c-Met overexpression or amplification, which is more common in lung adenocarcinoma. In hepatocellular carcinoma (HCC), about 30%~50% of HCC patients have c-MET overexpression or amplification, and c-MET expression is up-regulated in gastric cancer (GC), colorectal cancer (CRC), renal cancer (renal cell carcinoma, RCC), breast cancer, ovarian cancer, pancreatic cancer and the like, which has become an attractive biomarker for solid tumor imaging and treatment. Although many radio-pharmaceutical therapies have been developed, most of them have problems such as insufficient tumor specificity and short tumor retention time, which shows that further improvement is needed.

[0003] Crizotinib is an antitumor drug, which is a tyrosine kinase inhibitor, and the main target is c-MET, which is used for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) positive for anaplastic lymphoma kinase (ALK) determined by the NMPA approved detection method. Crizotinib can specifically target tumor tissue, activate the pathway to further cause tumor cell apoptosis, and play a tumor treatment role. In the development of nuclide probes with tumor specificity, crizotinib with c-MET overexpression tumor specificity has certain research value, can be used for the development of specific targeting nuclide probes, and can be used for preoperative PET imaging of tumors.

[0004] Surgery is still the most effective means for treating tumors, which can not only increase the 5-year survival rate of patients by 11 times, but also increase the postoperative survival rate by nearly 2~5 times. Accurate positioning of tumors is the premise for achieving complete resection of tumors and reducing the local recurrence rate. Positron emission tomography (PET) can realize non-invasive tumor diagnosis and monitoring with higher penetration depth and quantitative whole-body imaging.

[0005] Therefore, the present application is proposed. SUMMARY

[0006] 1. Objectives of the Invention

[0007] The present application aims to provide a c-MET targeted nuclide probe and its preparation method and application. Through the strategy of enhancing the target affinity of chemical probes, using the structural selectivity of crizotinib, using a covalent method to optimize the parent compound, a new compound is obtained, which is used as a c-MET targeted radioactive ligand, and is used for PET imaging. From its design, synthesis and in vitro and in vivo evaluation, the nuclide probe can specifically target c-MET overexpressing tumors, realize non-invasive tumor diagnosis and monitoring.

[0008] 2. Technical solution

[0009] In order to achieve the above-mentioned purpose of the present application, the following technical solutions are adopted:

[0010] In a first aspect, the present application provides a compound represented by formula I:

[0011]

[0012] Formula I;

[0013] wherein,

[0014] The Y group is selected from any one of the following groups:

[0015] , ;

[0016] m is selected from a positive integer between 1 and 10, and n is selected from a positive integer between 1 and 10.

[0017] Preferably, m is selected from a positive integer between 1 and 6, and n is selected from a positive integer between 1 and 6.

[0018] Preferably, m is selected from a positive integer between 1 and 3, and n is selected from a positive integer between 1 and 3.

[0019] Preferably, m is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0020] Preferably, n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0021] Preferably, m is selected from 1 or 2.

[0022] Preferably, n is selected from 1 or 2.

[0023] Preferably, m is selected from 1, and n is selected from 1.

[0024] Preferably, m is selected from 2, and n is selected from 2.

[0025] In a second aspect, the present application provides a class of compounds, which is selected from any one of the following structures:

[0026]

[0027] CR-PEG2-C1-NOTA;

[0028]

[0029] CR-PEG2-C1-DOTA;

[0030]

[0031] CR-PEG4-C2-NOTA;

[0032]

[0033] CR-PEG4-C2-DOTA.

[0034] Thirdly, the present invention provides a c-MET-targeting nuclide probe, the c-MET-targeting nuclide probe comprising a radiolabeled compound of formula I:

[0035]

[0036] Formula I;

[0037] in,

[0038] The Y group is selected from any one of the following groups. Linkage sites of representative groups:

[0039] , ;

[0040] m is selected from positive integers between 1 and 10, and n is selected from positive integers between 1 and 10.

[0041] Preferably, m is selected from positive integers between 1 and 6, and n is selected from positive integers between 1 and 6.

[0042] Preferably, m is selected from a positive integer between 1 and 3, and n is selected from a positive integer between 1 and 3.

[0043] Preferably, m is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0044] Preferably, n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0045] Preferably, m is selected from 1 or 2.

[0046] Preferably, n is selected from 1 or 2.

[0047] Preferably, m is selected from 1, and n is selected from 1.

[0048] Preferably, m is selected from 2, and n is selected from 2.

[0049] Fourthly, the present invention provides a c-MET-targeting nuclide probe, wherein the c-MET-targeting nuclide probe comprises any one of the following radiolabeled compounds:

[0050]

[0051] CR-PEG2-C1-NOTA;

[0052]

[0053] CR-PEG2-C1-DOTA;

[0054]

[0055] CR-PEG4-C2-NOTA;

[0056]

[0057] CR-PEG4-C2-DOTA.

[0058] Preferably, the radionuclide includes 68 Ga、 64 Cu、 86 Y、 89 Zr、 90 Y、 111 In、 123 I or 124 Any one of I, preferably 68 Ga.

[0059] Fifthly, the present invention provides a method for preparing a compound as described in the first or second aspect, the method comprising:

[0060] (1) Crizotinib and compound PG-L-PEG 2n -C m -COOH undergoes a condensation reaction to yield compound A; where PG represents a protecting group, L group is selected from NH or C=O, m is selected from positive integers between 1 and 10, and n is selected from positive integers between 1 and 10. The reaction formula is shown below:

[0061] ;

[0062] (2) Compound A is deprotected to obtain compound B; wherein the L' group is selected from NH2 or COOH, and the reaction formula is shown below:

[0063] ;

[0064] (3) Compound B and Y with a protecting group undergo a condensation reaction, followed by deprotection treatment, to obtain the compound as described in the first aspect or the second aspect; wherein the reaction formula is shown below:

[0065] ;

[0066] Wherein, the Y with the protecting group is selected from any one of the following compounds:

[0067] , ;

[0068] As further explanation, the corresponding values ​​after deprotection of Y with a protecting group are as follows:

[0069] , .

[0070] Preferably, in step (1), the protecting group PG is tert-butyloxycarbonyl (Boc).

[0071] Preferably, in step (1), the L group is NH.

[0072] Preferably, in step (1), the protecting group PG is tert-butyloxycarbonyl and the L group is NH.

[0073] Preferably, in step (1), crizotinib and Boc-NH-PEG 2n -C m -COOH undergoes a condensation reaction to yield compound A; the reaction equation is shown below:

[0074] .

[0075] Preferably, in step (2), compound A undergoes deprotection treatment to obtain compound B; wherein the reaction formula is shown below:

[0076] .

[0077] Preferably, in step (3), the protecting group is two tert-butyl ester (bis(tBu)ester) groups.

[0078] Preferably, in step (3), the Y with the protecting group is Y-bis(tBu)ester.

[0079] Preferably, in step (3), compound B and Y-bis(tBu)ester undergo a condensation reaction, followed by deprotection treatment to obtain the compound; wherein the reaction formula is shown below:

[0080] ;

[0081] Preferably, in step (1), the crizotinib and Boc-NH-PEG 2n -C m The molar ratio of -COOH is (0.5~2):1.

[0082] Preferably, in step (1), the temperature of the condensation reaction is 30~40℃ and the time of the condensation reaction is 12~24 h.

[0083] Preferably, in step (1), the condensation reaction is carried out in a solvent selected from dimethyl sulfoxide and / or N,N -Dimethylformamide.

[0084] Preferably, in step (1), the condensation reaction is carried out under a protective gas atmosphere, wherein the protective gas is nitrogen.

[0085] Preferably, in step (1), the condensation reaction is carried out in the presence of a condensing agent, wherein the condensing agent is a dipyrrolidinyl ( N ⁻-Succinylimino)carbomon hexafluorophosphate.

[0086] Preferably, in step (1), the Boc-NH-PEG 2n -C m The molar ratio of -COOH to condensing agent is 1:(1.1~2).

[0087] Preferably, in step (1), the condensation reaction is carried out in the presence of a base, wherein the base is... N,N -Diisopropylethylamine.

[0088] Preferably, in step (1), the Boc-NH-PEG 2n -C m The molar ratio of COOH to base is 1:(0.5~5).

[0089] Preferably, in step (2), the reagent used for the deprotection treatment is trifluoroacetic acid.

[0090] Preferably, in step (2), the temperature of the deprotection treatment is 30~40℃, and the time of the deprotection treatment is 1~3 h.

[0091] Preferably, in step (3), the molar ratio of compound B to Y-bis(tBu)ester is (0.5~2):1.

[0092] Preferably, in step (3), the temperature of the condensation reaction is 30~40℃ and the time of the condensation reaction is 12~24 h.

[0093] Preferably, in step (3), the condensation reaction is carried out in a solvent selected from dimethyl sulfoxide and / or N,N -Dimethylformamide.

[0094] Preferably, in step (3), the condensation reaction is carried out under a protective gas atmosphere, wherein the protective gas is nitrogen.

[0095] Preferably, in step (3), the condensation reaction is carried out in the presence of a condensing agent, wherein the condensing agent is a dipyrrolidinyl ( N ⁻-Succinylimino)carbomon hexafluorophosphate.

[0096] Preferably, in step (3), the molar ratio of compound B to condensing agent is 1:(1.1~2).

[0097] Preferably, in step (3), the condensation reaction is carried out in the presence of a base, wherein the base is... N,N -Diisopropylethylamine.

[0098] Preferably, in step (3), the molar ratio of compound B to base is 1:(0.5~5).

[0099] Preferably, in step (3), the reagent used for the deprotection treatment is trifluoroacetic acid.

[0100] Preferably, in step (3), the temperature of the deprotection treatment is 30~40℃, and the time of the deprotection treatment is 1~3 h.

[0101] In a sixth aspect, the present invention provides a method for preparing a targeted c-MET nuclide probe as described in the third or fourth aspect, the method comprising: radiolabeling a compound as described in either the first or second aspect with a radionuclide to obtain the targeted c-MET nuclide probe.

[0102] Preferably, the radioactive labeling includes the following steps:

[0103] The sodium acetate solution, the compound described in either the first or second aspect, and the radionuclide solution are mixed and reacted to obtain the targeted c-MET nuclide probe.

[0104] Preferably, the radioactivity of the radionuclide solution is 1~10 mCi.

[0105] Preferably, the molar volume ratio of the compound described in either the first or second aspect to the radionuclide solution is (0.5~1.7)×10⁻⁶. -8 mol / mL. Preferably, it is 1.135 × 10⁻⁶. -8 mol / mL.

[0106] Preferably, the compound described in either the first aspect or the second aspect is added by adding a solution of the compound described in either the first aspect or the second aspect, wherein the compound described in either the first aspect or the second aspect is first dissolved in 1×PBS buffer.

[0107] Preferably, the concentration of the compound solution described in either the first or second aspect is 5 × 10⁻⁶. -6 M.

[0108] Preferably, the volume ratio of the sodium acetate solution to the radionuclide solution is 1:1.

[0109] Preferably, the sodium acetate solution has a concentration of 1-3 M and a pH of 4.

[0110] Preferably, the temperature of the radioactive labeling is 85~95℃, and the radioactive labeling time is 5~20 min.

[0111] In a seventh aspect, the present invention provides a metal complex comprising a radionuclide and an organic ligand, wherein the radionuclide comprises... 68 Ga、 64 Cu、 86 Y、 89 Zr、 90 Y、 111 In、 123 I or 124 Any one of I; the organic ligand includes the compound described in either the first or second aspect; the radionuclide and the organic ligand form a metal complex through coordination.

[0112] Eighthly, this invention provides the use of a targeted c-MET nuclide probe as described in either the third or fourth aspect and / or a metal complex as described in the seventh aspect, or its racemic mixture, stereoisomer, or pharmaceutically acceptable salt, in the preparation of a reagent for tumor imaging. In animal experiments, the radiocomplex of this invention exhibits a high tumor / muscle ratio, demonstrating promising application prospects.

[0113] Preferably, the tumor includes any one of liver cancer, pancreatic cancer, colon cancer, gastric cancer, breast cancer, or head and neck cancer.

[0114] In a ninth aspect, the present invention provides the use of a c-MET-targeting nuclide probe as described in any of the third or fourth aspects, or a metal complex as described in the seventh aspect, or a racemic mixture, stereoisomer, or pharmaceutically acceptable salt thereof, in the preparation of a reagent for identifying c-MET-overexpressing tumors.

[0115] In a tenth aspect, the present invention provides the use of a compound as described in the first or second aspect, or a targeted c-MET nuclide probe as described in the third or fourth aspect, or a metal complex as described in the seventh aspect, or a racemic mixture, stereoisomer, or pharmaceutically acceptable salt thereof, in the preparation of a drug for treating tumors.

[0116] Preferably, the tumor includes any one of liver cancer, pancreatic cancer, colon cancer, gastric cancer, breast cancer, or head and neck cancer.

[0117] In the eleventh aspect, the present invention provides a tumor contrast agent comprising any of the compounds described in the first or second aspect, or any of the c-MET targeting nuclide probes described in the third or fourth aspect, or the metal complexes described in the seventh aspect, or their racemic mixtures, stereoisomers, or pharmaceutically acceptable salts.

[0118] In a twelfth aspect, the present invention provides a reagent for identifying c-MET overexpressing tumors, comprising any compound described in the first or second aspect, or any c-MET-targeting nuclide probe described in the third or fourth aspect, or the metal complex described in the seventh aspect, or a racemic mixture, stereoisomer, or pharmaceutically acceptable salt thereof.

[0119] In a thirteenth aspect, the present invention provides a pharmaceutical composition comprising a compound described in any of the first or second aspects, or a c-MET-targeting nuclide probe described in any of the third or fourth aspects, or a metal complex described in the seventh aspect, or a racemic mixture, stereoisomer, pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier thereof.

[0120] In a fourteenth aspect, the present invention provides a method for diagnosing tumors, comprising administering to a subject a targeted c-MET nuclide probe as described in either the third or fourth aspect or a metal complex as described in the seventh aspect, or a racemic mixture, stereoisomer, or pharmaceutically acceptable salt thereof.

[0121] Preferably, the tumor includes any one of liver cancer, pancreatic cancer, colon cancer, gastric cancer, breast cancer, or head and neck cancer.

[0122] In a fifteenth aspect, the present invention provides a method of treating tumors, comprising administering to a subject a compound described in either the first or second aspect, or a targeted c-MET nuclide probe described in either the third or fourth aspect, or a metal complex described in the seventh aspect, or a racemic mixture, stereoisomer, or pharmaceutically acceptable salt thereof.

[0123] Preferably, the tumor includes any one of liver cancer, pancreatic cancer, colon cancer, gastric cancer, breast cancer, or head and neck cancer.

[0124] 3. Beneficial effects

[0125] Compared with the prior art, the advantages of this application are as follows:

[0126] (1) The present invention uses organic total synthesis to synthesize a novel compound ligand, including crizotinib, PEG group and chelating agent. Crizotinib is used as the recognition group. PEG end modification is performed on crizotinib. PEG is linked with chelating agent Y (NOTA, DOTA) to coordinate with radionuclides and can be used to prepare c-MET target nuclide probes.

[0127] (2) The metal complex provided by the present invention includes a compound ligand and a radionuclide coordinated thereto, which can specifically target c-MET overexpressing tumors for PET imaging, thereby realizing non-invasive tumor diagnosis and monitoring.

[0128] (3) The series of targeted c-MET nuclide probes synthesized in this invention utilize PEG groups to link crizotinib with chelating agent ligands of specific structures, which not only further improves its water solubility, but also enables it to be rapidly cleared in normal tissues, thereby quickly achieving the tumor background signal ratio that meets clinical needs.

[0129] (4) The series of c-MET-targeting nuclide probes synthesized in this invention have good active targeting effects in identifying c-MET-overexpressing tumors and have great development potential in the fields of tumor surgery and medical cell labeling. Attached Figure Description

[0130] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0131] Figure 1 The mass spectrum of CR-PEG2-C1-NOTA provided in Example 1.

[0132] Figure 2 Provided for Example 1 68 High performance liquid chromatogram of Ga-CR-PEG2-C1-NOTA.

[0133] Figure 3 The mass spectrum of CR-PEG2-C1-DOTA provided in Example 2.

[0134] Figure 4 Provided for Example 2 68High performance liquid chromatogram of Ga-CR-PEG2-C1-DOTA.

[0135] Figure 5 The mass spectrum of CR-PEG4-C2-DOTA provided in Example 3.

[0136] Figure 6 Provided for Example 3 68 High performance liquid chromatogram of Ga-CR-PEG4-C2-DOTA.

[0137] Figure 7 The targeted c-MET nuclide probe provided in Example 1 68 Liver tumor-specific targeted imaging map of Ga-CR-PEG2-C1-NOTA.

[0138] Figure 8 The targeted c-MET nuclide probe provided in Example 2 68 Liver tumor-specific targeted imaging of Ga-CR-PEG2-C1-DOTA.

[0139] Figure 9 The targeted c-MET nuclide probe provided in Example 3 68 Liver tumor-specific targeted imaging of Ga-CR-PEG4-C2-DOTA. Detailed Implementation

[0140] Unless otherwise defined herein, the scientific and technical terms used in conjunction with this invention shall have the meanings commonly understood by one of ordinary skill in the art. The meaning and scope of terms shall be clear; however, in any case of potential ambiguity, the definitions provided herein shall prevail over any dictionary or foreign definitions. In this application, unless otherwise stated, the use of "or" means "and / or". Furthermore, the use of the term "comprising" and other forms is non-limiting.

[0141] It should be noted that specific details are set forth in the following description to provide a full understanding of the invention. However, the invention can be practiced in many ways other than those described herein, and those skilled in the art can make similar extensions without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0142] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0143] In a first aspect, the present invention provides a c-MET-targeting nuclide probe, the c-MET-targeting nuclide probe comprising a radiolabeled compound of formula I:

[0144]

[0145] Formula I;

[0146] in,

[0147] The Y group is selected from any one of the following groups:

[0148] , ;

[0149] m is selected from a positive integer between 1 and 10, for example, it can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and is more preferably 1 or 2.

[0150] n is selected from a positive integer between 1 and 10, for example, it can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and is more preferably 1 or 2.

[0151] In this invention, several novel radionuclide probes with c-MET targeting capabilities were designed and synthesized. Using crizotinib as a recognition group, a c-MET inhibitor was modified with a PEG terminus, and then linked to a chelating agent Y (NOTA, DOTA) via PEG to construct a novel radionuclide probe with c-MET targeting capabilities. This probe can specifically target and identify c-MET-overexpressing tumors. The radionuclide probe obtained in this invention can specifically recognize c-MET-overexpressing tumors and is rapidly cleared from normal tissues, thereby quickly achieving a tumor background signal ratio (TBR>1.5) that meets clinical requirements for preoperative tumor PET imaging.

[0152] Crizotinib is an anti-tumor drug, belonging to the tyrosine kinase inhibitor class, with its primary target being c-MET. It is used to treat patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who are positive for anaplastic lymphoma kinase (ALK) as determined by NMPA-approved detection methods. Crizotinib specifically targets tumor tissue, activating pathways that further induce tumor cell apoptosis, thus playing a therapeutic role in tumor treatment. In the development of tumor-specific radionuclide probes, anti-tumor drugs with tumor-specific killing effects have certain research value and can be used in the development of specific targeted radionuclide probes to further expand the application value of drugs for tumor imaging and resection.

[0153] As an optional implementation, the compound represented by Formula I includes any one of the following compounds:

[0154]

[0155] CR-PEG2-C1-NOTA;

[0156]

[0157] CR-PEG2-C1-DOTA;

[0158]

[0159] CR-PEG4-C2-NOTA;

[0160]

[0161] CR-PEG4-C2-DOTA.

[0162] As an optional implementation, the radionuclide includes 68 Ga、 64 Cu、 86 Y、 89 Zr、 90 Y、 111 In、 123 I or 124 Any one of I, preferably 68 Ga.

[0163] In a preferred embodiment, the radionuclide is 68 Ga.

[0164] As an optional implementation, the present invention provides a method for preparing a targeted c-MET nuclide probe as described in the first aspect, the method comprising:

[0165] (1) Crizotinib and Boc-NH-PEG 2n -C m -COOH undergoes a condensation reaction to yield compound A; the reaction equation is shown below:

[0166] ;

[0167] (2) Compound A was deprotected to obtain compound B; the reaction formula is shown below:

[0168] ;

[0169] (3) Compound B and Y-bis(tBu)ester undergo a condensation reaction, followed by deprotection treatment, to obtain the compound shown in Formula I; wherein the reaction formula is as follows:

[0170] ;

[0171] The Y-bis(tBu)ester is selected from any one of the following compounds:

[0172] , ;

[0173] (4) Radiolabel the compound represented by Formula I with a radionuclide to obtain the targeted c-MET nuclide probe.

[0174] As an optional implementation, in step (1), the crizotinib and Boc-NH-PEG 2n -C m The molar ratio of -COOH is (0.5~2):1, for example, it can be 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2:1, etc.

[0175] As an optional implementation, in step (1), the temperature of the condensation reaction is 30~40℃, for example, it can be 30℃, 31℃, 32℃, 33℃, 34℃, 35℃, 36℃, 37℃, 38℃, 39℃, 40℃, etc.; the time of the condensation reaction is 12~24 h, for example, it can be 12 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 24 h, etc.

[0176] As an optional implementation, in step (1), the condensation reaction is carried out in a solvent selected from dimethyl sulfoxide and / or N,N -Dimethylformamide.

[0177] As an optional implementation, in step (1), the condensation reaction is carried out under a protective gas atmosphere, wherein the protective gas is nitrogen.

[0178] As an optional implementation, in step (1), the condensation reaction is carried out in the presence of a condensing agent, wherein the condensing agent is a dipyrrolidinyl ( N ⁻-Succinylimino)carbomon hexafluorophosphate.

[0179] As an optional implementation, in step (1), the Boc-NH-PEG 2n -C m The molar ratio of -COOH to condensing agent is 1:(1.1~2), for example, it can be 1:1.1, 1:1.2, 1:1.25, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, etc.

[0180] As an optional implementation, in step (1), the condensation reaction is carried out in the presence of a base, wherein the base is... N, N -Diisopropylethylamine.

[0181] As an optional implementation, in step (1), the Boc-NH-PEG 2n -C m The molar ratio of -COOH to base is 1:(0.5~5), for example, it can be 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, etc.

[0182] As an optional implementation, step (1) further includes a post-processing step after the condensation reaction is completed:

[0183] The reaction solution obtained after the reaction in step (1) was extracted with a mixture of water and dichloromethane. The lower dichloromethane phase was removed and evaporated to dryness to obtain compound A.

[0184] As an optional implementation, the volume ratio of water to dichloromethane in the mixture is 1:(0.5~2), for example, it can be 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.85, 1:0.9, 1:0.95, 1:1, 1:1.05, 1:1.1, 1:1.15, 1:1.2, 1:1.4, 1:1.6, 1:1.8, 1:2, etc.

[0185] As an optional implementation, in step (2), the reagent used for the deprotection treatment is trifluoroacetic acid.

[0186] As an optional implementation, in step (2), the deprotection treatment includes: using trifluoroacetic acid and stirring, and then evaporating the trifluoroacetic acid to obtain compound B.

[0187] As an optional implementation, in step (2), the temperature of the deprotection treatment is 30~40℃, for example, it can be 30℃, 31℃, 32℃, 33℃, 34℃, 35℃, 36℃, 37℃, 38℃, 39℃, 40℃, etc.; the time of the deprotection treatment is 1~3 h, for example, it can be 1 h, 1.2 h, 1.4 h, 1.6 h, 1.8 h, 2 h, 2.2 h, 2.4 h, 2.6 h, 2.8 h, 3 h, etc.

[0188] As an optional implementation, in step (3), the molar ratio of compound B to Y-bis(tBu)ester is (0.5~2):1, for example, it can be 0.5:1, 0.6:1, 0.8:1, 1:1, 1.2:1, 1.4:1, 1.5:1, 1.6:1, 1.8:1, 2:1, etc.

[0189] As an optional implementation, in step (3), the temperature of the condensation reaction is 30~40℃, for example, it can be 30℃, 31℃, 32℃, 33℃, 34℃, 35℃, 36℃, 37℃, 38℃, 39℃, 40℃, etc.; the time of the condensation reaction is 12~24 h, for example, it can be 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, 19 h, 20 h, 21 h, 22 h, 23 h, 24 h, etc.

[0190] As an optional implementation, in step (3), the condensation reaction is carried out in a solvent selected from dimethyl sulfoxide and / or N,N -Dimethylformamide.

[0191] As an optional implementation, in step (3), the condensation reaction is carried out under a protective gas atmosphere, wherein the protective gas is nitrogen.

[0192] As an optional implementation, in step (3), the condensation reaction is carried out in the presence of a condensing agent, wherein the condensing agent is a dipyrrolidinyl ( N -succinylimino)carbomon hexafluorophosphate

[0193] As an optional implementation, in step (3), the molar ratio of compound B to condensing agent is 1:(1.1~2), for example, it can be 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, etc.

[0194] As an optional implementation, in step (3), the condensation reaction is carried out in the presence of a base, wherein the base is... N, N -Diisopropylethylamine.

[0195] As an optional implementation, in step (3), the molar ratio of compound B to the base is 1:(0.5~5), for example, it can be 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, etc.

[0196] As an optional implementation, in step (3), the reagent used for the deprotection treatment is trifluoroacetic acid.

[0197] As an optional implementation, in step (3), the temperature of the deprotection treatment is 30~40℃, for example, it can be 30℃, 31℃, 32℃, 33℃, 34℃, 35℃, 36℃, 37℃, 38℃, 39℃, 40℃, etc.; the time of the deprotection treatment is 1~3 h, for example, it can be 1 h, 1.2 h, 1.4 h, 1.6 h, 1.8 h, 2 h, 2.2 h, 2.4 h, 2.6 h, 2.8 h, 3 h, etc.

[0198] As an optional implementation, in step (3), the deprotection treatment includes: adding the reaction liquid obtained after the condensation reaction in step (3) dropwise into a trifluoroacetic acid solution, filtering and drying to obtain the compound shown in formula I.

[0199] As an optional implementation, in step (4), the radioactive labeling includes the following steps:

[0200] The sodium acetate solution, the compound solution shown in Formula I, and the radionuclide solution are mixed and reacted to obtain the targeted c-MET nuclide probe.

[0201] As an optional implementation, the radioactivity of the radionuclide solution is 1~10 mCi, for example, it can be 1 mCi, 2 mCi, 3 mCi, 4 mCi, 5 mCi, 6 mCi, 7 mCi, 8 mCi, 9 mCi, 10 mCi, etc., preferably 5 mCi.

[0202] As an optional implementation, the mass-to-volume ratio of the compound represented by Formula I to the radioactive nuclide solution is (0.5~1.7)×10⁻⁶. -8 mol / mL. Preferably, it is 1.135 × 10⁻⁶. -8 mol / mL.

[0203] As an optional implementation, the volume ratio of the sodium acetate solution to the radionuclide solution is 1:1.

[0204] As an optional implementation, the concentration of the sodium acetate solution is 1~3 M, for example, it can be 1 M, 1.2 M, 1.5 M, 1.8 M, 2 M, 2.2 M, 2.5 M, 2.8 M, 3 M, etc., preferably 2 M, and the pH is 4.

[0205] As an optional implementation, in step (4), the temperature of the radioactive label is 85~95℃, for example, it can be 85℃, 86℃, 87℃, 88℃, 89℃, 90℃, 91℃, 92℃, 93℃, 94℃, 95℃, etc.; the radioactive labeling time is 5~20 min, for example, it can be 5 min, 6 min, 8 min, 10 min, 12 min, 14 min, 15 min, 16 min, 18 min, 20 min, etc.

[0206] In a preferred embodiment, step (4) specifically includes the following steps:

[0207] Using a 5 mL EP tube as the reaction vessel, 1 mL of 2M sodium acetate solution (pH=4), the compound solution shown in Formula I, and 1 mL of […] were added sequentially. 68 A GaCl3 radionuclide solution (5 mCi) was prepared by heating the mixture to 90°C and reacting for 10 min to obtain the targeted c-MET nuclide probe. 68 Ga-CR-PEG 2n -C m -Y.

[0208] Thirdly, the present invention provides the use of the targeted c-MET nuclide probe as described in the first aspect, or its racemic, stereoisomer, or pharmaceutically acceptable salt thereof, in the preparation of a reagent for tumor imaging.

[0209] This invention relates to a c-MET-targeting nuclide probe and its applications, specifically to a compound of Formula I, or its precursor compound, isotopic compound, salt, or hydrate. This compound, when labeled with a radionuclide, yields a class of c-MET-targeting nuclide probes, which can be used as diagnostic and therapeutic agents in lesions with high c-MET protein expression in humans or animals, particularly as tumor imaging agents and radionuclide therapeutic drugs. In animal experiments, the radiocomplex of this invention exhibits a high tumor / muscle ratio, demonstrating promising application prospects.

[0210] As an optional implementation, the tumor includes any one of liver cancer, pancreatic cancer, colon cancer, gastric cancer, breast cancer, or head and neck cancer.

[0211] As an optional implementation, the present invention provides a liver cancer tumor imaging model and a method for establishing the same, specifically including the following steps: inoculating a human liver cancer cell line with high c-MET expression into the axilla of a mouse, and injecting the c-MET nuclide probe of the present invention via tail vein injection.

[0212] It is important to note that after the liver tumor imaging model is established, small animal PET imaging equipment is used to visualize the small molecules in the liver tumor.

[0213] Fourthly, the present invention provides the use of the c-MET-targeting nuclide probe as described in the first aspect, or its racemic, stereoisomer, or pharmaceutically acceptable salt thereof, in the preparation of a reagent for identifying c-MET-overexpressing tumors.

[0214]

Terminology Explanation

[0215] As mentioned in this invention, the term "pharmaceutically acceptable salt" means that the salt is not only physiologically acceptable to the subject, but also refers to a synthetic substance that has pharmaceutical value, such as a salt formed as an intermediate during chiral resolution, although such intermediate salt cannot be directly given to the subject, but can play a role in obtaining the end product of this invention.

[0216] As mentioned in this invention, a pharmaceutically acceptable salt of the compound represented by Formula I is a salt formed with an alkali or alkali metal. Acids that form pharmaceutically acceptable salts with the compound represented by Formula I include inorganic acids and organic acids. More specifically, alkali metals that form pharmaceutically acceptable salts with the compound represented by Formula I include, but are not limited to, lithium, sodium, potassium, magnesium, calcium, aluminum, zinc, etc.; bases that form pharmaceutically acceptable salts with the compound represented by Formula I include, but are not limited to, choline, diethanolamine, morpholine, etc.

[0217] The present invention will be further illustrated below by way of examples. Unless otherwise specified, the materials in the examples are prepared according to existing methods or purchased directly from the market.

[0218]

Material

[0219] Materials and their sources mentioned in this invention:

[0220] Boc-NH-PEG2-C1-COOH (Boc-NH-PEG2-COOH, CAS: 108466-89-3); Boc-NH-PEG4-C2-COOH (Boc-NH-PEG4-COOH, CAS: 756525-91-4); dipyrrolidinyl ( N -Succinylimino)carbomon hexafluorophosphate (CAS: 207683-26-9); all purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd.

[0221] Crizotinib (CR) (CAS: 877399-52-5) was purchased from Nanjing Juyou Scientific Instruments Co., Ltd.

[0222] NOTA-bis(tBu)ester (CAS: 1161415-28-6), purchased from Nanjing Wanqing Chemical Glass Instrument Co., Ltd.

[0223] DOTA-bis(tBu)ester (CAS: 137076-54-1), purchased from Nanjing Wanqing Chemical Glass Instrument Co., Ltd.

[0224] Balb / c nude (nude mouse), Jiangsu Jicui Yaokang Biotechnology Co., Ltd.

[0225]

Detection Method

[0226] The compound ligands were characterized by mass spectrometry using a 4600 UPLC / Triple TOF instrument.

[0227] Targeting c-MET nuclide probes is detected using high-performance liquid chromatography (HPLC). Specific methods include:

[0228] The sample to be tested was dissolved in acetonitrile solution (15% acetonitrile + 85% water) and detected by high performance liquid chromatography under the following conditions:

[0229]

[0230] Example 1

[0231] This embodiment provides a c-MET-targeting nuclide probe, which is a radioactive nuclide. 68 Ga-labeled CR-PEG2-C1-NOTA (i.e., radionuclide) 68 (A metal complex formed by coordination of Ga with the compound ligand CR-PEG2-C1-NOTA), the structural formula of which is shown below:

[0232]

[0233] The radionuclide 68 Ga-labeled CR-PEG2-C1-NOTA (denoted as Ga) 68 The synthetic route for Ga-CR-PEG2-C1-NOTA is shown below:

[0234]

[0235] (1) Preparation of compound A1:

[0236] Under a nitrogen atmosphere, Boc-NH-PEG2-C1-COOH (263 mg, 1 mmol) was dissolved in 4 mL of N,N-dimethylformamide (DMF) and stirred until completely dissolved. Then, dipyrrolidinyl alkyl groups were added sequentially.N (-succinylimino)carbomon hexafluorophosphate (483 mg, 1.176 mmol), crizotinib (450 mg, 1 mmol), and N,N-diisopropylethylamine (DIEA, 151 mg, 1.176 mmol) were stirred at 37 °C for 24 h. After the reaction was completed, 20 mL of dichloromethane and 20 mL of water were added to the reaction system for extraction. The lower layer solution was collected, evaporated to dryness, and compound A1 was obtained.

[0237] (2) Preparation of compound B1:

[0238] Add 4 mL of trifluoroacetic acid to compound A1, stir at 37 °C for 2 h, and then evaporate the solution to dryness to obtain compound B1.

[0239] (3) Preparation of compound CR-PEG2-C1-NOTA:

[0240] Under a nitrogen atmosphere, Nota-bis(tBu)ester (415 mg, 1 mmol) was placed in a round-bottom flask, dissolved in 20 mL of DMF, and then dipyrrolidinyl ester was added sequentially. N ⁻-Succinylimino(2-)carbomony hexafluorophosphate (483 mg, 1.176 mmol), DIEA (258 mg, 2 mmol), and compound B1 (595.5 mg, 1 mmol) were stirred at 37 °C for 24 h. After the reaction was completed, 20 mL of dichloromethane and 20 mL of water were added to the reaction system for extraction. The lower layer solution was collected and evaporated to dryness to obtain compound C1. Compound C1 was added to trifluoroacetic acid solution and stirred at 37 °C for 2 h. After filtration and drying, compound CR-PEG2-C1-NOTA was obtained.

[0241] (4) Radionuclide labeling:

[0242] Using a 5 mL EP tube as the reaction vessel, 1 mL of 2M pH=4 sodium acetate solution was added sequentially, followed by 10 μg of compound CR-PEG2-C1-NOTA (compound CR-PEG2-C1-NOTA was prepared as a 1 mg / mL PBS stock solution; 10 μL of the stock solution was added to the reaction system, with a molar volume of 1.135 × 10⁻⁶). -8 mol), 1 mL [ 68 Ga]GaCl3 solution (5 mCi), the mixture was heated to 90℃ and reacted for 10 min to obtain a targeted c-MET nuclide probe. 68 Ga-CR-PEG2-C1-NOTA.

[0243] The structure of CR-PEG2-C1-NOTA was characterized using mass spectrometry, and the structural determination results are as follows: Figure 1As shown, LCMS(ESI): m / z: Chemical Formula: C 39 H 52 Cl2FN9O9, [M+H] + Found 880.5, [M+2H]2H + Found 440.8, [M+Na] + Found 902.5.

[0244] 68 Ga-CR-PEG2-C1-NOTA was detected using high-performance liquid chromatography, and the results are as follows: Figure 2 As shown, 68 The purity of Ga-CR-PEG2-C1-NOTA is 90.514%.

[0245] Example 2

[0246] This embodiment provides a c-MET-targeting nuclide probe, which is a radioactive nuclide. 68 Ga-labeled CR-PEG2-C1-DOTA, the structural formula of which is shown below:

[0247]

[0248] The radionuclide 68 Ga-labeled CR-PEG2-C1-DOTA (denoted as Ga) 68 The synthetic route for Ga-CR-PEG2-C1-DOTA is shown below:

[0249] .

[0250] (1) Preparation of compound A1: Same as in Example 1.

[0251] (2) Preparation of compound B1: Same as in Example 1.

[0252] (3) Preparation of compound CR-PEG2-C1-DOTA:

[0253] The preparation of CR-PEG2-C1-NOTA in Example 1 was similar, except that the NOTA-bis(tBu)ester was replaced with an equimolar amount of DOTA-bis(tBu)ester to prepare compound C2. Compound C2 was added to a trifluoroacetic acid solution and stirred at 37°C for 2 h. After filtration and drying, compound CR-PEG2-C1-DOTA was obtained.

[0254] (4) Radionuclide labeling: The difference from Example 1 is that the compound CR-PEG2-C1-NOTA is replaced with an equal mass of CR-PEG2-C1-DOTA to prepare a c-MET-targeted nuclide probe. 68 Ga-CR-PEG2-C1-DOTA.

[0255] The structure of CR-PEG2-C1-DOTA was characterized using mass spectrometry, and the structural determination results are as follows: Figure 3 As shown, LCMS(ESI): m / z: Chemical Formula: C 43 H 59 Cl2FN 10 O 11 [M+H] + Found 981.65, [M+2H]2H 2+ Found 492.3, [M+3H]3H 3+ Found 328.45, [M+Na] + Found 1003.55.

[0256] 68 Ga-CR-PEG2-C1-DOTA was detected using high-performance liquid chromatography, and the results are as follows: Figure 4 As shown, 68 The purity of Ga-CR-PEG2-C1-DOTA is 88.847%.

[0257] Example 3

[0258] This embodiment provides a c-MET-targeting nuclide probe, which is a radioactive nuclide. 68 Ga-labeled CR-PEG4-C2-DOTA, the structural formula of which is shown below:

[0259]

[0260] The radionuclide 68 Ga-labeled CR-PEG4-C2-DOTA (denoted as Ga) 68 The synthetic route for Ga-CR-PEG4-C2-DOTA is shown below:

[0261] .

[0262] (1) Preparation of compound A3:

[0263] The preparation of compound A3 is carried out in accordance with Example 1, except that Boc-NH-PEG2-C1-COOH is replaced with an equimolar amount of Boc-NH-PEG4-C2-COOH.

[0264] (2) Preparation of compound B3:

[0265] Add 4 mL of trifluoroacetic acid to compound A3, stir at 37 °C for 2 h, and then evaporate the solution to dryness to obtain compound B3.

[0266] (3) Preparation of compound CR-PEG4-C2-DOTA:

[0267] The preparation of CR-PEG2-C1-NOTA in Example 1 was similar, except that Nota-bis(tBu)ester was replaced with an equimolar amount of DOTA-bis(tBu)ester, and compound B1 was replaced with an equimolar amount of B3 to obtain compound C3. Compound C3 was added to a trifluoroacetic acid solution, stirred at 37°C for 2 h, filtered and dried to obtain compound CR-PEG4-C2-DOTA.

[0268] (4) Radionuclide labeling:

[0269] Referring to the radionuclide labeling in Example 1, the difference is that the compound CR-PEG2-C1-NOTA is replaced with an equimolar amount of CR-PEG4-C2-DOTA to prepare a c-MET-targeted nuclide probe. 68 Ga-CR-PEG4-C2-DOTA.

[0270] The structure of CR-PEG4-C2-DOTA was characterized by mass spectrometry, and the structural determination results are as follows: Figure 5 As shown, LCMS(ESI): m / z: Chemical Formula: C 48 H 69 Cl2FN 10 O 13 [M+H] + Found 1083.4, [M+2H]2H 2+ Found 543.3, [M+3H]3H 3+ Found 362.25.

[0271] 68 Ga-CR-PEG4-C2-DOTA was detected using high-performance liquid chromatography, and the results are as follows: Figure 6 As shown, 68 The purity of Ga-CR-PEG4-C2-DOTA is 91.951%.

[0272] Application Example 1

[0273] This application example demonstrates the use of a targeted c-MET nuclide probe in the specific identification of liver cancer.

[0274] The human hepatocellular carcinoma HepG2 cell line, which highly expresses c-MET, was seeded under the armpits of Balb / cnude mice. After successful model establishment, each mouse was injected via the tail vein with 1 nmol of the c-MET-targeting nuclide probe provided in Example 1. 68 The efficacy of Ga-CR-PEG2-C1-NOTA molecules in diagnosing liver cancer was evaluated using a small animal PET / MR in vivo imaging system.

[0275] Figure 7 The targeted c-MET nuclide probe provided in Example 1 68 A diagram illustrating the liver tumor-specific targeting effect of Ga-CR-PEG2-C1-NOTA. (See diagram for reference.) Figure 7 As shown, 1 hour after injection, HepG2 tumor-bearing mice exhibited high radioactive signals in the tumor area, indicating that... 68 Ga-CR-PEG2-C1-NOTA exhibits good specificity in identifying c-MET overexpressing tumors.

[0276] Application Example 2

[0277] This application example demonstrates the use of a targeted c-MET nuclide probe in the specific identification of liver cancer.

[0278] The human hepatocellular carcinoma HepG2 cell line, which highly expresses c-MET, was seeded under the armpits of Balb / cnude mice. After successful model establishment, each mouse was injected via the tail vein with 1 nmol of the c-MET-targeting nuclide probe provided in Example 2. 68 The efficacy of Ga-CR-PEG2-C1-DOTA molecules in diagnosing liver cancer was evaluated using a small animal PET / MR in vivo imaging system.

[0279] Figure 8 The targeted c-MET nuclide probe provided in Example 2 68 A diagram illustrating the liver tumor-specific targeting effect of Ga-CR-PEG2-C1-DOTA. (See diagram for reference.) Figure 8 As shown, imaging of mice was performed 30 min, 1 h, and 2 h after injection. The results showed that HepG2 tumor-bearing mice exhibited high radioactive signals in the tumor area at each time point, and the distribution throughout the body was significantly higher than that of mice with tumors that were not invasive. 68 Ga-CR-PEG2-C1-NOTA was significantly reduced, and the ratio of tumor to non-tumor cells was significantly higher than that of other cells. 68 Ga-CR-PEG2-C1-NOTA; it also has a faster removal effect. This indicates that... 68Ga-CR-PEG2-C1-DOTA also exhibits good specificity in identifying c-MET overexpressing tumors.

[0280] Application Example 3

[0281] This application example demonstrates the use of a targeted c-MET radionuclide probe in the specific identification of liver cancer.

[0282] The human hepatocellular carcinoma HepG2 cell line, which highly expresses c-MET, was seeded under the armpits of Balb / cnude mice. After successful model establishment, each mouse was injected via the tail vein with 1 nmol of the c-MET-targeting nuclide probe provided in Example 3. 68 The efficacy of Ga-CR-PEG4-C2-DOTA molecules in diagnosing liver cancer was evaluated using a small animal PET / MR in vivo imaging system.

[0283] Figure 9 The targeted c-MET nuclide probe provided in Example 3 68 A diagram illustrating the liver tumor-specific targeting effect of Ga-CR-PEG4-C2-DOTA. (See diagram for reference.) Figure 9 As shown, imaging of mice was performed 30 min, 1 h, and 2 h after injection. The results showed that HepG2 tumor-bearing mice exhibited high radioactive signals in the tumor region at each time point, and the absorption in the liver region was relatively high. 68 Ga-CR-PEG2-C1-DOTA was further reduced, demonstrating good in vivo metabolism (renal excretion), and the tumor-to-non-tumor ratio was significantly higher than that of other drugs. 68 Ga-CR-PEG2-C1-NOTA and 68 Ga-CR-PEG2-C1-DOTA, this illustrates that 68 Ga-CR-PEG4-C2-DOTA also exhibits good specificity in identifying c-MET overexpressing tumors.

[0284] In summary, this invention provides three crizotinib-based radionuclide probes, their preparation methods, and applications. These probes can actively target c-MET-overexpressing tumors and exhibit specificity for PET imaging. Simultaneously... 68 Ga-CR-PEG4-C2-DOTA exhibits good in vivo metabolism (renal excretion), rapidly clearing from normal tissues while remaining for a prolonged period at tumor sites, thus enabling in vivo diagnostics. It demonstrates excellent active targeting in identifying liver cancer and shows great potential for development in areas such as tumor surgery and medical cell labeling.

[0285] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A compound selected from any one of the following structures: CR-PEG2-C1-NOTA; CR-PEG2-C1-DOTA; CR-PEG4-C2-NOTA; CR-PEG4-C2-DOTA.

2. A c-MET targeting radionuclide probe, characterized in that, The targeting c-MET radionuclide probe comprises any one of the following compounds labeled with a radionuclide: CR-PEG2-C1-NOTA; CR-PEG2-C1-DOTA; CR-PEG4-C2-NOTA; CR-PEG4-C2-DOTA. The radionuclide is 68 Ga.

3. A process for the preparation of a compound according to claim 1, characterized in that, The preparation method comprises: (1) crizotinib and compound PG-L-PEG 2n -C m -COOH by condensation reaction to obtain compound A; wherein PG represents a protecting group, L group is NH, m = n = 1 or m = n = 2, and the reaction formula is as shown below: ； (2) Compound A is subjected to deprotection treatment to obtain compound B; wherein, the L' group is NH2, and the reaction formula is as shown below: ； (3) Compound B and Y with a protective group are subjected to condensation reaction, and then subjected to deprotection treatment to obtain a compound; wherein, the reaction formula is as shown below: ； wherein, the Y with a protective group is selected from any one of the following compounds: ， 。 4. The preparation method according to claim 3, wherein, In step (1), the molar ratio of crizotinib and PG-L-PEG 2n -C m -COOH (0.5-2): 1; in step (1), the condensation reaction is carried out at a temperature of 30-40°C for 12-24 h; and / or, in step (1), the condensation reaction is carried out in a solvent selected from dimethyl sulfoxide and / or N,N dimethylformamide; in step (1), the condensation reaction is carried out in a protective gas atmosphere, and the protective gas is nitrogen; And / or, in step (1), the condensation reaction is carried out in the presence of a condensing agent, which is a dipyrrolidinyl N - succinimidoxyl) carbocationic hexafluorophosphate; and / or, in step (1), the PG-L-PEG 2n -C m -COOH and the condensing agent is in a molar ratio of 1 : (1.1-2). And / or, in step (1), the condensation reaction is carried out in the presence of a base, which is N,N - diisopropylethylamine; and / or, in step (1), the PG-L-PEG 2n -C m -COOH and the base is in a molar ratio of 1 : (0.5-5).

5. The preparation method according to claim 3, wherein, in step (2), the deprotection treatment uses trifluoroacetic acid as a reagent; in step (2), the deprotection treatment is carried out at a temperature of 30-40°C for 1-3 h.

6. The preparation method according to claim 3, wherein, in step (3), the molar ratio of compound B to Y with a protective group is (0.5-2):1; in step (3), the condensation reaction is carried out at a temperature of 30-40°C for 12-24 h; and / or, in step (3), the condensation reaction is carried out in a solvent selected from the group consisting of dimethyl sulfoxide and / or N,N dimethylformamide; in step (3), the condensation reaction is carried out in a protective gas atmosphere, and the protective gas is nitrogen; And / or, in step (3), the condensation reaction is carried out in the presence of a condensing agent, which is a dipyrrolidinyl N - succinimidoxyl) carbocationic hexafluorophosphate; in step (3), the molar ratio of compound B to condensing agent is 1:(1.1-2); And / or, in step (3), the condensation reaction is carried out in the presence of a base, which is N,N - diisopropylethylamine; in step (3), the molar ratio of compound B to base is 1:(0.5-5); in step (3), the deprotection treatment uses trifluoroacetic acid as a reagent; in step (3), the deprotection treatment is carried out at a temperature of 30-40°C for 1-3 h.

7. A method of preparing the targeted c-MET nuclide probe of claim 2, wherein, The preparation method comprises: radiolabeling the compound according to claim 1 by using a radionuclide to obtain the c-MET targeted radionuclide probe; and the radionuclide is 68 Ga.

8. The production method according to claim 7, characterized by, The radiolabeling comprises the following steps: a sodium acetate solution, the compound of claim 1, and a radionuclide solution are mixed, and after reaction, the targeting c-MET radionuclide probe is obtained.

9. The preparation method according to claim 8, wherein, the radionuclide solution has a radioactivity of 1-10 mCi; and / or the molar volume ratio of the compound to the radionuclide solution is (0.5-1.7) x 10 -8 mol / mL; in the radiolabeling, the temperature is 85-95°C, and the time is 5-20 min.

10. Use of the targeted c-MET nuclide probe of claim 2, or a pharmaceutically acceptable salt thereof, in the manufacture of a reagent for tumor imaging. wherein The tumor includes any one or more of a liver cancer tumor, a pancreatic cancer tumor, a colon cancer tumor, a stomach cancer tumor, a breast cancer tumor, or a head and neck cancer tumor.

11. Use of the targeted c-MET nuclide probe of claim 2, or a pharmaceutically acceptable salt thereof, in the manufacture of a reagent for identifying a c-MET overexpressing tumor.

12. An agent for identifying a c-MET overexpressing tumor, characterized by, The targeted c-MET nuclide probe of claim 2.

13. A pharmaceutical composition, characterized by, The targeted c-MET nuclide probe of claim 2, and a pharmaceutically acceptable carrier thereof.

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