Marking precursor, probe and preparation method and application thereof

Abstract

The invention relates to the technical field of nuclear medicine and radiopharmaceuticals, in particular to a labeled precursor, a probe and a preparation method and application of the labeled precursor and the probe. The probe prepared by using the cyclopeptide nuclide ligand disclosed by the invention has good stability, excellent pharmacokinetics, good binding specificity with EPHA2, relatively high tumor uptake, relatively high tumor-muscle uptake ratio and good in-vivo metabolism performance, and has a good clinical application prospect.

Description

Technical Field

[0001] This invention relates to the fields of nuclear medicine and radiopharmaceuticals, and particularly to labeled precursors, probes, their preparation methods and applications. Background Technology

[0002] EphA2 belongs to the receptor tyrosine kinase (RTK) family, which includes 16 receptors and 9 membrane-bound ligands. Based on extracellular domain sequence homology, structure, and binding affinity, the Eph receptor and its ligand Ephrin can be divided into two subtypes, A and B. EphrinA1 is the major ligand of EphA2, enabling EphA2 to contact ligands on neighboring cells and induce various signaling pathways. EphA2 has a molecular weight of 130 kDa and contains 967 amino acid residues. It is a type I transmembrane glycoprotein composed of an extracellular region, a transmembrane region, and an intracellular region. The extracellular region is relatively large and complex, firstly containing an N-terminal ligand-binding domain that recognizes specific ligands, followed by a cysteine-rich binding domain that stabilizes the overall receptor structure, and two fibronectin type III repeat structures. The transmembrane region is a hydrophobic α-helix structure that acts as a bridge connecting the intracellular and extracellular regions. The intracellular region is the docking site for signal transduction proteins, interacting with other domains around a tyrosine kinase domain to transmit signals.

[0003] A growing body of research indicates that EphA2 is overexpressed in various cancers, and is closely associated with breast cancer, prostate cancer, lung cancer, and colorectal cancer. Members of the Eph family are involved in cell metastasis, transformation, and angiogenesis; among them, EphA2 expression increases tumor metastatic potential, leading to poor patient prognosis and reduced survival. Furthermore, EphA2 is not only a biomarker of malignancy but also plays a crucial role in malignant progression. Therefore, EphA2 demonstrates significant potential in the diagnosis and treatment of cancer.

[0004] In the field of oncology treatment, targeted delivery of cytotoxic drugs is a core requirement for optimizing efficacy and controlling side effects, directly driving the innovation of antibody-drug conjugates (ADCs). ADCs achieve targeted delivery through the molecular conjugation of monoclonal antibodies and cytotoxins, and their mechanism of action relies on the antibody's ability to recognize tumor-specific antigens. For example, MEDI-547, a drug constructed by conjugating an anti-EphA2 monoclonal antibody with the microtubule inhibitor mcMMAF, showed excellent anti-tumor activity in preclinical studies. However, in a Phase I clinical trial, it exhibited serious adverse reactions such as dose-dependent liver enzyme abnormalities and coagulation disorders, ultimately leading to the termination of the study with no further clinical plans. Although ADC technology has achieved success in some indications, its inherent limitations still restrict clinical translation: insufficient tumor tissue penetration due to its macromolecular characteristics, hepatobiliary / gastrointestinal toxicity caused by the release of toxins from non-target organs, and systemic toxicity caused by the liver's metabolic-dominated clearance pathway are all key factors limiting dosage. Currently, the only approved EphA2 inhibitor is dasatinib; other drugs have failed to overcome clinical research bottlenecks due to safety concerns. Against this backdrop, the emergence of bicyclic peptide technology has made targeting EphA2 possible. BT5528 is a novel bicyclic peptide toxin conjugate (BTC) drug developed by Bicycle Therapeutics. This compound has a molecular weight approximately 1 / 40th that of traditional ADC drugs (about 4 kDa), and its small molecular size significantly enhances its penetration into solid tumor tissues. Under the influence of the tumor-specific microenvironment, the MMAE toxin component is released spatiotemporally in a controlled manner after specific enzymatic hydrolysis, exerting antitumor activity through a dual mechanism of direct cytotoxicity and bystander killing. Overall, these findings confirm that EphA2 is an effective therapeutic target for various solid tumors and provide insights for the further clinical development, research, and improvement of drugs targeting EphA2.

[0005] During first-pass metabolism of drugs via the portal vein, the vast majority of the parent drug is converted into active metabolites by hepatic microsomal enzymes. Because the EphA2 receptor is structurally expressed on the apical membrane of hepatic sinusoidal endothelial cells and intestinal epithelial cells, drug-receptor binding may interfere with cell signaling, leading to functional abnormalities. Furthermore, metabolic overload or cumulative dose effects can cause hepatotoxicity / gastrointestinal toxicity. Addressing these toxicity bottlenecks, novel cyclic peptide-nucleoside conjugation technology demonstrates significant advantages. It not only significantly reduces molecular weight, increasing tumor tissue targeting and enrichment efficiency several times that of conventional antibodies, but also achieves a dual mechanism of action through the emission of β-particles by introducing a radionuclide. The drug no longer acts solely as a cytotoxic agent, but rather uses the nuclide as a therapeutic tool. This integrated diagnostic and therapeutic approach significantly reduces clinical drug dosage and hepatic uptake compared to traditional methods, effectively avoiding the toxicity risks associated with first-pass metabolism.

[0006] Nuclear medicine technology utilizes radionuclides and their radiation to diagnose, treat, and study diseases; it can both diagnose and treat diseases. Combining diagnostic imaging and therapeutic radionuclides with targeted molecules to achieve integrated diagnosis and treatment is a future trend in radiopharmaceutical development. Currently, there are no reported radionuclide cyclic peptide diagnostic and therapeutic drugs targeting the EphA2 tumor target. Summary of the Invention

[0007] In view of this, the present invention provides labeling precursors, probes, methods for their preparation, and applications.

[0008] The purpose of this invention is to provide a labeled precursor for a tumor-targeting EPHA2 cyclic peptide nuclide probe, as shown in Formula I, or a EPHA2-targeting cyclic peptide nuclide ligand, with the structure Cyclic(Ac-da-Me3Py-NL-Hgn-MeE-W1Me-KCOpipzaa-W1Me-T-Hgn-C)-RKX. It can be used with diagnostic and / or therapeutic nuclides to prepare probes or drugs for integrated diagnosis and treatment of EPHA2-overexpressing tumors.

[0009] In a first aspect, the present invention provides a cyclic peptide nucleoside ligand (also referred to herein as a labeled precursor) targeting EPHA2, having the structure shown in Formula I:

[0010]

[0011] Wherein, R is a group represented by formula II, formula III, or formula IV.

[0012]

[0013] X is a group represented by formula V, formula VI, formula VII, formula VIII, formula IX or formula X;

[0014]

[0015] Wherein, a is an integer from 1 to 4, preferably an integer from 1 to 3; b is an integer from 1 to 12, preferably an integer from 3 to 12; and c is an integer from 1 to 12, preferably an integer from 3 to 12.

[0016] In some embodiments of the present invention, in the above-mentioned labeled precursor, R is a group represented by Formula II, wherein a is 1.

[0017] In some embodiments of the present invention, in the above-mentioned labeled precursor, R is a group represented by Formula III, wherein b is 4, 8 or 12.

[0018] In some embodiments of the present invention, in the above-mentioned labeled precursor, R is a group represented by formula IV, wherein c is 6, 8 or 10.

[0019] In some embodiments of the present invention, X in the above-mentioned labeled precursor is a group represented by formula V and formula VIII:

[0020]

[0021] More preferably, the cyclic peptide nuclide ligand is a compound represented by Formulas 1-4, i.e., the compound of application number EP1-4:

[0022]

[0023]

[0024] Secondly, the present invention provides a cyclic peptide nuclide probe targeting tumor EPHA2, wherein the nuclide probe is a radiolabeled precursor of the cyclic peptide nuclide probe targeting tumor EPHA2.

[0025] This invention presents an EphA2-targeting molecular imaging probe constructed using cyclic peptide technology, providing an innovative solution for nuclear medicine imaging techniques. This probe utilizes radionuclides (such as...) 68 Ga、 18 F) Labeled cyclic peptide structures enable visualization of biological processes at the molecular level using SPECT / PET imaging equipment. Compared to traditional EphA2-targeting imaging agents that rely on labeled monoclonal antibodies, cyclic peptide probes exhibit significant advantages: their modular design allows for controllable radiolabeling sites, rapid blood clearance reduces systemic radiation dose, their nanoscale size provides excellent vascular penetration, and improves uptake efficiency in solid tumors; and their specific binding sites optimize the target / background ratio. This non-invasive functional metabolic imaging technology provides crucial technical support for the early differential diagnosis of solid tumors, radiotherapy target delineation, and monitoring of targeted therapy efficacy. Its clinical translation will drive the optimization of precision medicine protocols for EphA2-positive tumors.

[0026] In this invention, the radionuclide is a diagnostic radionuclide or a therapeutic radionuclide.

[0027] The diagnostic radionuclide is selected from... 68 Ga、 64 Cu、 18 F, 86 Y、 90 Y、 89 Zr、 111 In、 99m Tc, 11 C 123 I, 125 I and 124 At least one of I.

[0028] The therapeutic radionuclide is selected from...177 Lu、 125 I, 131 I, 211 At、 111 In、 153 Sm、 186 Re、 188 Re、 67 Cu、 212 Pb, 225 Ac、 213 Bi、 212 Bihe 212 At least one of Pb.

[0029] Thirdly, the present invention provides a method for preparing a cyclic peptide nuclide probe labeled precursor for targeting tumor EPHA2 as shown in Formula I.

[0030] In this invention, the preparation method includes: sequentially coupling the following protected groups onto a solid support:

[0031] Lysine, R group, S-triphenylmethyl-L-cysteine, N-triphenylmethyl-L-homoglutamine, O-tert-butyl-L-threonine, 1-methyl-tryptophan, (S)-2-(amino)-6-[4-[2-(tert-butoxy)-2-oxoethyl]piperazine-1-formylamino]hexanoic acid, 1-methyl-tryptophan, N-methyl-L-glutamate-5-tert-butyl ester, N-triphenylmethyl-L-homoglutamine, L-leucine, N-triphenylmethyl-L-asparagine, N-methyl-3-(3-pyridine)-alanine, D-alanine, chloroacetic acid, to obtain peptide resin;

[0032] The peptide resin was cleaved to obtain a linear polypeptide; the linear polypeptide was then cyclized and coupled to the X group.

[0033] In the above preparation method, the selection of X and R groups is as described above.

[0034] In some embodiments, a purification step is included after lysis to obtain the linear polypeptide. In some specific embodiments, the purification is liquid-phase purification. Liquid-phase purification yields a pure linear polypeptide with a purity greater than 95%.

[0035] In this invention, the linear polypeptide is cyclized to obtain a crude cyclic peptide. Some embodiments further include a step of purifying the crude cyclic peptide. In some specific embodiments, the purification is liquid-phase purification.

[0036] In the above preparation method, the selection of R group and X group is as described above.

[0037] Fourthly, the present invention provides the application of a labeled precursor of a cyclic peptide nuclide probe targeting tumor EPHA2 as shown in Formula I. Specifically, the application is in tumor diagnosis or in the preparation of tumor diagnostic reagents.

[0038] Fifthly, the present invention provides applications of cyclic peptide nuclide probes targeting EPHA2 as shown in Formulas 1-4. Specifically, these applications are in tumor diagnosis or in the preparation of tumor diagnostic reagents.

[0039] Furthermore, the tumor is an EPHA2-high expression tumor.

[0040] Furthermore, the tumors with high EPHA2 expression include at least one of prostate cancer, lung cancer, esophageal cancer, colorectal cancer, cervical cancer, ovarian cancer, and breast cancer.

[0041] In a sixth aspect, the present invention also provides diagnostic reagents or therapeutic agents, comprising at least one of the following a to b:

[0042] a. The cyclic peptide nuclide ligand or the cyclic peptide nuclide ligand prepared by the preparation method;

[0043] b. The cyclic peptide nuclide probe described above or the cyclic peptide nuclide probe prepared by the method described above.

[0044] In a seventh aspect, the present invention also provides a diagnostic method for tumors with high EPHA2 expression, comprising: detecting a sample using the cyclic peptide nuclide probe or the diagnostic reagent described in the present invention.

[0045] Eighthly, the present invention also provides a treatment method for tumors with high EPHA2 expression, comprising: administering the cyclic peptide nuclide probe or the therapeutic drug described herein.

[0046] The cyclic peptide nuclide probe targeting EPHA2 of this invention has good stability, excellent pharmacokinetics, good binding specificity to EPHA2, high tumor uptake and high tumor to muscle uptake ratio, good in vivo metabolic performance, and good clinical application prospects. Attached Figure Description

[0047] Figure 1 Mass spectra of EP1-4;

[0048] Figure 2 The image shows the Radio-HPLC detection results of Example 2, where Figure A is […]. 68 Ga]Ga-EP1 and [Al 18 [F]-EP1 cyclic peptide nuclide probe radiochemically purified; Figure B shows [ 68 Ga]Ga-EP2 and [Al 18F]-EP2 cyclic peptide nucleoside probe purified to radiochemical purity; Figure C shows [ 68 Ga]Ga-EP3 and [Al 18 [F]-EP3 cyclic peptide nucleoside probe purified to radiochemical purity; Figure D shows [ 68 Ga]Ga-EP4 and [Al 18 The F-EP4 cyclic peptide nucleoside probe was purified to radiochemical purity, with the white arrow indicating the prostate tumor area;

[0049] Figure 3 200 μCi of [a certain substance] was injected into Balb / c nude mice (a prostate cancer PC3 tumor model) and NSG mice (a LNCaP tumor model). 68 Ga]Ga-EP1 whole-body Micro-PET / CT MIP images at 30 min, 1 h, and 2 h;

[0050] Figure 4 200 μCi of [a certain substance] was injected into Balb / c nude mice (a prostate cancer PC3 tumor model) and NSG mice (a LNCaP tumor model). 68 Ga]Ga-EP2 whole-body Micro-PET / CT MIP images at 30 min, 1 h, and 2 h, respectively;

[0051] Figure 5 200 μCi of [a certain substance] was injected into Balb / c nude mice (a prostate cancer PC3 tumor model) and NSG mice (a LNCaP tumor model). 68 Ga]Ga-EP3 whole-body Micro-PET / CT MIP images at 30 min, 1 h, and 2 h;

[0052] Figure 6 200 μCi of [a certain substance] was injected into Balb / c nude mice (a prostate cancer PC3 tumor model) and NSG mice (a LNCaP tumor model). 68 Ga]Ga-EP4 whole-body Micro-PET / CT MIP images at 30 min, 1 h, and 2 h. Detailed Implementation

[0053] This invention provides a cyclic peptide ligand targeting EPHA2, its probe, drug, and applications. Those skilled in the art can refer to this document and appropriately modify the process parameters to achieve the desired results. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included in this invention. The methods and applications of this invention have been described through preferred embodiments; those skilled in the art will clearly be able to modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit, and scope of this invention to implement and apply the technology of this invention.

[0054] The test materials used in this invention are all common commercial products and can be purchased on the market.

[0055] To further illustrate the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. These embodiments are purely illustrative and are only used to specifically describe the present invention, and should not be construed as limiting the present invention.

[0056] This invention provides a cyclic peptide nuclide ligand targeting EPHA2, its probe, drug, and application, aiming to solve the problem of providing detection probes for early non-invasive screening of EPHA2-positive patients.

[0057] Example 1

[0058] This embodiment discloses a method for synthesizing the EPHA2-targeting cyclic peptide EP1-4, the specific steps of which are as follows:

[0059] The R groups in EP1 to EP4 are Fmoc-β-alanine (EP1), Fmoc-PEG4-propionic acid and Fmoc-glycine (EP2), Fmoc-PEG12-propionic acid and Fmoc-glycine (EP3), and Fmoc-SAR10 and Fmoc-glycine (EP4), respectively.

[0060] Selecting Fmoc-amino resin, and following the Fmoc solid-phase synthesis strategy, sequentially coupling Fmoc-lysine (BOC), R group, Fmoc-S-triphenylmethyl-L-cysteine, Fmoc-N-triphenylmethyl-L-homocytamine, Fmoc-O-tert-butyl-L-threonine, 1-methyl-N-Fmoc-tryptophan, (S)-2-(Fmoc-amino)-6-[4-[2-(tert-butoxy)-2-oxoethyl]piperazine-1-formylamino]hexanoic acid, 1-methyl After coupling with -N-Fmoc-tryptophan, Fmoc-N-methyl-L-glutamic acid-5-tert-butyl ester, Fmoc-N-triphenylmethyl-L-homoglutamine, Fmoc-L-leucine, Fmoc-N-triphenylmethyl-L-asparagine, Fmoc-N-methyl-3-(3-pyridine)-alanine, Fmoc-D-alanine, and chloroacetic acid, the peptide was cleaved from the resin to obtain a crude linear peptide. This crude linear peptide was purified by preparative liquid chromatography to obtain a pure linear peptide (>95%). Subsequently, cyclization was performed to obtain a crude cyclic peptide without metal chelate fragments. The crude cyclic peptide was then coupled with an X group (i.e., 1,4,7-triazacyclononane-1,4,7-triacetic acid, NOA) to obtain crude cyclic peptide precursors EP1-4. These were purified by preparative liquid chromatography and lyophilized to obtain the target ligands EP1-4.

[0061] Ligands EP2-4 were prepared using the method described above. Mass spectrometry analysis revealed the structures of ligands EP1-4 as follows: Figure 1 As shown.

[0062] Example 2

[0063] This embodiment discloses the synthesis of the EPHA2 cyclic peptide nuclide probe compound. The specific synthesis method is as follows:

[0064] 1. 68 Method for Ga-labeled EPHA2 cyclic peptide nuclide probe

[0065] Prepare an aqueous solution (concentration 10 mg / ml) of the EPHA2 cyclic peptide precursor EP1-4. Place 5 μL of the precursor solution into a reaction flask, add 200 μL of 1M sodium acetate and 1 mL of freshly rinsed solution to the flask. 68 Ga rinsing solution ( 68 Ga was rinsed in 0.1M hydrochloric acid solution. The pH of the reaction solution was about 4.0. After mixing, the EP1-4 mixture was placed at 37℃ for 10-15 min. After the reaction was completed, it was purified using a C18 column. The radiochemical purity of the product was greater than 98% as determined by Radio-HPLC.

[0066] 2. 18 Method for labeling EPHA2 cyclic peptide nuclide probes with F

[0067] Dissolve 50 μg of EP1-4 lyophilized powder in 10 μL of deionized water, add approximately 1.6 μg of AlCl3 solution (6 μL, 2 mM), 10 μL of glacial acetic acid, and 30-50 mCi 18 Add F, and 4-5 times the total volume of anhydrous acetonitrile to the above solution, and adjust the pH to approximately 3. Mix thoroughly, then incubate the mixture in a 100°C constant-temperature metal heater for 10 minutes. After the reaction is complete, purify using a C18 column. Radio-HPLC analysis showed that the radiochemical purity of the product was greater than 98%.

[0068] Quality control:

[0069] 68 Ga and 18 The radiochemical purity of the F-labeled complexes was determined using radio-HPLC (radio-high performance liquid chromatography). The radiochemical purity of all complexes was greater than 98%, as shown in the figure below. Figure 2 .

[0070] Example 3

[0071] This embodiment discloses the compound of the present invention. 68 In vivo imaging experiment of Ga]Ga-EP1-4:

[0072] 1. Micro-PET / CT imaging of nude mice with PC3 model of human prostate cancer

[0073] PC3 xenograft tumor model nude mice were used to infiltrate tumor tissue to a depth of 100-300 mm. 3 Administer via tail vein injection at the appropriate time. 68 Ga-EP1-4 (200 μCi / animal) was used for static scanning at different time points (30, 60, and 120 min) after injection, with clear tumor visualization. After the scan, iterative reconstruction (OSEM 3D) scan data was used, and two tumors and other tissues were delineated as regions of interest (ROIs) using ASIProVM software to calculate the radioactive uptake %ID / cc of each ROI.

[0074] 2. Micro-PET / CT imaging of LNCaP model NSG mice

[0075] In LNCaP model NSG mice, tumor tissue grew to 100-300 mm. 3 Administer via tail vein injection at the appropriate time. 68 Ga-EP1-4 (200 μCi / animal) was used for static scanning at different time points (30, 60, and 120 min) after injection, with clear tumor visualization. After the scan, iterative reconstruction (OSEM 3D) scan data was used, and two tumors and other tissues were delineated as regions of interest (ROIs) using ASIProVM software to calculate the radioactive uptake %ID / cc of each ROI.

[0076] The imaging results of the human prostate PC3 model and LNCaP model are shown below. Figures 3-6 .

[0077] Depend on Figures 3-6 It can be seen that, 68 Ga-labeled EP1-4 was significantly enriched in the tumor region of the PC3 tumor model Balb / c nude mice, with high uptake values ​​between 30 and 120 min, and the highest uptake values ​​between 30 and 60 min.

[0078] 68 Ga-labeled EP1–4 were not enriched in the tumor regions of the LNCaP tumor model NSG mice.

[0079] The above studies show that, compared with EP4, EP1-3 all have superior PET / CT diagnostic effects and good prospects for clinical treatment and research.

[0080] Finally, it should be noted that the above embodiments are merely preferred embodiments of the present invention used to illustrate the technical solutions of the present invention, and are not intended to limit the invention, nor are they intended to limit the patent scope of the present invention. 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 therein. 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. That is to say, any changes or refinements made to the main design concept and spirit of the present invention that are not of substantial significance, but whose technical problems are still consistent with the present invention, should be included within the protection scope of the present invention. In addition, the direct or indirect application of the technical solutions of the present invention to other related technical fields are similarly included within the patent protection scope of the present invention.

Claims

1. A cyclic peptide nuclide ligand targeting EPHA2, characterized in that, It has the structure shown in Equation I: Wherein, R is a group represented by formulas II, III, and IV. X is the group shown in formulas V, VI, VII, VIII, IX and X; Where a is an integer from 1 to 4; b is an integer from 1 to 12; and c is an integer from 1 to 12.

2. The cyclic peptide nuclide ligand according to claim 1, characterized in that, a is an integer from 1 to 3, preferably 1; b is an integer from 3 to 12, preferably 4, 8 or 12; c is an integer from 3 to 12, preferably 6, 8 or 10.

3. The cyclic peptide nuclide ligand according to any one of claims 1 to 2, characterized in that, It has any of the structures shown in Equations 1 to 4 below:

4. The method for preparing the cyclic peptide nuclide ligand according to any one of claims 1 to 3, characterized in that, include: The following groups, protected by protecting groups, are sequentially coupled onto a solid support: Lysine, R group, S-triphenylmethyl-L-cysteine, N-triphenylmethyl-L-homoglutamine, O-tert-butyl-L-threonine, 1-methyl-tryptophan, (S)-2-(amino)-6-[4-[2-(tert-butoxy)-2-oxoethyl]piperazine-1-formylamino]hexanoic acid, 1-methyl-tryptophan, N-methyl-L-glutamate-5-tert-butyl ester, N-triphenylmethyl-L-homoglutamine, L-leucine, N-triphenylmethyl-L-asparagine, N-methyl-3-(3-pyridine)-alanine, D-alanine, chloroacetic acid, to obtain peptide resin; The peptide resin was cleaved to obtain a linear polypeptide; The linear polypeptide is cyclically closed and then coupled with the X group to obtain the cyclic peptide nuclide ligand.

5. A cyclic peptide nuclide probe targeting tumor EPHA2, characterized in that, Including radiolabeled cyclic peptide ligands as described in any one of claims 1 to 3 or cyclic peptide ligands prepared by the preparation method described in claim 4.

6. The cyclic peptide nuclide probe according to claim 5, characterized in that, The radionuclide includes diagnostic radionuclides or therapeutic radionuclides; the diagnostic radionuclide is selected from... 68 Ga、 64 Cu、 18 F, 86 Y、 90 Y、 89 Zr、 111 In、 99m Tc, 11 C 123 I, 125 I and 124 At least one of I; the therapeutic radionuclide is selected from... 177 Lu、 125 I, 131 I, 211 At、 111 In、 153 Sm、 186 Re、 188 Re、 67 Cu、 212 Pb, 225 Ac、 213 Bi、 212 Bihe 212 At least one of Pb.

7. The method for preparing the cyclic peptide nuclide probe according to claim 5 or 6, characterized in that, include: The cyclic peptide probe is obtained by reacting the radionuclide with the cyclic peptide nuclide ligand according to any one of claims 1 to 3 or the cyclic peptide nuclide ligand prepared by the preparation method according to claim 4.

8. The use of at least one of the following (1) to (2) in the preparation of tumor diagnostic reagents or tumor therapeutic drugs: (1) The cyclic peptide nuclide ligand according to any one of claims 1 to 3 or the cyclic peptide nuclide ligand prepared by the preparation method according to claim 4; (2) The cyclic peptide nuclide probe according to claim 5 or 6 or the cyclic peptide nuclide probe prepared by the preparation method according to claim 7.

9. The application according to claim 8, characterized in that, The tumors include at least one of the following: prostate cancer, lung cancer, esophageal cancer, colorectal cancer, cervical cancer, ovarian cancer, and breast cancer.

10. A diagnostic reagent or therapeutic drug, characterized in that, Includes at least one of the following: a to b a. The cyclic peptide nuclide ligand according to any one of claims 1 to 3 or the cyclic peptide nuclide ligand prepared by the preparation method according to claim 4; b. The cyclic peptide nuclide probe according to claim 5 or 6, or the cyclic peptide nuclide probe prepared by the preparation method according to claim 7.

Images