CN118725026A

CN118725026A - Glycopeptide targeting tumor-associated fibroblast activation protein, radionuclide marker and application thereof

Info

Publication number: CN118725026A
Application number: CN202410739299.6A
Authority: CN
Inventors: 程震; 瞿春容; 宋苗苗; 曹蕊
Original assignee: Shanghai Institute of Materia Medica of CAS
Current assignee: Shanghai Institute of Materia Medica of CAS
Priority date: 2024-06-07
Filing date: 2024-06-07
Publication date: 2024-10-01

Abstract

The invention relates to FAP glycopeptides shown in a formula I, and a radionuclide label and application thereof. The FAP glycopeptide is obtained by modifying a linker part forming a cyclic peptide based on the structure of the polypeptide FAP-2286 and further introducing monosaccharide or disaccharide molecules. The glycopeptide shows better tumor uptake and lower liver uptake relative to FAP-2286 after being marked by the radionuclide, has better imaging results, is favorable for obtaining candidate radionuclide diagnosis and treatment medicines with further research and development values, and finally obtains the FAP targeting cyclopeptide radiopharmaceuticals with independent intellectual property rights.

Description

Glycopeptide targeting tumor-associated fibroblast activation protein, radionuclide marker and application thereof

Technical Field

The invention relates to the technical field of polypeptides targeting tumor-associated fibroblast active protein (Fibroblast activation protein, FAP), in particular to FAP glycopeptides, radionuclide markers thereof and application thereof.

Background

The development of radiopharmaceuticals has become an important development direction for the development of new medicines in China, and attracts attention of a plurality of research institutions, enterprises and markets. In particular to a diagnosis and treatment integrated tumor targeting radioactive drug which can effectively diagnose tumors and treat radionuclides, and is more the front direction of the current drug research. Radiolabeled polypeptide Lutathera (lutetium oxyoctreotide) targeting somatostatin receptors and small radioactive molecule Pluvicto (original name ¹⁷⁷ Lu-PSMA-617) targeting Prostate Specific Membrane Antigen (PSMA) were also approved by the us FDA for marketing in 2018 and 2022, respectively.

Malignant tumors include tumor cells and the microenvironment in which the tumor cells are located. Tumor microenvironments are also known as tumor stroma, which includes a variety of non-malignant cells that together shape an environment suitable for tumor growth. Wherein the non-cancerous stromal cells promote extracellular matrix remodeling, induction of angiogenesis, cell migration, drug resistance, and escape of immune surveillance by producing various growth factors, chemokines, and cytokines, thereby promoting tumor invasion and metastasis. Research has demonstrated that tumor-associated fibroblasts (Cancer associated fibroblasts, CAFs) are the major component of tumor microenvironment non-cancerous stromal cells, while Fibroblast Activation Protein (FAP) is ubiquitously expressed on the surface of CAFs, a very potential tumor biomarker.

FAP is a membrane-bound glycoprotein belonging to the family of dipeptidyl peptidases 4 (DIPEPTIDYL PEPTIDASE, DPP 4) and having dipeptidyl peptidase and endopeptidase activities with 52% homology to DPP4 at the protein level. The protein consists of 760 amino acids, including a short intracellular region (6 amino acids), a transmembrane region (20 amino acids) and a large extracellular region (734 amino acids). FAP is not expressed or expressed in a small amount in normal tissues, but is overexpressed in CAFs, and is also highly expressed in more than 90% of epithelial tumors. It can directly promote proliferation, migration and invasion of mesenchymal fibroblasts and other cell types, leading to tumor angiogenesis, extracellular matrix degradation, evasion immune surveillance, etc.

In recent years, the research shows that FAP is a very promising target point of the tumor radiodiagnosis and treatment integrated drug. A series of small molecule probes targeting FAP, such as FAPI-02 and FAPI-04, were successfully developed by the university of Heidelberg, germany, and were labeled with ⁶⁸ Ga and ¹⁷⁷ Lu as diagnostic-integrated radiopharmaceuticals. Clemens Kratochwil et al, evaluated a total of 80 patients with ⁶⁸ Ga-FAPIPET/CT scan, who could not be accurately diagnosed using ¹⁸ F-FDG imaging or other conventional imaging, but after ⁶⁸ Ga-FAPI-04 administration, among the 28 cancer species analyzed, detected 54 primary tumors and 229 metastases [Kratochwil C.,et al.(68)Ga-FAPIPET/CT:Tracer Uptake in 28Different Kinds of Cancer.J Nucl Med,2019,60(6),801-805.]. and ¹⁸ F-FDG, ⁶⁸ Ga-FAPI-04 detected more tumor primary and metastases. The probe can accurately diagnose and stage the metastasis of various tumors, has very high application prospect, and can become a screening and radionuclide therapy tool widely applied in tumor clinic. In addition, the imaging operation flow of the probe is simplified, no fasting and sugar control are needed, and the probe is more acceptable to patients.

FAP-2286 as a cyclic peptide probe targeting FAP has a structure comprising 7 amino acids of cyclic peptide and metal ligand moiety with an affinity in the range of 0.4-1.4 nM. Compared with the FAP small molecule inhibitor probe ¹⁷⁷ Lu-FAPI series, ¹⁷⁷ Lu-FAP-2286 still has high tumor uptake signals after 72 hours of administration, while FAPI-46 has only weak signals in tumors, so that the cyclopeptide FAP-2286-based radioactive therapeutic drug has higher development potential in tumor treatment.

Currently, ⁶⁸ Ga-FAP-2286 and ¹⁷⁷ Lu-FAPI-2286 have been studied in clinical stage I/II (NCT 04939610). Although ⁶⁸ Ga-FAP-2286 and ¹⁷⁷ Lu-FAPI-2286 have high uptake on FAP-highly expressed tumors, the residence time in the kidney is long, 2.2% ID/g, 1.1% ID/g and 0.6% ID/g are higher than those of the small molecule probes FAPI-46 when administered for 3 hours, 24 hours and 72 hours respectively, which is liable to cause radioactive nephrotoxicity or aggravate kidney burden [Zboralski D.,et al.Preclinical evaluation of FAP-2286for fibroblast activation protein targeted radionuclide imaging and therapy.Eur J Nucl Med Mol Imaging,2022,49(11),3651-3667.]. although the radiopharms themselves are not harmful to normal tissues in normal use because of small use amount. However, when the tissue is enriched in a large amount and retained for a long period of time, the normal tissue is damaged by the accumulation of the radioactive amount for a long period of time. In addition, patients treated by radioactivity mostly have advanced cancer, and most patients undergo radiotherapy and chemotherapy, and liver and kidney functions of the patients may have certain damage or basic diseases.

Thus, radiopharmaceutical studies require special attention to renal residence time and are an important direction of concern for the beginning of drug design. Therefore, the molecule is modified by structural transformation, the enrichment in liver and kidney metabolic organs is reduced while the high tumor uptake is maintained, and the 'best-in-class' FAP targeting cyclopeptide radiopharmaceuticals with independent intellectual property are developed, so that the molecular has very high clinical transformation value and feasibility.

Disclosure of Invention

Based on the structure of the polypeptide FAP-2286, the linker part forming the cyclic peptide is modified, and monosaccharide or disaccharide molecules are further introduced to obtain a series of novel glycopeptides. The glycopeptide shows better tumor uptake and lower liver uptake relative to FAP-2286 after being marked by the radionuclide, has better imaging results, is beneficial to obtaining candidate radionuclide diagnosis and treatment medicines with further research and development values, and finally obtains the 'best-in-class' FAP targeting cyclopeptide radiopharmaceuticals with independent intellectual property rights.

In one aspect, the present invention provides a compound of formula I below, or a salt thereof, or a radionuclide label therefor:

Each G independently represents a monosaccharide, disaccharide or trisaccharide group, or a phenyl group substituted with a monosaccharide, disaccharide or trisaccharide group; l represents a dipeptide or tripeptide linker;

M represents a metal chelating group capable of binding radionuclides;

n is an integer from 1 to 3, in particular 1 or 2.

In some embodiments, each G is independently selected from the following groups:

In some embodiments, L is selected from the following groups:

In some embodiments, M is linked to L through an amide bond (i.e., M is linked to the NH-linking end of L), M is selected from the group of the following structures:

more preferably, M is Here, "- -" means that the substituent is attached thereto.

In some embodiments, the compound of formula I is selected from:

In some embodiments, the radionuclide is selected from the group consisting of a radiodiagnostic nuclide and the radionuclide, but is not limited thereto. The radioactive diagnosis nuclide marker can be used for tumor imaging, is beneficial to tumor diagnosis, and can be used for tumor diagnosis and treatment.

The radiodiagnostic nuclides may be any one or more selected from ⁸⁶Y、¹⁸F、⁵¹Mn、^52mMn、^52gMn、Al[¹⁸F]、⁶⁴Cu、⁶⁷Ga、⁶⁸Ga、⁸⁹Zr、^99mTc、¹¹¹In、¹²³I、¹²⁴I、¹²⁵I、⁴⁴Sc、⁴⁷Sc, preferably ⁸⁶Y、Al[¹⁸F]、⁶⁴Cu、⁶⁸Ga、⁸⁹Zr、⁹⁹mTc、¹²⁴ I; ⁶⁸ Ga or ⁶⁴ Cu is more preferable.

The radionuclide may be any one or more selected from ⁶⁷Cu、⁹⁰Y、¹²⁵I、¹³¹I、¹⁵³Sm、¹⁶⁶Ho、¹⁷⁷Lu、²²⁷Th,¹⁸⁶Re、¹⁸⁸Re、²¹¹At、²¹²Pb、²⁰³Pb、²¹²Bi、²¹³Bi、²²³Ra、²²⁵Ac、²²⁷Th; preferably ⁶⁷Cu、⁹⁰Y、¹²⁵I、¹³¹I、¹⁷⁷Lu、²²⁷Th、²²³Ra、²²⁵Ac、²¹¹At, any one or more of the following; more preferably ²²⁷Th、¹⁷⁷Lu、²²⁵ Ac or ²¹² Pb;

In some embodiments, the radionuclide label is:

In another aspect, the present invention provides the use of the above compounds or salts thereof or radionuclide labels thereof for the preparation of tumor imaging agents or antitumor drugs.

In some embodiments, the tumor is a solid tumor. In particular, the solid tumor is an epithelial tumor, and in particular, the tumor includes sarcoma, mesothelioma, medulloblastoma, colorectal tumor, pancreatic cancer, lung cancer, breast cancer, pancreatic cancer, gastric cancer, melanoma, and the like, but is not limited thereto.

In another aspect the present invention relates to a compound of formula II or a salt thereof,

Wherein M, L, n are defined as described above, respectively.

In some embodiments, the compound of formula II is selected from:

another aspect of the invention relates to a compound of the formula:

The compounds according to the invention can be prepared by a person skilled in the art by reference to the synthetic methods in the examples in combination with the prior art.

Drawings

FIG. 1 is a PET/CT image of ⁶⁸ Ga-labeled FAP2286 in a U87 tumor murine model for 30min,1h, 2h.

FIG. 2 is a PET/CT image of ⁶⁸ Ga-labeled compound g4 in a U87 tumor murine model for 30min,1h,2 h.

Detailed Description

For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments.

Unless otherwise indicated, all materials, reagents, methods and the like used in the examples are those conventionally used in the art.

Experimental materials and analytical instruments:

H-Cys (Trt) -2-Chlorotrityl Resin was purchased from Gill Biochemical (Shanghai) Inc.;

C18 reverse phase chromatography preparation system: preparing a liquid chromatographic instrument (LC-20 AR), wherein the C18 column is an Xbridge BEH C18 chromatographic column (4.6 mm X150 mm);

the MALDI-TOF mass spectrometer is a matrix-assisted laser desorption ionization time-of-flight mass spectrometer;

The Sep-Pak C18 column is WAT023501Sep-PAK LIGHT C;

The model of the biological molecule interaction instrument is Biacore T200;

Recombinant Human FAP Protein with a protein Sino Biological;

reagents for chip coupling and regeneration were purchased from cytivo company;

The model of a counter for measuring the radioactivity of tissue biodistribution is WIZARD2 2-Detector gamma counter, and the model is 2470-0020;

The rest reagents are purchased from Chinese medicine.

English abbreviations are defined:

DCM: dichloromethane;

DMF: n, n-dimethylformamide;

HBTU: benzotriazole-N, N, N, N-tetramethylurea hexafluorophosphate;

DIEA: n, N-diisopropylethylamine

TFA: trifluoroacetic acid

EDT:1, 2-ethanedithiol

TIS: triisopropylsilane

TBu-DOTA: tri-tert-butyl 1,4,7, 10-tetraazacyclododecane-1, 4,7, 10-tetraacetic acid

EXAMPLE 1 Synthesis of Compound a

S1: the procedure was set by placing 0.6g of resin H-Cys (Trt) -2-Chlorotrityl Resin with a degree of substitution of 0.336mmol/g into a polypeptide synthesizer (CS Bio, CS 336X);

s2: swelling of the resin: adding about 10mL of DMF into a reaction bottle, and vibrating for 30min;

S3: deprotection was carried out 2 times, each time adding a 20% by volume solution of piperidine in DMF (10 mL) and reacting for 15min, then washing the resin 3 times with DMF and 3 times with DCM;

S4: the first amino acid Fmoc-L-Phe-OH: fmoc-L-Phe-OH, based on the amino acid 4-fold molar amount of HBTU and 8-fold molar amount of DIEA, was added, the condensation was performed for 3h, the resin was washed 3 times with DMF and 3 times with DCM;

S5: repeating S3-S4, and sequentially connecting Fmoc-L-Gln (Trt) -OH, fmoc-L-Thr (tBu) -OH, fmoc-L-Pro-OH, fmoc-L-Pro-OH and Fmoc-L-Cys (Trt) -OH;

S6: deprotection was carried out 2 times, each time adding a 20% by volume solution of piperidine in DMF (10 mL) and reacting for 15min, then washing the resin 3 times with DMF and 3 times with DCM;

S7: removing the solvent, and putting 5mLDMF solution of hexanoic acid with the molar quantity of 4 times that of the hexanoic acid prepared in advance into the last XX1 of the procedure for condensation;

S8: cutting resin: solvent was removed and TFA was added in the volume ratio: TIS: EDT: ddH ₂ o=95%: 2.5%:1.25%: 20mL of 1.25% lysate, and reacting for 2.5h;

s9: after cleavage, the solvent was removed by rotary evaporator to give crude peptide dissolved in TFA;

S10: precipitation of the polypeptide: transferring the crude peptide dissolved in TFA into a centrifuge tube, adding 10 times of volume of glacial ethyl ether into the centrifuge tube, and centrifuging 8000g of the centrifuge tube at 4 ℃ to remove the solvent to obtain precipitated crude peptide;

S11: 10mg of crude polypeptide was taken and added in a volume ratio of 1:3=acetonitrile: dissolving the mixed solution of dd water, collecting target peak solution from 0.5mg sample in a C18 reversed phase chromatographic preparation system, and setting HPLC parameters: wavelength:210nm and 254nm; flow Rate:3mL/min; vol:1mL; column Temp:25 ℃; phase A: 0.1% tfa in water; and B phase: acetonitrile. The target peak solution was lyophilized to give compound a, which was a FAP-2286 precursor, stored at-20 ℃.

EXAMPLE 2 Synthesis of Compounds b and b1-b4

S1: the procedure was set by placing 0.5g of resin H-Cys (Trt) -2-Chlorotrityl Resin having a degree of substitution of 0.336mmol/g into a polypeptide synthesizer (CS Bio, CS 336X);

s3: deprotection was performed 2 times, 20% piperidine in DMF (10 mL) was added each time and reacted for 15min, then the resin was washed 3 times with DMF and 3 times with DCM;

S4: the first amino acid Fmoc-L-Lys (Boc) -OH: fmoc-L-Lys (Boc) -OH, based on 4-fold molar amount of HBTU and 8-fold molar amount of DIEA, was added, condensed for 3h, DMF was washed 3 times, DCM was washed 3 times;

S5: repeating S3-S4, and sequentially connecting Fmoc-L-Val-OH and Fmoc-L-Met-OH;

S6: deprotection was carried out 2 times, each time adding 20% piperidine in DMF (10 mL) and reacting for 15min, washing resin with DMF 3 times, washing resin with DCM 3 times;

S7: removing the solvent, and putting a DMF solution with the molar quantity of tBu-DOTA being 4 times that of the solvent prepared in advance into the final XX1 of the procedure for condensation;

S7: cutting resin: solvent was removed and TFA was added in the volume ratio: TIS: EDT: ddH ₂ o=95%: 2.5%:1.25%:1.25% of lysate, reacting for 3h;

s8: after cleavage, the solvent was removed by rotary evaporator to give crude peptide dissolved in TFA;

S7: precipitation of the polypeptide: transferring the crude peptide dissolved in TFA into a centrifuge tube, adding 10 times of glacial ethyl ether thereto, and removing the solvent by using 8000g of a centrifuge at 4 ℃ to obtain precipitated crude peptide;

S8: 10mg of crude polypeptide was taken and added in a volume ratio of 1:3=acetonitrile: dissolving the mixed solution of dd water, collecting target peak solution from 0.5mg sample in a C18 reversed phase chromatographic preparation system, and setting HPLC parameters: wavelength:210nm and 254nm; flow Rate:3mL/min; vol:1mL; column Temp:25 ℃; phase A: 0.1% tfa in water, phase B: acetonitrile. And freeze-drying the target peak solution to obtain a compound b, and preserving at-20 ℃.

Compounds b1 to b4 were obtained in the same manner except that the amino acid to be linked was replaced with the amino acid in the following Table 1 in step S5.

TABLE 1

Compounds of formula (I)	Amino acids
		b1	Fmoc-L-Val-OH，Fmoc-L-Nle-OH
b2	Fmoc-L-Phe-OH，Fmoc-L-Gly-OH
		b3	Fmoc-L-Ala-OH，Fmoc-L-Pro-OH，Fmoc-L-Gly-OH
b4	Fmoc-L-Lys(Boc)-OH，Fmoc-L-Ala-OH，Fmoc-L-Pro-OH，Fmoc-L-Gly-OH

EXAMPLE 3 Synthesis of Compound d

Compound a (3 mg,3.363 μmol) and compound C (1 mg,4.036 μmol) were dissolved in a mixed solution of acetonitrile and dd water, saturated sodium bicarbonate was added to adjust pH to about 8, reacted at room temperature for 3 hours, quenched with formic acid, concentrated with nitrogen blowing to remove excess solvent, the target peak solution was collected in a C18 reverse phase chromatography preparation system, and HPLC parameters were set: wavelength:210nm and 254nm; flow Rate:3mL/min; vol:1mL; column Temp:25 ℃; mobile phase a:0.1% tfa in water; mobile phase B: acetonitrile to obtain a compound d.

EXAMPLE 4 Synthesis of Compounds e and e1 to e4

Compound d (1 mg,0.876 μmol) and compound b (0.8 mg,0.876 μmol) were dissolved in 500 μl acetonitrile and 500 μl dd water, saturated sodium bicarbonate was added to adjust pH to around 8, reacted overnight at room temperature, quenched with formic acid, concentrated to remove solvent, the target peak solution was collected in a C18 reverse phase chromatography preparation system, and HPLC parameters were set: wavelength:210nm and 254nm; flow Rate:3mL/min; vol:1mL; column Temp:25 ℃; mobile phase a:0.1% aqueous tfa, mobile phase B: acetonitrile to obtain a compound e.

Compounds e1 to e4 were synthesized in the same manner except that compounds b1 to b4 were used instead of compound b, respectively.

EXAMPLE 5 Synthesis of Compounds g and g1-10

Compound e (0.5 mg,0.249 μmol) and compound f (0.234 mg,0.747 μmol) were dissolved in DMF, DIEA (0.161 mg,1.245 mmol) was added, reacted overnight at room temperature, diluted with dd water, the target peak solution was collected in a C18 reverse phase chromatography preparation system, and HPLC parameters were set: wavelength:210nm and 254nm; flow Rate:3mL/min; vol:1mL; column Temp:25 ℃; mobile phase a:0.1% aqueous tfa, mobile phase B: acetonitrile to give compound g.

The corresponding compounds g1 to g10 were obtained in the same manner by changing the compound e to the compounds e1 to e4 and the compound f to the following f1, f2 or f3 according to the following Table 2.

TABLE 2

Table 3 shows MALDI-TOF data for the above synthesized compounds.

TABLE 3 Table 3

Comparative example 1FAP-2286

As a comparative example, the known FAP-2286 (commercially available from MedChemExpress) was used.

EXAMPLE 6 preparation of ⁶⁸ Ga-labeled Compound

Radiolabeled compounds ⁶⁸Ga-g、⁶⁸ Ga-g4 and ⁶⁸ Ga-FAP-2286 were prepared by the following methods, with compounds g, g4 and FAP-2286 as precursor compounds, respectively.

S1: 1uL (concentration 10 ug/uL) of the precursor compound dissolved in dd water was taken in an ep tube, and 180 uL of 3M sodium acetate was added to adjust pH;

S2: 400uL of 3M radioactive ⁶⁸ Ga is added into an ep tube to react for 10min at 95 ℃;

S3: after the reaction, the purity is detected by paper chromatography, the developing agent is methanol, 1M ammonium formate=1:1, and if the purity is not more than 90%, the purification is performed by using a Sep-Pak C18 small column, and the specific operation is as follows: the radioactive sample is loaded by activating with 20mL of absolute ethyl alcohol and then rinsing with 20mL of dd water once, eluting with 75% of ethyl alcohol, discarding the product of the previous 500uL, measuring the radioactive dose by taking one tube with the highest radioactive dose as ⁶⁸ Ga marked product every 100 uL.

Example 7 PET imaging method of ⁶⁸ Ga-labeled Compound in glioblastoma model U87

Imaging experiments were performed using ⁶⁸ Ga-g4 and ⁶⁸ Ga-FAP-2286 prepared in example 6 as radiolabelled compounds.

About 150. Mu. Ci of the radiolabeled compound was injected into mice of glioblastoma model (U87 cells) via the tail vein, after waiting 10min, the mice were anesthetized with isoflurane, and the anesthetized mice were placed in a Siemens mouse Pet/CT apparatus for 10min CT scan and 15min PET scan.

The results are shown in FIGS. 1 and 2, respectively. FIG. 1 shows images of 30min, 1h and 2h after injection ⁶⁸ Ga-FAP-2286, and FIG. 2 shows images of 30min, 1h and 2h after injection ⁶⁸ Ga-g 4. Comparing the results of FIGS. 1-2, it can be seen that PET/CT imaging at 30min of ⁶⁸ Ga-g4 shows higher tumor uptake and lower liver uptake compared to ⁶⁸ Ga-FAP-2286; second, since ⁶⁸ Ga-g4 metabolizes faster than ⁶⁸ Ga-FAP-2286, the damage in vivo to radioactivity can be better reduced.

The uptake rate of the radiolabeled compound was directly quantified by using software on the imaging results plot, the results are shown in table 4.

TABLE 4 uptake rates of tumors, liver and kidneys

As can be seen from Table 4, the ⁶⁸ Ga-g4 of the present invention has better uptake in tumors after injection than ⁶⁸ Ga-FAP-2286, and lower liver and kidney uptake, better imaging results, and better reduction of radiation damage in vivo.

Example 8SPR surface plasmon resonance determination of affinity Kd

Affinity Kd of FAP protein to FAP-2286, compound g, g1 was determined by SPR surface plasmon resonance.

Experiments were performed in a Biacore T200 apparatus (universal electric) according to the operating manual. The chip used was a CM5 series chip with a carboxyl surface, and the coupling conditions were experimentally selected to be ph=5.5, the regeneration conditions were Glycine-HCl pH2.0, and the resulting affinity data are shown in table 5.

TABLE 5

Compounds of formula (I)	Kd(M)
		FAP-2286	4.87E-08
g	1.61E-08
		g1	2.27E-08

The results in Table 5 show that the affinity of the compound g, g1 and FAP-2286 are above the same order of magnitude and even better than that of FAP-2286, and the compound g series has better affinity for human FAP proteins.

Claims

1. A compound of formula I below, or a salt thereof, or a radionuclide label therefor:

each G independently represents a monosaccharide, disaccharide, trisaccharide group or a phenyl group substituted with a monosaccharide, disaccharide or trisaccharide group; l represents a dipeptide or tripeptide linker;

M represents a metal chelating group capable of binding radionuclides;

n is an integer from 1 to 3.

2. The compound of claim 1, or a salt thereof, or a radionuclide label thereof, wherein each G is independently selected from the group consisting of:

L is selected from the following groups:

m and L are connected through an amide bond and are groups selected from the following structures:

3. the compound of claim 1, or a salt thereof, or a radionuclide label therefor,

Each G is independently selected from the following groups:

M is

4. The compound of claim 1, or a salt thereof, or a radionuclide label thereof, wherein the radionuclide is selected from the group consisting of a radiodiagnostic nuclide and a radiotherapeutic nuclide;

in particular the number of the elements to be processed,

The radionuclide is any one or more selected from ⁸⁶Y、¹⁸F、⁵¹Mn、^52mMn、^52gMn、Al[¹⁸F]、⁶⁴Cu、⁶⁷Ga、⁶⁸Ga、⁸⁹Zr、^99mTc、¹¹¹In、¹²³I、¹²⁴I、¹²⁵I、⁴⁴Sc、⁴⁷Sc; preferably ⁸⁶Y、Al[¹⁸F]、⁶⁴Cu、⁶⁸Ga、⁸⁹Zr、⁹⁹mTc、¹²⁴ I any one or more; more preferably ⁶⁸ Ga or ⁶⁴ Cu;

The radionuclide is any one or more selected from ⁶⁷Cu、⁹⁰Y、¹²⁵I、¹³¹I、¹⁵³Sm、¹⁶⁶Ho、¹⁷⁷Lu、²²⁷Th,¹⁸⁶Re、¹⁸⁸Re、²¹¹At、²¹²Pb、²⁰³Pb、²¹²Bi、²¹³Bi、²²³Ra、²²⁵Ac、²²⁷Th; preferably ⁶⁷Cu、⁹⁰Y、¹²⁵I、¹³¹I、¹⁷⁷Lu、²²⁷Th、²²³Ra、²²⁵Ac、²¹¹At, any one or more of the following; more preferably ²²⁷Th、¹⁷⁷Lu、²²⁵ Ac or ²¹² Pb.

5. The compound of claim 1, or a salt thereof, or a radionuclide label therefor,

The compound is preferably selected from:

The radionuclide label is selected from:

6. Use of a compound according to any one of claims 1 to 5, or a salt thereof, or a radionuclide label thereof, in the preparation of a tumor imaging agent or an antitumor drug.

7. The use of claim 6, wherein the tumor is a solid tumor, in particular an epithelial tumor, more particularly comprising sarcoma, mesothelioma, medulloblastoma, glioblastoma, colorectal tumor, pancreatic cancer, lung cancer, breast cancer, pancreatic cancer, gastric cancer.

8. The use of claim 7, wherein the solid tumor is glioblastoma.

9. A compound of formula II:

Wherein M, L, n is defined as in claim 1,

Specifically, the compound of formula II is selected from:

10. A compound of formula d: