Polypeptide compound as well as complex and application thereof

Abstract

The invention discloses a polypeptide compound as well as a complex and application thereof, and particularly relates to the technical field of medicinal chemistry, the multi-peptide compound provided by the invention can target alphavbeta5, alpha5beta1 and alphavbeta3 integrin proteins, is enriched in tumor cells with high integrin expression, and can be used for preparing tumor cells with high integrin expression. The invention plays an important role in diagnosis and / or treatment of diseases related to integrin alpha v beta 5, alpha 5 beta 1 and alpha v beta 3.

Description

[0001] This application is required to be submitted to the China Patent Office on June 21, 2023, with application number 2023

[0002] 107454362, the priority of the Chinese patent application entitled “A polypeptide compound and its complex, and application”, the entire contents of which are incorporated into the present application by reference. Technical Field

[0003] The present invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to a class of polypeptide compounds and complexes and applications thereof. Background Art

[0004] Integrins are a class of transmembrane glycoproteins that are ubiquitous in cells. They are members of the cell adhesion molecule family and the most important molecules that mediate the interaction between cells and the extracellular matrix (ECM). They are a class of cell membrane surface receptors that can recognize and bind to corresponding ligands in the extracellular matrix, provide attachment points for cell adhesion, regulate cell movement, proliferation and apoptosis, mediate mutual recognition and adhesion between cells and between cells and the extracellular matrix, and have the function of connecting the external effects of cells with the internal structures of cells. Integrins are heterodimers composed of two subunits, α and β, connected by non-covalent bonds in a ratio of 1:1. They consist of three parts: the extracellular region, the transmembrane region and the intracellular region. They are connected into a spherical region in the extracellular region and contain a divalent cation binding domain. According to the specificity of integrin recognition of ligands, integrins can be roughly divided into integrins that recognize the arginase-glycinase-aspartase peptide (RGD tripeptide) sequence, laminin-linked integrins, leukocyte integrins and collagen-linked integrins. Integrins bind to ECM proteins such as collagen, laminin, vitronectin, fibronectin or some cell surface molecules through their extracellular regions. Integrins are involved in many important physiological processes, including embryogenesis, coagulation, and maintaining the integrity of tissues and organs in the body. Many pathological processes, such as inflammation, thrombosis, angiogenesis, and the growth, infiltration and metastasis of malignant tumors, are all related to abnormal regulation of integrins.

[0005] Dysregulation of integrin expression on cancer cells has been extensively studied in both cell and animal models, and targeting integrins has been shown to inhibit tumor growth, reduce resistance to chemotherapy or radiotherapy, and mitigate invasion and metastasis. Studies using transgenic mouse models or using immunodeficient mouse xenograft models have shown that loss of integrins in cancer cells or prevention of integrin function by blocking antibodies or peptides interferes with tumor growth, metastasis, and resistance to chemotherapy or radiotherapy. For β1 integrin, dual roles in growth and metastasis suggest that it may serve as a potential therapeutic target. Integrins, such as αvβ3, αvβ5, and α5β1, are not only expressed on tumor cells but are also induced on endothelial cells during angiogenesis, and these integrins have been shown to be targets for anti-angiogenic therapy of cancer.

[0006] Recent studies have found that a series of other subtypes of integrins are involved in the process of cancer development, including the establishment of pre-metastatic niches, epithelial-mesenchymal transition (EMT), metabolic reorganization, and cancer cell stemness and dormancy. Integrin αvβ6 is involved in the activation of TGFβ and is associated with SOX4-mediated cancer immune escape: αvβ6 blocking antibodies can inhibit SOX4 expression and sensitize triple-negative breast cancer mouse models to T cell-mediated killing responses caused by immune checkpoint inhibitors. Integrin αvβ8 can be used as a target for regulating anti-tumor immunity. αvβ8 blocking antibodies or specific blockade of integrin αvβ8 on the surface of regulatory T cells can attenuate TGFβ-mediated inhibition of CD8 + T cell suppression, thereby restoring CD8 + T cells have tumor-killing ability and are synergistic with radiation or immunotherapy.

[0007] Expression of integrin αvβ3 is widely associated with the progression of melanoma from the early radial growth stage to invasive vertical growth and metastasis. Studies have found that αvβ3 is significantly upregulated in malignant primary neuroendocrine prostate cancer and its lung metastatic lesions, and αvβ3 may serve as a biomarker for the early detection of malignant transformation in prostate cancer. Expression of integrin αvβ5 is considered a predictive biomarker in several cancer types, including breast cancer, liver cancer, and gastric cancer. Elevated levels of αvβ5 have been detected in patients with glioblastoma or colorectal cancer, and overexpression of αvβ5 is associated with unfavorable overall survival. Integrin α5β1 is involved in tumor-promoting processes such as angiogenesis, proliferation, and metastasis. In patients with early breast cancer, expression of α5β1 in primary tumors was associated with the presence of disseminated tumor cells in bone marrow aspirates and poor metastasis-free survival. The same study showed that silencing of the α5 gene or pharmacological inhibition of α5β1 with vorximab attenuated bone colonization in mice after intravenous injection of tumor cells. Integrin α5β1 has also been found to be upregulated in some gastrointestinal tumors, among which enhanced expression of ITGA5 corresponds to poor prognosis.

[0008] The abnormal expression of integrin proteins such as αvβ3, αvβ5, and α5β1 in various tumors and their role in the occurrence and development of tumors make them drug targets for tumor targeted therapy. Drug molecules targeting integrins can not only directly kill tumor cells, but also serve as targeted carriers to accurately deliver cytotoxins, radionuclides, etc. to tumor cells to achieve the purpose of killing tumors. In addition, the combination of radionuclides, fluorescent molecules and integrin targeting molecules can be used in the fields of tumor diagnosis and surgical navigation.

[0009] It can be seen that the research on drugs that inhibit integrins is of great significance. Summary of the invention

[0010] In view of this, the purpose of the present invention is to provide a class of polypeptide compounds and their complexes and applications. The polypeptide compounds provided by the present invention can target integrin proteins such as αvβ5, α5β1, αvβ3, etc., can inhibit the growth and proliferation of tumor cells, and play an important role in the diagnosis or treatment of tumors.

[0011] In order to achieve the above object, the present invention adopts the following technical solutions:

[0012] In the first aspect, the present invention provides a polypeptide compound, and pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotope labels, metabolites and prodrugs thereof, wherein the compound is obtained by coupling ZT and PD, or by coupling ZT, Linker and PD, and the compound has the following structural formula:

[0013] ZT-PD, or

[0014] ZT-Linker-PD

[0015] The connection between ZT and PD, or between ZT, Linker and PD forms an amide bond, a sulfonamide bond, a sulfenamide bond, an ester bond, a carbonate bond or a urea; including the following forms:

[0016] The amino group and the carboxyl group condense to form an amide bond; and / or,

[0017] The amino group and the sulfonic acid group are condensed to form a sulfonamide bond; and / or,

[0018] The amino groups condense with the amino groups to form urea; and / or,

[0019] A structure in which an amino group and a hydroxy group are condensed to form a carbonate bond; and / or,

[0020] A structure in which a carboxyl group and a hydroxyl group are condensed to form an ester bond; and / or,

[0021] The amino group and the sulfinic acid group condense to form a sulfenamide bond.

[0022] The structural formula of ZT in the above formula is as follows:

[0023]

[0024] Wherein, n is selected from an integer of 1 to 8;

[0025] R a1 , R a2 , R a3 is a substituted or unsubstituted alkylene phosphite group, a substituted or unsubstituted alkylene phosphite group, a substituted or unsubstituted C1-C6 alkylene group, a substituted or unsubstituted C5-C20 arylene group, a substituted or unsubstituted C1-C20 heteroarylene group, a substituted or unsubstituted C1-C6 alkyleneoxy group, a substituted or unsubstituted C5-C20 aryleneoxy group, a substituted or unsubstituted C1-C6 alkylenesulfonyl group, a substituted or unsubstituted C1-C6 alkylenesulfonic acid group, a substituted or unsubstituted C1-C6 alkylenesulfonate group, or a substituted or unsubstituted C1-C6 alkylenephosphate group;

[0026] R b1 , R b2 , R b3 is hydrogen, hydroxyl, carboxyl, halogen, thiol, seleno, amide, amino, cyano, nitro, substituted or unsubstituted phosphino, substituted or unsubstituted phosphite, substituted or unsubstituted C1-C6 hydrocarbon, substituted or unsubstituted C5-C20 aryl, substituted or unsubstituted C1-C20 heteroaryl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C5-C20 aryloxy, substituted or unsubstituted C1-C6 sulfonyl, substituted or unsubstituted C1-C6 sulfonic acid, substituted or unsubstituted C1-C6 sulfonate, substituted or unsubstituted C1-C6 phosphate;

[0027] R b1 , R b3 At least one of them is a carboxyl group, an amino group or a hydroxyl group.

[0028] Preferably, n is selected from an integer of 1 to 4;

[0029] R a1 , R a2 , R a3 is a substituted or unsubstituted alkylene phosphite group, a substituted or unsubstituted alkylene phosphite group, a substituted or unsubstituted C1-C6 alkylene group, or a substituted or unsubstituted C1-C6 alkyleneoxy group;

[0030] R b1 , R b2 , R b3is hydrogen, hydroxyl, carboxyl, halogen, amino, substituted or unsubstituted phosphino, substituted or unsubstituted phosphite, substituted or unsubstituted C1-C6 hydrocarbon, substituted or unsubstituted C1-C6 alkoxy;

[0031] R b1 , R b3 At least one of them is a carboxyl group.

[0032] More preferably, R a1 , R a2 , R a3 is a C1-C3 alkylene group, a C1-C3 alkyleneoxy group, a C1-C3 alkylenephosphite group or a C1-C3 alkylenephosphite group;

[0033] R b1 , R b2 , R b3 is hydrogen, hydroxyl, carboxyl, amino, C1-C3 alkylene phosphite, C1-C3 alkylene phosphite, C1-C3 hydrocarbon, C1-C3 alkoxy;

[0034] R b1 , R b3 At least one of them is a carboxyl group.

[0035] In a specific embodiment of the present invention, the structure of ZT is shown in formulas ZT1 to ZT4:

[0036]

[0037] In formulae ZT1 to ZT4, n is an integer of 1 to 4.

[0038] In the most preferred embodiment of the present invention, the structure of ZT is formula ZT1, wherein n is 1 or 2.

[0039] The structure of Linker in the above formula is as follows:

[0040]

[0041] Wherein, d is selected from an integer of 0 to 17;

[0042] R L1 , R L3 -(CH2) d1 COOH, amino, thiol, carboxyl or hydroxyl, d1 is an integer selected from 0 to 13;

[0043] R L2-Arg-Gly-Asp-, -Arg-Gly-, -Arg-, imino, imido, substituted or unsubstituted C1-C20 alkylene, substituted or unsubstituted C1-C20 alkylene ether, substituted or unsubstituted C5-C20 arylene ether;

[0044] Preferably, R L1 is an amino group or a carboxyl group;

[0045] R L2 It is an imino group, a nitrilo group, an imido group, a substituted or unsubstituted C1-C20 alkylene group, a substituted or unsubstituted C1-C20 alkylene ether, or a substituted or unsubstituted C6-C20 arylene ether.

[0046] In a specific embodiment of the present invention, the structure of Linker is shown in formulas Linker1 to Linker4:

[0047]

[0048] In the formulas Linker1 to Linker4, n1, n2, n3, n4, n5, and n6 are independently selected as integers between 0 and 13;

[0049] Y2 is hydrogen, hydroxyl, carboxyl, sulfonic acid, mercapto, amino, amide, sulfonamide, -OMe, -OEt, -SMe, -SEt, -CONHMe, -CONHEt, -SO2NHMe, -SO2NHEt.

[0050] In the above formula, PD is a compound and / or its derivative obtained by condensing one or more compounds of Formulae 1 to 6;

[0051]

[0052] In Formulae 1 to 6, m, e, and n1 are independently selected from integers of 0 to 5;

[0053] R is selected from hydrogen, -OH, -NH2, substituted or unsubstituted C1~C6 hydrocarbon group, substituted or unsubstituted C5~C20 aryl group, substituted or unsubstituted C1~C20 heteroaryl group; R is preferably an alkyl group having 1 to 5 carbon atoms, and most preferably a methyl or ethyl group.

[0054] R1, R2, R3, R4, R5, R6 are independently selected from substituted or unsubstituted C1-C6 alkylene, substituted or unsubstituted C5-C20 arylene, substituted or unsubstituted C1-C20 heteroarylene; the substituent group is selected from halogen, haloalkyl, lower alkyl, alkoxy, -O-(CH2) q-OR", alkylthio (or seleno), halogenated alkylthio (or seleno), thiol (or seleno), alkylthio (or seleno) ether, arylthio (or seleno) ether, hydroxyl, cyano, nitro, carboxyl derivative group, aryloxy, amide, acylamine, amino, hydroxylamine, alkylamine, dialkylamine, trifluoroalkoxy, trifluoromethyl, ester, sulfonyl, alkylsulfonyl, halogenated alkylsulfonyl, sulfonic acid, sulfonamide, phosphate, phosphate ester, unsubstituted aryl, aryl heterocyclic group, monocyclic heterocyclic group, N, O, SH, SeH, hydrogen, carboxyl, methylthio (or seleno) ether, ethylthio (or seleno) ether, -SOMe, -SO2Me, -CONH2, -COOMe, -COOEt, -NHOCH, -NHOCCH3, -NHSO2Me, p-toluenesulfonamide, sulfonate; the q is 1 or 2; the R" is a C1-C6 alkyl group.

[0055] The alkylene group in R1, R2, R3, R4, R5 and R6 is selected from a hydrocarbon group having 1 to 20 carbon atoms, more preferably a hydrocarbon group having 1 to 10 carbon atoms; the hydrocarbon group is preferably an alkyl group, an alkynyl group, an alkenyl group or an aliphatic chain. The substituent group in the substituted alkylene group in R1, R2, R3, R4, R5 and R6 is selected from N, O, SH or SeH.

[0056] The arylene group in R1, R2, R3, R4, R5 and R6 is selected from an aliphatic ring or an aromatic ring.

[0057] The substituents in the substituted arylene or substituted heteroarylene in R1, R2, R3, R4, R5, and R6 are selected from -F, -Cl, -Br, -I, -OH, -NH2, -NHOH, -COOH, -COH, -SO3H, -SH, -SMe, -SEt, -OPO3H, -NO2, -NO, -SOMe, -SO2Me, -SOEt, -SO2Et, -CONH2, -COOMe, -COOEt, -NHOCH, -NHOCCH3, -NHSO2Me, -OSO2Ph, phosphate, and sulfonate.

[0058] X, Y1, and Z are independently selected from hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C5-C20 aryloxy, -O-(CH2) q-OR", thiol, seleno, amide, amino, hydroxyl, cyano, nitro, carboxyl, substituted or unsubstituted C1-C6 ester, substituted or unsubstituted C1-C6 sulfonyl, substituted or unsubstituted C1-C6 sulfonic acid, substituted or unsubstituted C1-C6 sulfonate, sulfonamide, phosphate, substituted or unsubstituted C1-C6 phosphate, substituted or unsubstituted C5-C20 aryl, substituted or unsubstituted C5-C20 aryl and heterocyclic, substituted or unsubstituted C3-C6 heterocyclic; the substituents in the substituted C1-C6 alkyl, substituted C1-C6 alkyl ether, substituted C5-C20 aryl ether are one or more of -SH, SeH, hydroxyl, amino, carboxyl, sulfonic acid, phosphate, and halogen; q is 1 or 2; R" is a C1-C6 alkyl;

[0059] Alternatively, R1, R2, and R6 are H. In this case, X, Y1, Z, does not exist;

[0060] Alternatively, R3, R4, and R5 are H. In this case, R3 and R4 do not form a ring, and R5 and the C atom where it is located do not form a ring.

[0061] Preferably, X, Y1, and Z are independently selected from hydrogen, amino, carboxyl, thiol, -SMe, -SEt, phosphate, nitro, -F, -Cl, -Br, -I, -CHF2, -CF3, -NHOH, -SO3H, -SOMe, -SO2Me, -SOEt, -SO2Et, -CONH2, -COOMe, -COOEt, -NHOCH, -NHOCCH3, -NHSO2Me, -SeMe, -SeEt, p-toluenesulfonamide, phosphate, sulfonate, halogen, haloalkyl, lower Alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio (or seleno), halogenated alkylthio (or seleno), mercapto (or seleno), alkylthio (or seleno) ether, arylthio (or seleno) ether, hydroxyl, cyano, carboxyl derivative groups, aryloxy, amide, acylamine, hydroxylamine, alkylamine, dialkylamine, trifluoroalkoxy, trifluoromethyl, ester, sulfonyl, alkylsulfonyl, halogenated alkylsulfonyl, sulfonic acid, sulfonamide, phosphate, unsubstituted aryl, aryl heterocyclic group, monocyclic heterocyclic group, methylthio (or seleno), ethylthio (or seleno), -NHOH and other substituted groups.

[0062] Preferably, PD is synthesized by condensing one or more amino acids or amino acid-like groups in Formulae 1 to 6 through an amide bond formed by condensing an amino group and a carboxyl group, and / or through an amino group and a sulfonic acid group to form a sulfonamide bond; and / or through an amino group and a sulfinic acid group to form a sulfinamide bond. Preferably, 5 amino acids or amino acid-like groups are condensed to form 4 amide bonds, sulfonamide bonds and / or sulfinamide bonds, and the amino acid or amino acid-like structure preferably has a nitrogen end at the left end and a carbon end at the right end.

[0063] In a preferred embodiment of the present invention, the compounds (amino acids or amino acid-like compounds) of formula 1 to formula 6 are selected from one or more of Gln, Glu, Asn, Asp, homoaspartic acid, homoasparagine, homoglutamine, homoglutamic acid, Arg-Gly-Asp, Gly, Ala, Leu, Val, Leu, Phe, Ser, Thr, Phe, Tyr, Tyr(Me) and Tyr(Et); the amino acids in the compounds of formula 1 to formula 6 preferably include one or both of L-configuration and D-configuration structures.

[0064] More preferably, PD is selected from one of the compounds of formula II to formula VII:

[0065]

[0066] In Formula II, the selection ranges of m, e, n1, n2, n3, n4, m1, m2, m3, and m4 are consistent with the selection ranges of m, e, and n1 in Formulas 1 to 6 described in the above technical solution;

[0067] R1 is selected from -H, -OH, -NH2, -NHNZ 1 Z 2 、-NHZ 1 、-NZ 1 Z 2 、-OZ 1 、-NHOZ 1 , -SH, -SeH, -SZ 1 、-SeZ 1 ,-Arg-Gly-Asp-Z 3 , connected with the carbonyl group to form lipid derivative groups, amine derivative groups, Z 1 , Z 2 independently selected from alkyl, Z 3 Selected from hydrogen, hydroxyl, amino, ester derivative group formed with the carbon end of Asp amino acid, amine derivative group, hydrocarbon group or substituted hydrocarbon group;

[0068] R2 is selected from hydrogen, -OH, -NH2, a hydrocarbon group or a substituted hydrocarbon group, an acyl derivative group, a sulfonyl derivative group, X5-Arg-Gly-Asp-;

[0069] R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 independently selected from hydrogen, hydrocarbon or substituted hydrocarbon, heteroatom substituted hydrocarbon, alkene or alkene derivative, alkynyl or alkynyl derivative, aryl and substituted aryl, heteroaryl or substituted heteroaryl;

[0070] X, X1, X2, X3, X4, and X5 are independently selected from hydrogen, hydroxy, amino, hydrocarbon or substituted hydrocarbon.

[0071]

[0072] In formula III, k1 and k2 are independently selected from integers between 0 and 16;

[0073] R', R'1, R'2 and R'3 are independently selected from hydrogen, hydroxyl, amino, hydrocarbon or substituted hydrocarbon;

[0074] X1, X2 and X3 are independently selected from -H, -OH, -NH2, -NHNZ 1 Z 2 、-NHZ 1 、-NZ 1 Z 2 、-OZ 1 、-NHOZ 1 , -SH, -SeH, -SZ 1 、-SeZ 1 ,-Arg-Gly-Asp-Z 3 , connected with the carbonyl group to form lipid derivative groups, amine derivative groups, Z 1 , Z 2 independently selected from alkyl, Z 3 Selected from hydrogen, hydroxyl, amino, an ester derivative group formed with the carbon end of Asp, an amine derivative group, a hydrocarbon group or a substituted hydrocarbon group;

[0075] AA1 is selected from one of the structures of Formula 7 to Formula 12:

[0076]

[0077] In Formulae 7 to 12: the acyl end of AA1 is coupled to the nitrogen end of the main chain;

[0078] m, e, and n1 are independently selected from integers between 0 and 5;

[0079] R, Z' are independently selected from hydrogen, -OH, -NH2, hydrocarbon or substituted hydrocarbon, acyl derivative groups, sulfonyl derivative groups;

[0080] R1, R2, R3, R4, R5, and R6 are independently selected from hydrogen, alkylene or substituted alkylene, alkylene or alkylene derivatives, alkynylene or alkynylene derivatives, arylene and substituted arylene, heteroarylene or substituted heteroarylene;

[0081] If R1, R2, R3, R4, R5, and R6 are selected from hydrogen substitution, X, Y1, and Z are unsubstituted;

[0082] When R1, R2, R3, R4, R5, and R6 are selected from non-hydrogen substitutions, X, Y1, and Z are independently selected from hydrogen, halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio (or seleno), haloalkylthio (or seleno), mercapto (or seleno), alkylthio (or seleno) ether, arylthio (or seleno) ether, hydroxyl, cyano, nitro, carboxyl derivative group, aryloxy, amide, acylamine, amino, hydroxylamine, alkylamine, dialkylamine, trifluoroalkoxy, trifluoromethyl, ester, sulfonyl, alkylsulfonyl, haloalkylsulfonyl, sulfonic acid, sulfonamide, phosphate, phosphate ester, unsubstituted aryl, aryl heterocyclic group, and monocyclic heterocyclic group.

[0083]

[0084] In formula IV, k1 and k2 are independently selected from integers between 0 and 16;

[0085] R', R'1, R'2 and R3 are independently selected from hydrogen, hydroxyl, hydrocarbon or substituted hydrocarbon;

[0086] X' is selected from hydrogen, hydrocarbyl or substituted hydrocarbyl;

[0087] X1, X2 and X3 are independently selected from -H, -OH, -NH2, -NHNZ 1 Z 2 、-NHZ 1 、-NZ 1 Z 2 、-OZ 1 、-NHOZ 1 , -SH, -SeH, -SZ 1 、-SeZ 1 ,-Arg-Gly-Asp-Z 3 , connected with the carbonyl group to form lipid derivative groups, amine derivative groups, Z 1 , Z 2 independently selected from alkyl, Z 3 Selected from hydrogen, hydroxyl, amino, ester derivative group formed with the carbon end of Asp, amine derivative group, hydrocarbon group or substituted hydrocarbon;

[0088] AA2 is selected from one of the structures of Formula 13 to Formula 18:

[0089]

[0090] In Formula 13 to Formula 18: the acyl end of AA2 is coupled to the nitrogen end of the main chain, and the acyl end of the main chain is coupled to the nitrogen end of the general formula of AA2;

[0091] m, e, and n1 are independently selected from integers between 0 and 5;

[0092] R is selected from hydrogen, -OH, -NH2, a hydrocarbon group or a substituted hydrocarbon group;

[0093] R1, R2, R3, R4, R5, and R6 are independently selected from hydrogen, alkylene or substituted alkylene, alkylene or alkylene derivatives, alkynylene or alkynylene derivatives, arylene and substituted arylene, heteroarylene or substituted heteroarylene;

[0094] If R1, R2, R3, R4, R5, and R6 are selected from hydrogen substitution, X, Y1, and Z are unsubstituted;

[0095] When R1, R2, R3, R4, R5, and R6 are selected from non-hydrogen substitutions, X, Y1, and Z are independently selected from hydrogen, halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio (or seleno), haloalkylthio (or seleno), mercapto (or seleno), alkylthio (or seleno) ether, arylthio (or seleno) ether, hydroxyl, cyano, nitro, carboxyl derivative group, aryloxy, amide, acylamine, amino, hydroxylamine, alkylamine, dialkylamine, trifluoroalkoxy, trifluoromethyl, ester, sulfonyl, alkylsulfonyl, haloalkylsulfonyl, sulfonic acid, sulfonamide, phosphate, phosphate ester, unsubstituted aryl, aryl heterocyclic group, and monocyclic heterocyclic group.

[0096]

[0097] In formula V, k, k1 and k2 are independently selected from integers between 0 and 16;

[0098] R', R'2 and R'3 are independently selected from hydrogen, hydroxyl, amino, hydrocarbon or substituted hydrocarbon;

[0099] X' is selected from hydrogen, hydrocarbyl or substituted hydrocarbyl;

[0100] X1, X2 and X3 are independently selected from -H, -OH, -NH2, -NHNZ 1 Z 2 、-NHZ 1 、-NZ 1 Z 2 、-OZ 1 、-NHOZ 1 , -SH, -SeH, -SZ 1、-SeZ 1 ,-Arg-Gly-Asp-Z 3 , connected with the carbonyl group to form lipid derivative groups, amine derivative groups, Z 1 , Z 2 independently selected from alkyl, Z 3 Selected from hydrogen, hydroxyl, amino, ester derivative group formed with the carbon end of Asp, amine derivative group, hydrocarbon group or substituted hydrocarbon;

[0101] The selection range of AA3 is consistent with the selection range of AA2 in formula III described in the above technical solution.

[0102]

[0103] In Formula VI, k, k1 and k2 are independently selected from integers between 0 and 16;

[0104] R', R'1 and R'3 are independently selected from hydrogen, hydroxyl, amino, hydrocarbon or substituted hydrocarbon;

[0105] X' is selected from hydrogen, hydrocarbyl or substituted hydrocarbyl;

[0106] X1, X2 and X3 are independently selected from -H, -OH, -NH2, -NHNZ 1 Z 2 、-NHZ 1 、-NZ 1 Z 2 、-OZ 1 、-NHOZ 1 , -SH, -SeH, -SZ 1 、-SeZ 1 ,-Arg-Gly-Asp-Z 3 , connected with the carbonyl group to form lipid derivative groups, amine derivative groups, Z 1 , Z 2 independently selected from alkyl, Z 3 Selected from hydrogen, hydroxyl, amino, ester derivative group formed with the carbon end of Asp, amine derivative group, hydrocarbon group or substituted hydrocarbon;

[0107] The selection range of AA4 is consistent with the selection range of AA2 in formula III described in the above technical solution.

[0108]

[0109] In Formula VII, k and k1 are independently selected from integers between 0 and 16;

[0110] R', R'1, R'2 are independently selected from hydrogen, hydroxyl, amino, hydrocarbon or substituted hydrocarbon;

[0111] X' is selected from hydrogen, hydrocarbyl or substituted hydrocarbyl;

[0112] X1, X2 are independently selected from -H, -OH, -NH2, -NHNZ 1 Z 2 、-NHZ 1 、-NZ 1 Z 2 、-OZ 1 、-NHOZ 1 , -SH, -SeH, -SZ 1 、-SeZ 1 ,-Arg-Gly-Asp-Z 3 , connected with the carbonyl group to form lipid derivative groups, amine derivative groups, Z 1 , Z 2 independently selected from alkyl, Z 3 Selected from hydrogen, hydroxyl, amino, ester derivative group formed with the carbon end of Asp, amine derivative group, hydrocarbon group or substituted hydrocarbon;

[0113] AA5 is selected from one of the structures of Formula 19 to Formula 24:

[0114]

[0115] In Formulae 19 to 24: the main chain acyl end is coupled to the general nitrogen end of AA5;

[0116] m, e, and n1 are independently selected from integers between 0 and 5;

[0117] R is selected from hydrogen, -OH, -NH2, a hydrocarbon group or a substituted hydrocarbon group;

[0118] R1, R2, R3, R4, R5, and R6 are independently selected from hydrogen, alkylene or substituted alkylene, alkylene or alkylene derivatives, alkynylene or alkynylene derivatives, arylene and substituted arylene, heteroarylene or substituted heteroarylene;

[0119] If R1, R2, R3, R4, R5, and R6 are selected from hydrogen substitution, X, Y1, and Z are unsubstituted;

[0120] When R1, R2, R3, R4, R5, and R6 are selected from non-hydrogen substitutions, X, Y1, and Z are independently selected from hydrogen, halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio (or seleno), haloalkylthio (or seleno), mercapto (or seleno), alkylthio (or seleno) ether, arylthio (or seleno) ether, hydroxyl, cyano, nitro, carboxyl derivative group, aryloxy, amide, acylamine, amino, hydroxylamine, alkylamine, dialkylamine, trifluoroalkoxy, trifluoromethyl, ester, sulfonyl, alkylsulfonyl, haloalkylsulfonyl, sulfonic acid, sulfonamide, phosphoric acid, phosphoric acid ester, unsubstituted aryl, aryl heterocyclic group, and monocyclic heterocyclic group;

[0121] R x Selected from -H, -OH, -NH2, -NHNZ 1 Z 2 、-NHZ 1 、-NZ 1 Z 2 、-OZ 1 、-NHOZ 1 , -SH, -SeH, -SZ 1 、-SeZ 1 ,-Arg-Gly-Asp-Z 3 , connected with the carbonyl group to form a lipid derivative group, an amine derivative group, an olefin group or an olefin derivative, an alkynyl group or an alkynyl derivative, an aryl group and a substituted aryl group, a heteroaryl group or a substituted heteroaryl group, Z 1 , Z 2 independently selected from alkyl, Z 3 It is selected from hydrogen, hydroxyl, amino, an ester derivative group formed with the carbon end of Asp, an amine derivative group, a hydrocarbon group or a substituted hydrocarbon.

[0122] In the most preferred embodiment of the present invention, PD is selected from the compounds of the following structures:

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130] In a specific embodiment of the present invention, the structure of the polypeptide compound is as follows:

[0131]

[0132]

[0133] In a second aspect, the present invention provides a polypeptide complex, wherein the polypeptide complex is formed by reacting the above-mentioned polypeptide compound, and pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotope labels, metabolites and prodrugs thereof with a metal; the metal is selected from rare earth elements, Cu, Ga, In, Bi, Al 18 One of F, At, Ac, Bi or an isotope thereof.

[0134] The “rare earth elements” mentioned above include lanthanum (La), cerium (Ce), rhodium (Pr), neodymium (Nd), promethium (Pm), samarium (Sm), europium (Eu), gadolinium (Gd), terbium (Tb), dysprosium (Dy), holmium (Ho), erbium (Er), thulium (Tm), ytterbium (Yb), lutetium (Lu), yttrium (Y), and scandium (Sc).

[0135] Preferably, the metal is 177 Lu, 64 Cu, 68 Ga, 111 In、Al 18 F. 211 At 225 Ac, 90 Y. 213 One of Bi and Gd or an isotope thereof.

[0136] In a specific embodiment of the present invention, the structure of the polypeptide complex is as follows:

[0137]

[0138]

[0139]

[0140] The polypeptide complex is preferably formed by chelating the polypeptide compound with a metal; the preparation method thereof preferably comprises the following steps: reacting the polypeptide compound with a metal compound; the reaction is preferably a mixed reaction of the polypeptide compound with a metal chloride, or a mixed reaction of the polypeptide compound with a metal acid salt; the metal in the metal acid salt is preferably Al 18 F, Gd, 177 Lu, 64 Cu, 68 Ga, 111In, 211 At 225 Ac, 90 Y. 213 One of Bi and At or its isotope, preferably Al 18 F. 177 Lu, Gd and 68 Ga or its isotopes.

[0141] Mixing a polypeptide compound and a metal chloride for reaction; the equivalent ratio of the metal chloride to the polypeptide compound is (1-10):1; the reaction temperature is preferably 20-150°C, the pH is 3-11; the reaction temperature is more preferably 60-70°C, the pH is 3.0-6.0, and the reaction time is 2-3h;

[0142] Alternatively, the polypeptide compound and the metal acid salt are mixed for reaction; the mass ratio of the metal acid salt to the polypeptide compound is preferably (1-10):1, preferably (1-4):1; the metal acid salt is preferably nitrate, more preferably gallium nitrate; the reaction temperature is preferably 20-150°C, the pH is 3-11; the reaction temperature is more preferably 60-70°C, the pH is 3.0-7.0, and the reaction time is 2-3h.

[0143] Preferably, the preparation method of the polypeptide complex preferably comprises the following steps:

[0144] The polypeptide compound is dissolved in a solvent, mixed with an alkaline solution, the pH is adjusted to 3-11, and then a metal chloride is added, the pH is adjusted to 3-11, and then excess metal ions are precipitated to obtain a polypeptide complex;

[0145] Alternatively, the polypeptide compound is dissolved in a solvent, heated to 20-150°C, then mixed with a metal acid salt solution for reaction, and then the pH is adjusted to 3-11, and the reaction is carried out for 2-3 hours to obtain a polypeptide complex. The solvent of the solvent and the metal acid salt solution is preferably water, and the pH is preferably adjusted with KOH or NaOH.

[0146] After the polypeptide compound and the metal chloride are mixed and reacted, or after the polypeptide compound and the metal acid salt are mixed and reacted, the system is preferably purified by high performance liquid chromatography (HPLC).

[0147] In a third aspect, the present invention provides a pharmaceutical composition comprising the above-mentioned polypeptide compounds, and pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotope labels, metabolites and prodrugs and / or polypeptide complexes thereof.

[0148] Preferably, the pharmaceutical composition further comprises pharmaceutically acceptable excipients and / or carriers.

[0149] In a fourth aspect, the present invention provides a polypeptide compound, and its pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotope labels, metabolites and prodrugs and / or polypeptide complexes and / or the use of the above-mentioned pharmaceutical compositions in the preparation of drugs for diagnosing and / or treating diseases related to integrin αvβ5, and / or integrin α5β1, and / or integrin αvβ3, and / or integrin αvβ6.

[0150] The diagnosis includes but is not limited to PET / CT and magnetic resonance imaging.

[0151] The diseases associated with integrin αvβ5, and / or integrin α5β1, and / or integrin αvβ3, and / or integrin αvβ6 described in the present invention include one or more of lung adenocarcinoma, breast cancer, pancreatic cancer, melanoma, malignant primary neuroendocrine prostate cancer and its lung metastatic lesions, breast cancer, ovarian cancer, and gastrointestinal tumors.

[0152] The polypeptide compounds provided by the present invention can target integrin proteins such as αvβ5, α5β1, αvβ3, αvβ6, etc., and are enriched in tumor cells with high integrin expression. They can achieve the purpose of killing tumors by inhibiting the growth and proliferation of tumor cells, or provide tumor-targeting carriers for cytotoxic molecules to enhance the precise killing of tumors by cytotoxic molecules. In addition, targeting carriers can also be provided for nuclides and fluorescent molecules to achieve the purpose of accurate diagnosis and / or treatment of tumors. As confirmed by the test examples of the present invention, the affinity KD of the polypeptide compounds of the present invention for α5β1, αvβ3, αvβ5, and αvβ6 are all at the nM level.

[0153] In the present invention, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0154] In the present invention, the term "alkyl" refers to a straight or branched aliphatic hydrocarbon group. For example, the term "C1-6 alkyl" refers to an alkyl group having 1 to 6 carbon atoms. In the present invention, alkyl includes (but is not limited to) methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, etc. The alkyl group in the present invention is optionally substituted by one or more substituents described in the present invention (such as halogen).

[0155] In the present invention, the term "haloalkyl" refers to an alkyl group substituted by one or more (such as 1 to 3) the same or different halogen atoms. For example, the term "C1-C6 haloalkyl" refers to a haloalkyl group having 1 to 6 carbon atoms. In the present invention, haloalkyl includes (but is not limited to) -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, -CH2CH2CF3, -CH2Cl, etc. The haloalkyl group in the present invention is optionally substituted by one or more substituents described in the present invention.

[0156] In the present invention, the term "alkoxy" refers to an alkyl group connected to the rest of the molecule through an oxygen atom. In the present invention, alkoxy includes (but is not limited to) methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, etc. The alkoxy in the present invention is optionally substituted with one or more substituents described in the present invention.

[0157] In the present invention, the term "cycloalkyl" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic hydrocarbon group. For example, the term "C3-C8 cycloalkyl" refers to a cycloalkyl group having 3 to 8 carbon atoms. In the present invention, cycloalkyl includes (but is not limited to) monocyclic cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.; or bicyclic cycloalkyl, including fused rings, bridged rings or spiro rings, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, decahydronaphthyl, etc. The cycloalkyl in the present invention is optionally substituted by one or more substituents described in the present invention (such as methyl).

[0158] In the present invention, the term "heterocycloalkyl" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic group, whose ring atoms are composed of carbon atoms and at least one heteroatom selected from nitrogen, oxygen and sulfur. If the valence bond requirements are met, the heterocycloalkyl can be connected to the rest of the molecule through any one of the ring atoms. For example, the term "3-8 membered heterocycloalkyl" refers to a heterocycloalkyl having 3 to 8 ring atoms. In the present invention, heterocycloalkyl includes, but is not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuryl, dioxolinyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dithianyl or trithianyl. The heterocycloalkyl in the present invention is optionally substituted with one or more substituents described herein.

[0159] In the present invention, the term "aryl" refers to a monocyclic or fused polycyclic aromatic hydrocarbon group having a conjugated π electron system. For example, the term "C6-C20 aryl" refers to an aryl group having 6 to 20 carbon atoms. In the present invention, aryl includes (but is not limited to) phenyl, naphthyl, anthracenyl, phenanthrenyl, acenaphthenyl, azulenyl, fluorenyl, indenyl, pyrenyl, etc. The aryl group in the present invention is optionally substituted by one or more substituents described in the present invention (such as halogen, hydroxyl, cyano, nitro, C1-C6 alkyl, etc.).

[0160] In the present invention, the term "heteroaryl" refers to an aromatic group having a conjugated π electron system, a monocyclic or fused polycyclic (especially a benzo-fused polycyclic) ring atom consisting of carbon atoms and at least one heteroatom selected from nitrogen, oxygen and sulfur. If the valence bond requirements are met, the heterocycloalkyl group can be connected to the rest of the molecule through any one of the ring atoms. For example, the term "C6-C20 heteroaryl" refers to a heteroaryl group having 6 to 20 carbon atoms. In the present invention, heteroaryl includes (but is not limited to) thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and benzo derivatives thereof. The heteroaryl in the present invention is optionally substituted with one or more substituents described in the present invention (e.g., halogen, C1-6 alkyl, etc.).

[0161] In the present invention, the term "alkenyl" refers to a straight or branched aliphatic hydrocarbon group having at least one C=C double bond. For example, the term "C2-C6 alkenyl" refers to an alkenyl group having 2 to 6 carbon atoms. In the present invention, alkenyl includes (but is not limited to) vinyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, n-octenyl, n-decenyl, etc. The alkenyl group in the present invention is optionally substituted by one or more substituents described in the present invention.

[0162] In the present invention, the term "alkynyl" refers to a straight or branched aliphatic hydrocarbon group having at least one C≡C triple bond. For example, the term "C2-C6 alkynyl" refers to an alkynyl group having 2 to 6 carbon atoms. In the present invention, alkynyl includes (but is not limited to) ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. The alkynyl group in the present invention is optionally substituted by one or more substituents described in the present invention.

[0163] In the present invention, the term "substituted" means that one or more (e.g., 1, 2, 3, or 4) atoms (e.g., hydrogen atoms) or groups of atoms (e.g., triflate groups) on the specified group are replaced by other atoms or groups of atoms, provided that the specified group meets the valence requirements in the current case and forms a stable compound after substitution. Combinations of substituents and / or variables are allowed only when the combination can form a stable compound. If a substituent is described as "optionally substituted by...", the substituent can be unsubstituted or substituted. If a first substituent is described as optionally substituted by one or more of the substituents listed in the second substituent, one or more hydrogen atoms in the first substituent can be replaced individually or independently by one or more of the substituents listed in the second substituent, or not replaced.

[0164] In the present invention, the term "alkylene group" refers to a group obtained by removing two hydrogen atoms from a straight chain, branched chain or cyclic, saturated or unsaturated hydrocarbon compound.

[0165] In the present invention, the term "arylene group" refers to a group obtained by removing two hydrogen atoms from an aromatic hydrocarbon; and "heteroarylene group" refers to a group obtained by removing two hydrogen atoms from an aromatic compound containing a heteroatom.

[0166] In the present invention, the term "alkyleneoxy group" refers to a group obtained by removing one hydrogen atom from an alkoxy group.

[0167] In the present invention, the term "alkylene phosphite" refers to a group in which an alkylene group and a phosphite group are linked by a covalent bond, an alkylene group refers to a group obtained by removing two hydrogen atoms from a straight-chain or branched hydrocarbon, and a phosphite group refers to a group obtained by removing one hydrogen atom connected to a phosphorus atom from hypophosphorous acid; "alkylene phosphite" refers to a group in which an alkylene group and a phosphite group are linked by a covalent bond, and a phosphite group refers to a group obtained by removing one hydrogen atom connected to a phosphorus atom from phosphorous acid.

[0168] In the present invention, the term "alkylene ether" refers to a group obtained by removing one hydrogen atom from an alkyl ether.

[0169] In the present invention, the term "arylene ether" refers to a group obtained by removing one hydrogen atom from an aryl ether.

[0170] In the present invention, the term "alkylene sulfonyl group" refers to a group in which an alkylene group and a sulfonyl group are linked by a covalent bond, "alkylene sulfonic acid group" refers to a group in which an alkylene group and a sulfonic acid group are linked by a covalent bond, "alkylene sulfonate group" refers to a group in which an alkylene group and a sulfonate group are linked by a covalent bond, and "alkylene phosphate group" refers to a group in which an alkylene group and a phosphate group are linked by a covalent bond.

[0171] In the present invention, the term "each independently" means that at least two groups (or ring systems) with the same or similar value ranges in the structure may have the same or different meanings under certain circumstances. For example, substituent 1 and substituent 2 are each independently hydrogen, halogen, hydroxyl, cyano, alkyl or aryl. When substituent 1 is hydrogen, substituent 2 may be either hydrogen or halogen, hydroxyl, cyano, alkyl or aryl. Similarly, when substituent 2 is hydrogen, substituent 1 may be either hydrogen or halogen, hydroxyl, cyano, alkyl or aryl.

[0172] In the present invention, the term "polymorph" (or "polymorphic form") refers to a solid crystalline form of a compound or complex. Polymorphs of a molecule can be obtained by many known methods by those skilled in the art. These methods include (but are not limited to) melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion and sublimation.

[0173] In the present invention, the term "solvate" refers to a substance formed by the combination of the compound of the present invention (or its pharmaceutically acceptable salt) and at least one solvent molecule through non-covalent intermolecular forces. Common solvates include (but are not limited to) hydrates (including hemihydrates, monohydrates, dihydrates, trihydrates, etc.), ethanolates, acetoneates, etc.

[0174] In the present invention, the term "nitrogen oxide" refers to a compound formed by oxidation of a nitrogen atom in a tertiary amine or nitrogen-containing (aromatic) heterocyclic compound structure. For example, a nitrogen atom in a parent core structure can form a corresponding nitrogen oxide.

[0175] In the present invention, the term "isotope-labeled compound" refers to a derivative compound formed by replacing a specific atom in the compound of the present invention with its isotope atom. Unless otherwise specified, the compounds of the present invention include various isotopes of H, C, N, O, F, P, S, and Cl, such as 2 H(D), 3 H(T), 13 C. 14 C. 15 N. 17 O. 18 O. 18 F. 31 P. 32 P. 35 S. 36 S and 37 Cl.

[0176] In the present invention, the term "metabolite" refers to a derivative compound formed after metabolism of the compound of the present invention.

[0177] In the present invention, the term "prodrug" refers to a derivative compound that can directly or indirectly provide a compound of the present invention after being administered to an individual. Particularly preferred derivative compounds or prodrugs are compounds that can increase the bioavailability of the compound of the present invention when administered to an individual (e.g., more easily absorbed into the blood), or compounds that promote the delivery of the parent compound to the site of action (e.g., the lymphatic system). Unless otherwise indicated, all prodrug forms of the compounds of the present invention are within the scope of the present invention, and various prodrug forms are well known in the art.

[0178] In the present invention, the term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention that is substantially non-toxic to an organism. In the present invention, pharmaceutically acceptable salts generally include (but are not limited to) salts formed by reacting the compound of the present invention with a pharmaceutically acceptable inorganic / organic acid or inorganic / organic base. Such salts are also referred to as acid addition salts or base addition salts.

[0179] In the present invention, the term "pharmaceutically acceptable ester" refers to an ester that is substantially non-toxic to an organism and is hydrolyzed in vivo to form a compound of the present invention or a salt thereof. In the present invention, pharmaceutically acceptable esters generally include (but are not limited to) esters formed between a compound of the present invention and a pharmaceutically acceptable carboxylic acid or sulfonic acid, which are also referred to as carboxylic acid esters or sulfonic acid esters.

[0180] In the present invention, the term "isomer" refers to a compound having the same molecular weight due to the same number of atoms and atomic types, but different spatial arrangements or configurations of atoms. The term "stereoisomer" (or "optical isomer") refers to a stable isomer that has a vertical asymmetric plane due to at least one chiral factor (including chiral center, chiral axis, chiral plane, etc.), thereby being able to rotate plane polarized light. Since the compounds of the present invention have asymmetric centers and other chemical structures that may cause stereoisomerism, the present invention also includes these stereoisomers and mixtures thereof. Since the compounds of the present invention (or their pharmaceutically acceptable salts) include asymmetric carbon atoms, they can exist in the form of a single stereoisomer, a racemate, an enantiomer, and a mixture of diastereomers. Generally, these compounds can be prepared in the form of racemates. However, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., single enantiomers or diastereomers, or mixtures enriched in a single stereoisomer (purity ≥98%, ≥95%, ≥93%, ≥90%, ≥88%, ≥85%, or ≥80%). Single stereoisomers of a compound are prepared synthetically from optically active starting materials containing the desired chiral center, or by preparing a mixture of enantiomeric products followed by separation or resolution, such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatography, use of a chiral resolving agent, or direct separation of the enantiomers on a chiral chromatographic column. Starting compounds of a particular stereochemistry are either commercially available or prepared by methods well known in the art and resolved by methods well known in the art. The term "enantiomer" refers to a pair of stereoisomers that are non-superimposable mirror images of each other. The term "diastereomer" or "diastereomer" refers to optical isomers that do not form mirror images of each other. The term "racemic mixture" or "racemate" refers to a mixture containing equal parts of a single enantiomer (i.e., an equimolar mixture of two R and S enantiomers). The term "non-racemic mixture" refers to a mixture containing unequal parts of a single enantiomer. Unless otherwise indicated, all stereoisomeric forms of the compounds of the present invention are within the scope of the present invention. The term "tautomer" (or "tautomeric form") refers to structural isomers with different energies that can be converted to each other through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (or prototransfer tautomers) include (but are not limited to) interconversions carried out by proton migration, such as keto-enol isomerization, imine-enamine isomerization, amide-imino alcohol isomerization, etc. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

[0181] The present invention has no special restrictions on the preparation method of the polypeptide compound. The method of solid phase piece-by-piece, fragment synthesis, and liquid phase synthesis of polypeptide compounds by a person skilled in the art can be adopted, and the desired amino acids, quasi-amino acids, or polypeptide substances can be used for synthesis according to the compound structure; the general steps in the preparation process of the polypeptide compound preferably include: initial resin synthesis, deprotection group (Fmoc protecting group), coupling amino acid, and gradually synthesizing the desired polypeptide compound by repeated deprotection group and coupling amino acid operations; the connection mode between PD, ZT and Linker can form common functional group structures such as amides, carbonates, ureas, sulfonamides, sulfenamides, amines, etc. through the reaction of functional groups in the structure. BRIEF DESCRIPTION OF THE DRAWINGS

[0182] Figure 1 HPLC spectrum of compound TM1;

[0183] Figure 2 HPLC spectrum of compound TM2;

[0184] Figure 3 HPLC spectrum of compound TM3;

[0185] Figure 4 HPLC spectrum of compound Gd-TM1;

[0186] Figure 5 HPLC spectrum of compound Gd-TM2;

[0187] Figure 6 HPLC spectrum of compound Gd-TM3;

[0188] Figure 7 HPLC spectrum of compound Gd-TM7;

[0189] Figure 8 68 PET / CT imaging of Ga-TM1(2h) (H1975);

[0190] Fig. 9 68 PET / CT imaging of Ga-TM7(4h) (H1975);

[0191] Fig.10 68 PET / CT imaging of Ga-TM7(4h) (BxPC-3);

[0192] Fig.11 68 PET / CT imaging of Ga-TM7(4h) (PANC-1);

[0193] Fig.12 Magnetic resonance imaging (MR) images;

[0194] Fig.13 The ratio of tumor and muscle gray value of T1 signal on magnetic resonance imaging;

[0195] Fig.14 177 Lu-TM1 (abbreviated as 177Lu-057) radio purity;

[0196] Fig.15 177 Lu-TM7 (abbreviated as 177Lu-071) radio purity;

[0197] Fig.16 177 SPECT / CT imaging of mice (H1975) bearing Lu-TM1 (abbreviated as 177Lu-057) tumors (1 mCi, MIP image);

[0198] Fig.17 177 SPECT / CT imaging of mice (H1975) bearing Lu-TM7 (abbreviated as 177Lu-071) tumors (1 mCi, MIP image);

[0199] Fig.18 177 Lu-TM1 (abbreviated as 177Lu-057) tumor uptake data within 96 h (H1975);

[0200] Fig.19 177 Lu-TM7 (abbreviated as 177Lu-071) tumor uptake data within 96 hours (H1975). DETAILED DESCRIPTION

[0201] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only some embodiments of the present invention, not all. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0202] The raw materials used in the following examples of the present invention are all commercially available commodities. The metals used in the examples of the present invention are radioactive or non-radioactive metals.

[0203] Example 1

[0204] Preparation of polypeptide compound TM1, the compound structure is as follows:

[0205]

[0206] Step 1: Synthesis of Fmoc-Asn(Trt)-CTC Resin (M1)

[0207] Weigh 0.9 g (sub = 1.12 mmol / g) of CTC resin and add it to a peptide synthesis tube, add DCM (10 mL), and swell for 15 min; weigh Fmoc-Asn(Trt)-OH (0.72 g, 2 mmol, 1.2 eq), dissolve it in DCM (10 mL) solution, add DIEA (0.42 mL, 2.4 mmol), react for 1 h, and wash the resin 3 times with DCM (10 mL); add blocking solution (10 mL, volume ratio DCM: MeOH: DIEA = 75:20:5), block for 15 min, wash the resin 3 times with DMF (15 mL) to obtain intermediate M1, which is directly used in the next reaction.

[0208] Step 2: Synthesis of Fmoc-Asn(Trt)-Asp(tBu)-Aib-Ile-Asn(Trt)-CTC Resin (M2)

[0209] Deprotection of Fmoc: add 10 mL of piperidine / DMF (volume ratio 1 / 4) solution, deprotect for 5 min, drain and add 10 mL of piperidine / DMF (volume ratio 1 / 4) solution again, deprotect for 10 min, drain and wash the resin 3 times with DMF (15 mL), take a small amount of resin and detect with 5% ninhydrin ethanol solution (take a small amount of resin and add 1 mL of 5% ninhydrin solution and heat at 110°C for 3 min). The resin appears dark blue and is directly used in the next reaction.

[0210] Coupling: Dissolve Fmoc-Ile-OH (1g, 3mmol, 3eq) in DMF (15mL), add TBTU (0.96g, 3mmol, 3eq) and DIEA (1mL, 6mmol, 6eq) to the reaction solution and stir for 10min under ice bath. Then add the activation solution to the resin after Fmoc removal, react for 1h, take a small amount of resin and detect with 5% ninhydrin ethanol solution (take a small amount of resin and add 1ml of 5% ninhydrin solution and heat at 110℃ for 3min). The resin is colorless. Drain the reaction solution and wash it with DMF (10mL) 3 times. The obtained resin is directly used for the next reaction.

[0211] Coupling cycle, Fmoc-Aib-OH (0.97 g, 3 eq), Fmoc-Asp(OtBu)-OH (1.23 g, 3 eq), Fmoc-Asn(Trt)-OH (1.79 g, 3 eq) were coupled in sequence according to the above operation. The mixture was washed alternately 3 times with 10 mL of DCM and MeOH, dried, transferred to a vacuum oven, and dried at 35°C for 2 h to obtain intermediate M2 (1.36 g), which was directly used in the next reaction.

[0212] Step 3: Synthesis of Alloc-Lys(Octadecanedioic acid 1-tert-butyl ester-Glu(α-tBu)-PEG2-PEG2)-PEG4-Asn(Trt)-Asp(tBu)-Aib-Ile-Asn(Trt)-CTC Resin(M3)

[0213] Take the intermediate M2 (0.88 g, 0.5 mmol) and perform Fmoc removal and coupling operations in a peptide synthesis tube to obtain M3, which is directly used in the next step. (The coupling monomer sequence is as follows:

[0214] Fmoc-PEG4-OH (0.48g, 1mmol, 2eq, CAS:557756-85-1)

[0215] Alloc-Lys(Fmoc)-OH (0.45g, 1mmol, 2eq, CAS:186350-56-1)

[0216] Fmoc-PEG2-OH (0.39g, 1mmol, 2eq, CAS:166108-71-0)

[0217] Fmoc-PEG2-OH (0.39g, 1mmol, 2eq, CAS:166108-71-0)

[0218] Fmoc-Glu(α-tBu)-OH (0.43g, 1mmol, 2eq, CAS:84793-07-7)

[0219] Octadecanedioic acid 1-tert-butyl ester (0.25g, 1mmol, 2eq, CAS:843666-40-0)

[0220] Step 4: Synthesis of H-Lys(Octadecanedioic acid 1-tert-butyl ester-Glu(α-tBu)-PEG2-PEG2)-PEG4-Asn(Trt)-Asp(tBu)-Aib-Ile-Asn(Trt)-CTC Resin(M4)

[0221] De-Alloc protection: Add DCM (10 mL), PhSiH3 (0.65 g, 6 mmol, 12 eq), Pd(PPh3)4 (29 mg, 0.025 mmol, 5% mol) to the intermediate M3 in sequence. React for 2 h under nitrogen blowing. Take a small amount of resin and detect it with 5% ninhydrin ethanol solution (take a small amount of resin and add 1 mL of 5% ninhydrin solution and heat at 110 ° C for 3 min). The resin shows dark blue. Drain and wash the resin with DMF (15 mL) 3 times to obtain intermediate M4, which is directly used in the next step reaction.

[0222] Step 5: Synthesis of DOTA(tBu)3-Lys(Octadecanedioic acid 1-tert-butyl ester-Glu(α-tBu)-PEG2-PEG2)-PEG4-Asn(Trt)-Asp(tBu)-Aib-Ile-Asn(Trt)-CTC Resin(M5)

[0223] Coupling: DOTA(tBu)3 (0.43 g, 0.75 mmol, 1.5 eq) was dissolved in DMF (10 mL). TBTU (0.24 g, 0.75 mmol, 1.5 eq) and DIEA (0.26 mL, 0.5 mmol, 3 eq) were added to the reaction solution and stirred for 10 min under an ice bath. The activation solution was then added to the intermediate M4 after Alloc protection was removed and the reaction was continued for 16 h. A small amount of resin was tested with 5% ninhydrin ethanol solution (a small amount of resin was added to 1 ml of 5% ninhydrin solution and heated at 110 ° C for 3 min). The resin was colorless. The reaction solution was drained and washed with DMF (10 mL) 3 times. Then, the mixture was washed alternately with DCM and MeOH 10 mL each for 3 times, drained, transferred to a vacuum oven, and dried at 35 ° C for 2 h to obtain resin M5 (1 g).

[0224] Step 6: Synthesize TM1

[0225] Add cleavage solution (10 mL, TFA: Tis: H2O volume ratio is 95: 2.5: 2.5) to 1 g of resin, react for 1 h, filter, and wash the resin with cleavage solution (1 mL), add -5°C methyl tert-butyl ether (100 mL) dropwise to the combined filtrate, settle for 1 h (freezer), centrifuge, remove the supernatant; add MTBE (50 mL), wash, centrifuge, remove the supernatant, repeat this operation 3 times to obtain a white solid. Transfer the solid to a vacuum drying oven and dry at 35°C for 2 h to obtain 179 mg of crude peptide, which was purified by HPLC preparation to obtain a purified solution, concentrate the purified solution to remove most of the organic solvent, and freeze-dry it to obtain 128 mg of 99.80% pure product TM1, with a yield of 12.8%.

[0226] MS (ESI): m / z [M+2H + ] / 2=1019.6.

[0227] 1H NMR(600MHz,D2O)δ4.70-4.64(m,1H),4.42-4.18(m,22H),4.40-4.07(m,6H) ,3.82-3.62(m,31H),3.49-3.25(m,20H),2.98-2.80(m,5H),2.63-2.62(m,2 H),2.38-2.32(m,5H),2.17-1.74(m,4H),1.61-1.56(m,4H),1.49(s,3H),1. 46(s,3H),1.40-1.15(m,24H),0.94(d,J=6.6Hz,3H),0.88(t,J=7.2Hz,3H).

[0228] Example 2

[0229] Preparation of polypeptide compound TM2, the compound structure is as follows:

[0230]

[0231] Step 1: Synthesis of Fmoc-Asn(Trt)-CTC Resin (M1)

[0232] Weigh 0.9 g (sub = 1.12 mmol / g) of CTC resin and add it to a peptide synthesis tube, add DCM (10 mL), and swell for 15 min; weigh Fmoc-Asn(Trt)-OH (0.72 g, 2 mmol, 1.2 eq), dissolve it in DCM (10 mL) solution, add DIEA (0.42 mL, 2.4 mmol), react for 1 h, and wash the resin 3 times with DCM (10 mL); add blocking solution (10 mL, volume ratio DCM: MeOH: DIEA = 75:20:5), block for 15 min, wash the resin 3 times with DMF (15 mL) to obtain intermediate M1, which is directly used in the next reaction.

[0233] Step 2: Synthesis of Fmoc-Asn(Trt)-Asp(tBu)-Aib-Ile-Asn(Trt)-CTC Resin (M2)

[0234] Deprotection of Fmoc: add 10 mL of piperidine / DMF (volume ratio 1 / 4) solution, deprotect for 5 min, drain and add 10 mL of piperidine / DMF (volume ratio 1 / 4) solution again, deprotect for 10 min, drain and wash the resin 3 times with DMF (15 mL), take a small amount of resin and detect with 5% ninhydrin ethanol solution (take a small amount of resin and add 1 mL of 5% ninhydrin solution and heat at 110°C for 3 min). The resin appears dark blue and is directly used in the next reaction.

[0235] Coupling: Dissolve Fmoc-Ile-OH (1g, 3mmol, 3eq) in DMF (15mL), add TBTU (0.96g, 3mmol, 3eq) and DIEA (1mL, 6mmol, 6eq) to the reaction solution and stir for 10min under ice bath. Then add the activation solution to the resin after Fmoc removal, react for 1h, take a small amount of resin and detect with 5% ninhydrin ethanol solution (take a small amount of resin and add 1ml of 5% ninhydrin solution and heat at 110℃ for 3min). The resin is colorless. Drain the reaction solution and wash it with DMF (10mL) 3 times. The obtained resin is directly used for the next reaction.

[0236] Coupling cycle, Fmoc-Aib-OH (0.97 g, 3 eq), Fmoc-Asp(OtBu)-OH (1.23 g, 3 eq), Fmoc-Asn(Trt)-OH (1.79 g, 3 eq) were coupled in sequence according to the above operation. The mixture was washed alternately 3 times with 10 mL of DCM and MeOH, dried, transferred to a vacuum oven, and dried at 35°C for 2 h to obtain intermediate M2 (1.36 g), which was directly used in the next reaction.

[0237] Step 3: Synthesis of Alloc-Lys(Palmitic-tert-butyl ester-Glu(α-tBu)-PEG2-PEG2)-PEG4-Asn(Trt)-Asp(tBu)-Aib-Ile-Asn(Trt)-CTC Resin(M3)

[0238] Take the intermediate M2 (0.7 g, 0.5 mmol, batch number YH00047-001) and perform Fmoc removal and coupling operations in a peptide synthesis tube to obtain M3, which is directly used in the next step. (The coupling monomer sequence is as follows:

[0239] Fmoc-PEG4-OH (0.48g, 1mmol, 2eq, CAS:557756-85-1)

[0240] Alloc-Lys(Fmoc)-OH (0.45g, 1mmol, 2eq, CAS:186350-56-1)

[0241] Fmoc-PEG2-OH (0.39g, 1mmol, 2eq, CAS:166108-71-0)

[0242] Fmoc-PEG2-OH (0.39g, 1mmol, 2eq, CAS:166108-71-0)

[0243] Fmoc-Glu(α-tBu)-OH (0.43g, 1mmol, 2eq, CAS:84793-07-7)

[0244] Palmitic acid (0.25g, 1mmol, 2eq, CAS:57-10-3)

[0245] Step 4: Synthesis of H-Lys(Palmitic-tert-butyl ester-Glu(α-tBu)-PEG2-PEG2)-PEG4-Asn(Trt)-Asp(tBu)-Aib-Ile-Asn(Trt)-CTC Resin(M4)

[0246] De-Alloc protection: Add DCM (10 mL), PhSiH3 (0.65 g, 6 mmol, 12 eq), Pd(PPh3)4 (29 mg, 0.025 mmol, 5% mol) to the intermediate M3 in sequence. React for 2 h under nitrogen blowing. Take a small amount of resin and detect it with 5% ninhydrin ethanol solution (take a small amount of resin and add 1 mL of 5% ninhydrin solution and heat at 110 ° C for 3 min). The resin shows dark blue. Drain and wash the resin with DMF (15 mL) 3 times to obtain intermediate M4, which is directly used in the next step reaction.

[0247] Step 5: Synthesis of DOTA(tBu)3-Lys(Palmitic-tert-butyl ester-Glu(α-tBu)-PEG2-PEG2)-PEG4-Asn(Trt)-Asp(tBu)-Aib-Ile-Asn(Trt)-CTC Resin(M5)

[0248] Coupling: DOTA(tBu)3 (0.43 g, 0.75 mmol, 1.5 eq) was dissolved in DMF (10 mL). TBTU (0.24 g, 0.75 mmol, 1.5 eq) and DIEA (0.26 mL, 0.5 mmol, 3 eq) were added to the reaction solution and stirred for 10 min under an ice bath. The activation solution was then added to the intermediate M4 after Alloc protection was removed and the reaction was continued for 16 h. A small amount of resin was tested with 5% ninhydrin ethanol solution (a small amount of resin was added to 1 ml of 5% ninhydrin solution and heated at 110 ° C for 3 min). The resin was colorless. The reaction solution was drained and washed with DMF (10 mL) 3 times. Then, the mixture was washed alternately with DCM and MeOH 10 mL each for 3 times, drained, transferred to a vacuum oven, and dried at 35 ° C for 2 h to obtain resin M5 (1.2 g).

[0249] Step 6: Synthesize TM2

[0250] Add cleavage solution (12 mL, TFA: Tis: H2O volume ratio is 95: 2.5: 2.5) to 1 g of resin, react for 1 h, filter, and wash the resin with cleavage solution (1 mL), add -5°C methyl tert-butyl ether (120 mL) dropwise to the combined filtrate, settle for 1 h (freeze in refrigerator), centrifuge, remove the supernatant; add MTBE (50 mL), wash, centrifuge, remove the supernatant, repeat this operation 3 times to obtain a white solid. Transfer the solid to a vacuum drying oven and dry at 35°C for 2 h to obtain 540 mg of crude peptide, which is purified by HPLC preparation to obtain a purified solution, concentrate the purified solution to remove most of the organic solvent, and freeze-dry it to obtain 233+32 mg of 98.01% pure product TM2, with a yield of 26.8%.

[0251] MS (ESI): m / z [M+2H + ] / 2=990.6.

[0252] 1H NMR(600MHz,D2O)δ4.69-4.55(m,11H),4.31-3.54(m,40H),3.40-2.69(m,27H),2.56-2.50(m,2H),2.29-1.64(m,7 H),1.52-1.47(m,3H),1.39(s,3H),1.37(s,3H),1.32-1.29(m,2H),1.19-1.05(m,25H),0.84(d,J=6.3Hz,3H),0.82 -0.75(m,6H).

[0253] Example 3

[0254] Preparation of polypeptide compound TM3, the compound structure is as follows:

[0255]

[0256] The preparation steps were the same as those in Example 1, and the mass of the obtained product was 232 mg with a purity of 92.25%.

[0257] Example 4

[0258] Preparation of polypeptide compound TM4, the compound structure is as follows:

[0259]

[0260] The preparation steps were the same as those in Example 1, and the mass of the obtained product was 84.4 mg with a purity of 98.35%.

[0261] Example 5

[0262] Preparation of polypeptide compound TM5, the compound structure is as follows:

[0263]

[0264] The preparation steps were the same as those in Example 1, and the mass of the obtained product was 63.4 mg with a purity of 95.29%.

[0265] Example 6

[0266] Preparation of polypeptide compound TM6, the compound structure is as follows:

[0267]

[0268] The preparation steps were the same as those in Example 1, and the mass of the obtained product was 18.5 mg with a purity of 97.10%.

[0269] Example 7

[0270] Preparation of polypeptide compound TM7, the compound structure is as follows:

[0271]

[0272] The preparation steps were the same as those in Example 1, and the mass of the obtained product was 66.6 mg with a purity of 99.77%.

[0273] Example 8

[0274] Preparation of polypeptide complex Gd-TM1, the compound structure is as follows:

[0275]

[0276] 30.7 mg (0.015 mmol) of TM1 was dissolved in 2 mL of H2O. 0.25 mL of 0.5 M NaOH aqueous solution (8 eq) was added, the pH of the reaction solution was controlled between 6 and 8, and stirred at room temperature for 2.5 h. GdCl3·6H2O (6.2 mg, 1.1 eq) was added, and the pH was lowered to 5.5 with 5 w / v% HCl. The solution was stirred overnight, and the pH was raised to 12 with 0.1 M NaOH to precipitate excess Gd(III). The reaction mixture was centrifuged, and the supernatant was lyophilized to a white powder, which was purified by preparative HPLC and lyophilized to obtain 8.5 mg of the target product Gd-TM1 with a purity of 99.02%. The mass spectrometry results were: MS (ESI): m / z (M+2H + ) / 2=1096.2, (M+3H + ) / 3=730.6.

[0277] Example 9

[0278] Preparation of polypeptide complex Ga-TM2, the compound structure is as follows:

[0279]

[0280] The preparation method comprises the following steps:

[0281] Weigh TM2 (80.01 mg) and add 7 ml purified water to dissolve, heat to 70 ° C, dropwise add 1 ml aqueous solution containing 11.22 mg of gallium nitrate, stir to react, adjust the pH value to 3-5 with 1 mM sodium acetate, react for 2 hours, and after the reaction is completed, remove salt by reverse purification system to obtain the desired target compound Ga-TM2 (17.12 mg) with a purity of 95.36%. The mass spectrometry detection results are: MS (ESI): m / z (M+2H + ) / 2=1023.0, (M+3H + ) / 3=682.3.

[0282] Example 10

[0283] Preparation of polypeptide complex Ga-TM3, the compound structure is as follows:

[0284]

[0285] The preparation steps were the same as those in Example 9, and the product mass was 25 mg with a purity of 98.62%.

[0286] The mass spectrometry results are: MS (ESI): (M+2H + ) / 2=1027.8, (M+3H + ) / 3=685.7.

[0287] Embodiment 11

[0288] Preparation of polypeptide complex Gd-TM7, the compound structure is as follows:

[0289]

[0290] The preparation steps were the same as those in Example 8, and the product mass was 4.5 mg with a purity of 98.58%.

[0291] The mass spectrometry results are: MS (ESI): (M+2H + ) / 2=912.5, (M+3H + ) / 3=615.2.

[0292] Test Example 1 Target Affinity Test

[0293] The affinity of the example compounds to the target protein integrins α5β1, αvβ3, αvβ5, and αvβ6 was tested using the surface plasmon resonance (SPR) technique. Specifically, the following steps were performed:

[0294] The recombinant Integrin α5β1, αvβ3, αvβ5, and αvβ6 proteins were fixed on a CM5 chip (Biacore), and an SPR instrument (Biacore T200) was used to test the binding constants (Ka) and dissociation constants (Kd) of the compounds with Integrin α5β1, αvβ3, αvβ5, and αvβ6 under the conditions of an injection volume of 30 μL of the test solution, a flow rate of 30 μL / min, and 25°C. The affinity constant KD between the compound and the target protein Integrin α5β1, αvβ3, αvβ5, and αvβ6 was calculated according to the formula KD=Kd / Ka (the lower the KD value, the higher the affinity of the example compound with the target protein). The above compounds TM1, TM2, TM3, TM4, TM5, TM6, TM7, Gd-TM1, Ga-TM1, Ga-TM2, Gd-TM7, Ga-TM7 and other metal chelates have nanomolar KD for integrin α5β1, αvβ3, αvβ5 or αvβ6.

[0295] The in vitro affinity data are shown in Table 1:

[0296] Table 1 KD values ​​of compounds for integrin α5β1, αvβ3, αvβ5 or αvβ6

[0297] Compound No. / Target α5β1(nM) αvβ3(nM) αvβ5(nM) αvβ6(nM) TM1 27.5 127 556 356 TM2 124 221 1243 780 TM3 122 453 -- -- TM4 232 550 -- -- TM5 98 778 -- -- TM6 76 879 -- -- TM7 38.5 98.7 125 467 Gd-TM1 79 340 -- 670 Ga-TM1 56 98 234 550 Ga-TM2 468 -- -- 688 Gd-TM7 24 236 677 2340 Ga-TM7 37 337 1350 3550

[0298] Experimental Example 2 Radioactive compound labeling experiment

[0299] Radioactivity of compound TM1 68 Ga labeling

[0300] Add TM1 (20ug) aqueous solution into the prepared 68 The GaCl3 solution is adjusted to pH 3-5 with sodium acetate aqueous solution and acetic acid, and reacted at 70-95°C for 15 minutes. After the reaction is completed, it is purified to obtain the labeled 68 Solution of Ga-TM1.

[0301] All compounds prepared by the present invention 68 The Ga labeling method is the same as the above method.

[0302] PET / CT experiments

[0303] 1) Evaluation of lung adenocarcinoma model

[0304] M-NSG mice inoculated with H1975 were injected intravenously with approximately 100 μCi of 68 Ga-TM1 and 68 Ga-TM7 injection. PET / CT imaging was performed 1h, 2h, and 4h after injection, and the experimental data in Table 2 were obtained through image post-processing.

[0305] Table 2 PET / CT experimental results

[0306] %ID / g Heart liver lung kidney brain bone muscle intestinal Tumor <![CDATA[ 68 Ga-TM1(1h)]]> 29.50 22.40 11.30 11.80 9.10 5.20 5.40 8.80 9.00 <h2 style=";text-align:left;direction:ltr"><![CDATA[ <h2 style=";text-align:left;direction:ltr"> 68 <h2 style=";text-align:left;direction:ltr"> Ga-TM1(2h)<h2 style=";text-align:left;direction:ltr"> 27.20 20.50 8.60 11.00 8.50 3.90 4.70 10.10 11.80 <![CDATA[ 68 Ga-TM7(1h)]]> 6.80 5.30 3.00 3.50 2.20 1.50 1.30 1.90 3.10 <h2 style=";text-align:left;direction:ltr"><![CDATA[ <h2 style=";text-align:left;direction:ltr"> 68 <h2 style=";text-align:left;direction:ltr"> Ga-TM7(2h)]]><h2 style=";text-align:left;direction:ltr"> 8.80 7.20 3.50 5.70 3.40 1.80 2.20 2.90 4.30 <![CDATA[ 68 Ga-TM7(4h)]]> 8.40 6.80 3.40 4.90 2.60 1.40 2.10 3.90 5.20

[0307] The above animal experiment results show that 68 Ga-TM1 and 68 Ga-TM7 was significantly enriched in the tumor of M-NSG mice inoculated with H1975, and the uptake value (%ID / g) in the tumor site gradually increased with time. The drug was gradually eliminated in the values ​​of various tissues with time. From the slow accumulation of the tumor, its ligands TM1 and TM7 were used 68 Chelated Ga has the potential to diagnose and / or treat lung adenocarcinoma.

[0308] PCT / CT imaging images such as Figure 8-9 shown.

[0309] 2) Evaluation of pancreatic cancer model

[0310] About 100 μCi of BxPC-3 and PANC-1 nude mice were injected into the tail vein. 68 Ga-TM7 injection. PET / CT imaging was performed 1h and 4h after injection, and the experimental data in Table 3 were obtained through image post-processing.

[0311] Table 3 PET / CT experimental results

[0312]

[0313]

[0314] The above animal experiment results show that 68 Ga-TM7 was significantly enriched in the tumors of nude mice inoculated with BxPC-3 and PANC-1, and the uptake value (%ID / g) in the tumor site gradually increased with time. The drug was gradually eliminated in the values ​​of various tissues with time. Judging from the slow accumulation of the tumor, its ligand TM7 was used 68 Chelated Ga has the potential to diagnose and / or treat pancreatic cancer.

[0315] PCT / CT imaging images such as Figure 10-11 shown.

[0316] 3) Comparison of MRI data

[0317] Gd-dota, Gd-TM1 (indicated as 7013-001 in the figure) and Gd-TM7 (indicated as 7013-002 in the figure) were dissolved in normal saline to a concentration of 0.1mmol / ml, and filtered into a sterile EP tube using a 0.22um sterile filter. BALB / c nude mice with the breast cancer MD-MB-231 model were anesthetized by intraperitoneal injection of chloral hydrate (100uL). Cross-sectional MR imaging of mice was collected in all experimental groups before drug injection, and the acquisition time was recorded. The breast cancer model was injected with drugs through the tail vein at a dose of 0.1mmol / Kg, and the injection time was recorded. MR images (T1 signal, T2 signal) were collected 5min, 10min, 20min, 30min, 40min, 50min, 60min, 70min, 24h and 48h after the injection of the drug. After each MR image was collected, the mice were kept warm. Imaging data MR images are shown as follows Fig.12 As shown in the figure, the ratio of the gray value of the tumor to the muscle T1 signal in the MR image is as follows: Fig.13 shown.

[0318] Animal MR image data analysis, first, use Image J to circle the gray value of the entire tumor (T) excluding the tumor capsule in the T1 image and T2 image, and circle the gray value of the muscle (M), count three times and calculate the average value, and perform data statistical analysis on the T1 signal in the breast cancer tumor (as shown below) Fig.13As shown in the figure, the calculation formula is the ratio of tumor to muscle gray value = T / M. From the analysis of T1 signal ratio, Gd-TM1 is optimal between 10min and 30min, and Gd-TM1 and Gd-TM7 are better than Gd-Dota during 40min to 60min. After 24h, the tumor to muscle gray ratio of Gd-TM1 and Gd-TM7 is higher than that before injection. From the ratio and images, it can be found that Gd-TM1 and Gd-TM7 are specifically taken up in tumors.

[0319] 4) 177Lu treatment evaluation

[0320] 1. Labeling method

[0321] 1.1 Precursor aliquoting: Add the precursor to pure water to dissolve it into a concentration of 1 mg / mL, aliquot 50 μL into each tube and store it in a -20°C freezer.

[0322] 1.2 Sodium acetate preparation: Weigh 2.04642 g of sodium acetate and dissolve it in 50 mL of pure water. Use 37% concentrated hydrochloric acid to adjust the pH to 5.5.

[0323] 1.3 Labeling: Add 200 μL sodium acetate buffer (pH=5.5) to a cryovial containing 50 μg of labeled precursor, shake to completely dissolve it, and add 3 mCi of 177 LuCl3. The mixture was shaken and heated at 95°C for 30 min, and then cooled to room temperature.

[0324] 1.4 Nuclide purification and quality testing

[0325] Analysis and Identification

[0326] 1.4.1 Instrument: Waters 1525 / 2489, Raytest radioactivity detector

[0327] 1.4.2 Flow rate: 1 mL / min

[0328] 1.4.3 Column temperature: room temperature

[0329] 1.4.4 Elution procedure

[0330] Table 4

[0331] Time (min) <![CDATA[A%(H2O+0.1%TFA)]]> B%(ACN) 0 95 5 25 5 95 30 95 5

[0332] 1.4.5 The test results are as follows

[0333] 177 Lu-TM1 (abbreviated as 177Lu-057) radioactive purity 100% (such as Fig.14 Its structural formula is as follows:

[0334]

[0335] 177 Lu-TM7 (abbreviated as 177Lu-071) radioactive purity 100% (such as Fig.15 Its structural formula is as follows:

[0336]

[0337] 2. 177 SPECT / CT Study on Lu-057 / 071 Tumor Mice

[0338] 2.1 Tumor mouse model: M-NSG mice inoculated with H1975

[0339] 2.2 Mouse condition: good

[0340] 2.3 Test substance preparation: When administering to animals, dilute the test substance to 5 mCi / mL using sodium chloride injection.

[0341] 2.4 Experimental Grouping:

[0342] Table 5

[0343] Group Test substance Number of animals Route of administration Dose MBq / head <![CDATA[ 177 Lu-057]]> <![CDATA[ 177 Lu-057]]> 2 Ⅳ 37 <![CDATA[ 177 Lu-071]]> <![CDATA[ 177 Lu-071]]> 2 Ⅳ 37

[0344] Dispense the medicine according to the animal's dosage on the medicine dispensing table, and use a 1ml syringe to draw a certain volume of 177 The Lu-057 / 071 dilution was injected into the tail vein of tumor-bearing mice, and the injection time, dose and measurement time were recorded. 177 SPECT / CT scans were performed 1h, 4h, 24h, 48h, 72h, and 96h after Lu-057 / 071, with one frame of image collected every 20s at 1-4h, one frame of image collected every 35s at 24-48h, and one frame of image collected every 50s at 72-96h. During the scanning process, the animals continued to inhale isoflurane to maintain the anesthesia effect.

[0345] 3. SPECT / CT imaging

[0346] Fig.16 Two M-NSG mice inoculated with H1975 were injected with 37 MBq of 177 In the images of Lu-057 taken within 96 hours, it can be clearly observed that the tumor has specific uptake, and other tissues with uptake are gradually cleared through the kidneys over time.

[0347] Fig.17 Two M-NSG mice inoculated with H1975 were injected with 37 MBq of 177Lu-071 imaging within 96 hours clearly showed specific uptake in the tumor, and other uptake tissues were gradually cleared through the kidneys over time. Since the M1 mice died after 48 hours of imaging, no corresponding data were obtained at the subsequent 72 hours and 96 hours.

[0348] 4. Quantitative SPECT / CT imaging

[0349] Each mouse for SPECT / CT imaging was left with 1% of the injection dose at the time of administration, and the 1% injection dose of each mouse was used together with the mouse for SPECT / CT imaging circle value quantification, and the total uptake of each tissue was obtained by the above semi-quantitative method. The corresponding uptake is shown in Table 6-7 below. The total %ID of each tissue was the highest 4 hours after administration, and the heart, liver, muscle, lung, brain and intestine were quickly cleared 4 hours later, while the tumor clearance rate was much lower than that of normal tissues, that is, tumor-specific uptake.

[0350] The uptake value of the tumor portion was calculated by measuring the tumor volume. Figure 18-19 shown. Fig.18 , 19 In each group of bar charts, the left side is M1 and the right side is M2.

[0351] Table 6

[0352]

[0353] Table 7

[0354]

[0355]

[0356] 5. Efficacy evaluation

[0357] 177 Lu-057 and 177 Pharmacodynamics study of Lu-071 tumor-bearing mice

[0358] 5.1 Tumor mouse model: M-NSG mice inoculated with H1975

[0359] 5.2 Mouse condition: good

[0360] 5.3 Test substance preparation: When administering to animals, dilute the test substance to 5 mCi / mL using sodium chloride injection (1 mCi / ml per mouse).

[0361] 5.4 Experimental Grouping:

[0362] Table 8

[0363] Group Test substance Number of animals Route of administration Dose MBq / head Control Group Sodium Chloride Injection 5 Ⅳ / <![CDATA[ 177 Lu-057]]> <![CDATA[ 177 Lu-057]]> 5 Ⅳ 37 <![CDATA[ 177 Lu-071]]> <![CDATA[ 177 Lu-071]]> 5 Ⅳ 37

[0364] 5.5 Tumor Data Monitoring

[0365] The tumor volume monitoring of the drug-treated group and the saline group showed that the drug-treated group significantly inhibited tumor growth. The relevant detailed data are shown in Table 9 below.

[0366] Table 9

[0367] 177Lu-057 administration group 48h 96h 177Lu-071 administration group 48h 96h Normal saline group 48h 96h VM1(737) / mm3 160.71 265.64 VM1(808) / mm3 140 165.17 VM1(743) / mm3 262.82 306.36 VM1(804) / mm3 147.58 159.64 VM1(731) / mm3 192.05 179.71 VM1(729) / mm3 151.68 249.75 VM1(810) / mm3 190.8 176.39 VM1(800) / mm3 211.44 221.76 VM1(801) / mm3 176.91 209.65 VM1(738) / mm3 149.73 178.2 VM1(735) / mm3 122.48 143.26 VM1(803) / mm3 216.15 264.96 VM1(740) / mm3 157.02 199.53 VM1(736) / mm3 157.07 132.76 VM1(1363) / mm3 188.19 333.56 Average value / mm3 161.168 195.88 Average value / mm3 164.60 168.53 Average value / mm3 199.15 272.85

[0368] Representative data of TM1 and TM7 The above data fully prove that its chelated 68Ga, Gd and 177Lu can be used for the diagnosis and treatment of lung adenocarcinoma and pancreatic cancer models.

[0369] The 68Ga-TM1 and 68Ga-TM7 compounds listed in the present invention were subjected to PET / CT imaging in lung adenocarcinoma and pancreatic cancer models, and the data showed that there was specific uptake at the tumor site, and the uptake value was constantly increasing at 4h. Gd-TM1 and Gd-TM7 compounds were subjected to MR imaging on breast cancer model mice, and the imaging data showed that the compounds were specifically enriched at the tumor site and the data were better than Gd-DOTA, and the 48h tumor was significantly uptaken and enriched. The above data show that the compounds prepared by the present invention have tumor targeting specificity and can be used in long half-life radionuclide diagnosis and treatment, such as targeted compounds of radioactivity or their isotopes such as 177Lu, 64Cu, 68Ga, 111In, Al18F, 211At, 225Ac, 90Y, 213Bi, etc.

[0370] The results of PET / CT and MR imaging animal experiments indicate that the polypeptide compounds and polypeptide complexes prepared by the present invention can directly target tumor cells and can be used as targeting carriers to accurately deliver cytotoxins, nuclides, etc. to tumor cells.

[0371] The results of in vitro enzymology data experiments show that the polypeptide compounds and polypeptide complexes prepared by the present invention can be used for the diagnosis and / or treatment of various tumors such as lung adenocarcinoma, breast cancer, pancreatic cancer, melanoma, malignant primary neuroendocrine prostate cancer and its lung metastatic lesions, breast cancer, ovarian cancer, gastrointestinal tumors, etc.

[0372] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements 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 polypeptide compound, and pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotope labels, metabolites and prodrugs thereof, wherein the compound is obtained by coupling ZT and PD, or by coupling ZT, Linker and PD, and the compound has the following structural formula: ZT-PD, or ZT-Linker-PD in, The connection between ZT and PD, and between ZT, Linker and PD forms an amide bond, a sulfonamide bond, a sulfenamide bond, an ester bond, a carbonate bond or a urea; The structural formula of ZT in the above formula is as follows: Wherein, n is selected from an integer of 1 to 8; R a1 , R a2 , R a3 is a substituted or unsubstituted alkylene phosphite group, a substituted or unsubstituted alkylene phosphite group, a substituted or unsubstituted C1-C6 alkylene group, a substituted or unsubstituted C5-C20 arylene group, a substituted or unsubstituted C1-C20 heteroarylene group, a substituted or unsubstituted C1-C6 alkyleneoxy group, a substituted or unsubstituted C5-C20 aryleneoxy group, a substituted or unsubstituted C1-C6 alkylenesulfonyl group, a substituted or unsubstituted C1-C6 alkylenesulfonic acid group, a substituted or unsubstituted C1-C6 alkylenesulfonate group, or a substituted or unsubstituted C1-C6 alkylenephosphate group; R b1 , R b2 , R b3 is hydrogen, hydroxyl, carboxyl, halogen, thiol, seleno, amide, amino, cyano, nitro, substituted or unsubstituted phosphino, substituted or unsubstituted phosphite, substituted or unsubstituted C1-C6 hydrocarbon, substituted or unsubstituted C5-C20 aryl, substituted or unsubstituted C1-C20 heteroaryl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C5-C20 aryloxy, substituted or unsubstituted C1-C6 sulfonyl, substituted or unsubstituted C1-C6 sulfonic acid, substituted or unsubstituted C1-C6 sulfonate, substituted or unsubstituted C1-C6 phosphate; R b1 , R b3 At least one of them is a carboxyl group, an amino group or a hydroxyl group; The structure of Linker in the above formula is as follows: Wherein, d is selected from an integer of 0 to 17; R L1 , R L3 -(CH2) d1 COOH, amino, thiol, carboxyl or hydroxyl, d1 is an integer selected from 0 to 13; R L2 -Arg-Gly-Asp-, -Arg-Gly-, -Arg-, imino, imido, substituted or unsubstituted C1-C20 alkylene, substituted or unsubstituted C1-C20 alkylene ether, substituted or unsubstituted C5-C20 arylene ether; In the above formula, PD is a compound and / or its derivative obtained by condensing one or more compounds of Formulae 1 to 6; In Formulae 1 to 6, m, e, and n1 are independently selected from integers of 0 to 5; R is selected from hydrogen, -OH, -NH2, substituted or unsubstituted C1-C6 hydrocarbon group, substituted or unsubstituted C5-C20 aryl group, substituted or unsubstituted C1-C20 heteroaryl group; R1, R2, R3, R4, R5, R6 are independently selected from substituted or unsubstituted C1-C6 alkylene, substituted or unsubstituted C5-C20 arylene, substituted or unsubstituted C1-C20 heteroarylene; the substituent group is selected from halogen, haloalkyl, lower alkyl, alkoxy, -O-(CH2) q -OR", alkylthio (or seleno), halogenated alkylthio (or seleno), thiol (or seleno), alkylthio (or seleno) ether, arylthio (or seleno) ether, hydroxyl, cyano, nitro, carboxyl derivative group, aryloxy, amide, acylamine, amino, hydroxylamine, alkylamine, dialkylamine, trifluoroalkoxy, trifluoromethyl, ester, sulfonyl, alkylsulfonyl, halogenated alkylsulfonyl, sulfonic acid, sulfonamide, phosphate, phosphate ester, unsubstituted aryl, aryl heterocyclic group, monocyclic heterocyclic group, N, O, SH, SeH, hydrogen, carboxyl, methylthio (or seleno) ether, ethylthio (or seleno) ether, -SOMe, -SO2Me, -CONH2, -COOMe, -COOEt, -NHOCH, -NHOCCH3, -NHSO2Me, p-toluenesulfonamide, sulfonate; q is 1 or 2; R" is a C1-C6 alkyl group; X, Y1, and Z are independently selected from hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C5-C20 aryloxy, -O-(CH2) q -OR", thiol, seleno, amide, amino, hydroxyl, cyano, nitro, carboxyl, substituted or unsubstituted C1-C6 ester, substituted or unsubstituted C1-C6 sulfonyl, substituted or unsubstituted C1-C6 sulfonic acid, substituted or unsubstituted C1-C6 sulfonate, sulfonamide, phosphate, substituted or unsubstituted C1-C6 phosphate, substituted or unsubstituted C5-C20 aryl, substituted or unsubstituted C5-C20 aryl and heterocyclic, substituted or unsubstituted C3-C6 heterocyclic; the substituted C1-C6 alkyl, substituted C1-C6 alkyl ether, substituted C5-C20 aryl ether, the substituent group is one or more of -SH, SeH, hydroxyl, amino, carboxyl, sulfonic acid, phosphate, halogen; the q is 1 or 2; the R" is a C1-C6 alkyl; Alternatively, R1, R2, and R6 are H. In this case, X, Y1, Z, does not exist; Alternatively, R3, R4, and R5 are H. In this case, R3 and R4 do not form a ring, and R5 and the C atom where it is located do not form a ring.

2. The polypeptide compound according to claim 1, and its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, nitrogen oxides, isotope labels, metabolites and prodrugs, characterized in that: R in the PD structure is an alkyl group with 1 to 5 carbon atoms; The alkylene group in R1, R2, R3, R4, R5 and R6 is selected from a hydrocarbon group having 1 to 20 carbon atoms, wherein the hydrocarbon group is an alkyl group, an alkynyl group, an alkenyl group or an aliphatic chain; The substituent in the substituted alkylene group in R1, R2, R3, R4, R5, and R6 is selected from N, O, SH, or SeH; The arylene group in R1, R2, R3, R4, R5 and R6 is selected from an aliphatic ring or an aromatic ring; The substituents in the substituted arylene or substituted heteroarylene in R1, R2, R3, R4, R5, and R6 are selected from -F, -Cl, -Br, -I, -OH, -NH2, -NHOH, -COOH, -COH, -SO3H, -SH, -SMe, -SEt, -OPO3H, -NO2, -NO, -SOMe, -SO2Me, -SOEt, -SO2Et, -CONH2, -COOMe, -COOEt, -NHOCH, -NHOCCH3, -NHSO2Me, -OSO2Ph, phosphate, sulfonate; X, Y1, and Z are independently selected from hydrogen, amino, carboxyl, thiol, -SMe, -SEt, phosphate, nitro, -F, -Cl, -Br, -I, -CHF2, -CF3, -NHOH, -SO3H, -SOMe, -SO2Me, -SOEt, -SO2Et, -CONH2, -COOMe, -COOEt, -NHOCH, -NHOCCH3, -NHSO2Me, -SeMe, -SeEt, p-toluenesulfonamide, phosphate, sulfonate, halogen, haloalkyl, lower alkyl , alkoxy, methylenedioxy, ethylenedioxy, alkylthio (or seleno), halogenated alkylthio (or seleno), mercapto (or seleno), alkylthio (or seleno) ether, arylthio (or seleno) ether, hydroxyl, cyano, carboxyl derivative group, aryloxy, amide, acylamine, hydroxylamine, alkylamine, dialkylamine, trifluoroalkoxy, trifluoromethyl, ester, sulfonyl, alkylsulfonyl, halogenated alkylsulfonyl, sulfonic acid, sulfonamide, phosphate, unsubstituted aryl, aryl heterocyclic group, monocyclic heterocyclic group, methylthio (or seleno), ethylthio (or seleno), -NHOH substituted group.

3. The polypeptide compound according to claim 2, and its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, nitrogen oxides, isotope labels, metabolites and prodrugs, characterized in that: n in the ZT structure is an integer selected from 1 to 4; R a1 , R a2 , R a3 is a substituted or unsubstituted alkylene phosphite group, a substituted or unsubstituted alkylene phosphite group, a substituted or unsubstituted C1-C6 alkylene group, or a substituted or unsubstituted C1-C6 alkyleneoxy group; R b1 , R b2 , R b3 is hydrogen, hydroxyl, carboxyl, halogen, amino, substituted or unsubstituted phosphino, substituted or unsubstituted phosphite, substituted or unsubstituted C1-C6 hydrocarbon, substituted or unsubstituted C1-C6 alkoxy; R b1 , R b3 At least one of them is a carboxyl group; R in Linker structure L1 is an amino group or a carboxyl group; R L2 is an imino group, a nitrilo group, an imide group, a substituted or unsubstituted C1-C20 alkylene group, a substituted or unsubstituted C1-C20 alkylene ether, or a substituted or unsubstituted C6-C20 arylene ether; The compounds of formula 1 to formula 6 in the PD structure are selected from one or more of Gln, Glu, Asn, Asp, homoaspartic acid, homoasparagine, homoglutamine, homoglutamic acid, Arg-Gly-Asp, Gly, Ala, Leu, Val, Leu, Phe, Ser, Thr, Phe, Tyr, Tyr(Me) and Tyr(Et); the amino acids in the compounds of formula 1 to formula 6 include one or both of L-configuration and D-configuration structures.

4. The polypeptide compound according to claim 3, and its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, nitrogen oxides, isotope labels, metabolites and prodrugs, characterized in that: R in ZT structure a1 , R a2 , R a3 is a C1-C3 alkylene group, a C1-C3 alkyleneoxy group, a C1-C3 alkylenephosphite group or a C1-C3 alkylenephosphite group; R b1 , R b2 , R b3 is hydrogen, hydroxyl, carboxyl, amino, C1-C3 alkylene phosphite, C1-C3 alkylene phosphite, C1-C3 hydrocarbon, C1-C3 alkoxy; R b1 , R b3 At least one of them is a carboxyl group; PD is formed by condensing five amino acids or amino acid-like bonds in Formulas 1 to 6, forming four amide bonds, sulfonamide bonds and / or sulfenamide bonds, and the left end of the amino acid or amino acid-like structure is the nitrogen end, and the right end is the carbon end.

5. The polypeptide compound according to claim 4, and its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, nitrogen oxides, isotope labels, metabolites and prodrugs, characterized in that: The structure of ZT is shown in formula ZT1~ZT4: In formulae ZT1 to ZT4, n is an integer of 1 to 4.

6. The polypeptide compound according to claim 4, and its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, nitrogen oxides, isotope labels, metabolites and prodrugs, characterized in that: The PD structure is selected from one of the compounds of formula II to formula VII: In Formula II, the selection ranges of m, e, n1, n2, n3, n4, m1, m2, m3, and m4 are consistent with the selection ranges of m, e, and n1 in Formulas 1 to 6 described in the above technical solution; R1 is selected from -H, -OH, -NH2, -NHNZ 1 Z 2 、-NHZ 1 、-NZ 1 Z 2 、-OZ 1 、-NHOZ 1 , -SH, -SeH, -SZ 1 、-SeZ 1 ,-Arg-Gly-Asp-Z 3 , connected with the carbonyl group to form lipid derivative groups, amine derivative groups, Z 1 , Z 2 independently selected from alkyl, Z 3 Selected from hydrogen, hydroxyl, amino, ester derivative group formed with the carbon end of Asp amino acid, amine derivative group, hydrocarbon group or substituted hydrocarbon group; R2 is selected from hydrogen, -OH, -NH2, a hydrocarbon group or a substituted hydrocarbon group, an acyl derivative group, a sulfonyl derivative group, X5-Arg-Gly-Asp-; R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 independently selected from hydrogen, hydrocarbon or substituted hydrocarbon, heteroatom substituted hydrocarbon, alkene or alkene derivative, alkynyl or alkynyl derivative, aryl and substituted aryl, heteroaryl or substituted heteroaryl; X, X1, X2, X3, X4, and X5 are independently selected from hydrogen, hydroxyl, amino, hydrocarbon or substituted hydrocarbon; In formula III, k1 and k2 are independently selected from integers between 0 and 16; R', R'1, R'2 and R'3 are independently selected from hydrogen, hydroxyl, amino, hydrocarbon or substituted hydrocarbon; X1, X2 and X3 are independently selected from -H, -OH, -NH2, -NHNZ 1 Z 2 、-NHZ 1 、-NZ 1 Z 2 、-OZ 1 、-NHOZ 1 , -SH, -SeH, -SZ 1 、-SeZ 1 ,-Arg-Gly-Asp-Z 3 , connected with the carbonyl group to form lipid derivative groups, amine derivative groups, Z 1 , Z 2 independently selected from alkyl, Z 3 Selected from hydrogen, hydroxyl, amino, an ester derivative group formed with the carbon end of Asp, an amine derivative group, a hydrocarbon group or a substituted hydrocarbon group; AA1 is selected from one of the structures of Formula 7 to Formula 12: In Formulae 7 to 12: the acyl end of AA1 is coupled to the nitrogen end of the main chain; m, e, and n1 are independently selected from integers between 0 and 5; R, Z' are independently selected from hydrogen, -OH, -NH2, hydrocarbon or substituted hydrocarbon, acyl derivative groups, sulfonyl derivative groups; R1, R2, R3, R4, R5, and R6 are independently selected from hydrogen, alkylene or substituted alkylene, alkylene or alkylene derivatives, alkynylene or alkynylene derivatives, arylene and substituted arylene, heteroarylene or substituted heteroarylene; If R1, R2, R3, R4, R5, and R6 are selected from hydrogen substitution, X, Y1, and Z are unsubstituted; When R1, R2, R3, R4, R5, and R6 are selected from non-hydrogen substitutions, X, Y1, and Z are independently selected from hydrogen, halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio (or seleno), haloalkylthio (or seleno), mercapto (or seleno), alkylthio (or seleno) ether, arylthio (or seleno) ether, hydroxyl, cyano, nitro, carboxyl derivative group, aryloxy, amide, acylamine, amino, hydroxylamine, alkylamine, dialkylamine, trifluoroalkoxy, trifluoromethyl, ester, sulfonyl, alkylsulfonyl, haloalkylsulfonyl, sulfonic acid, sulfonamide, phosphoric acid, phosphoric acid ester, unsubstituted aryl, aryl heterocyclic group, and monocyclic heterocyclic group; In formula IV, k1 and k2 are independently selected from integers between 0 and 16; R', R'1, R'2 and R3 are independently selected from hydrogen, hydroxyl, hydrocarbon or substituted hydrocarbon; X' is selected from hydrogen, hydrocarbyl or substituted hydrocarbyl; X1, X2 and X3 are independently selected from -H, -OH, -NH2, -NHNZ 1 Z 2 、-NHZ 1 、-NZ 1 Z 2 、-OZ 1 、-NHOZ 1 , -SH, -SeH, -SZ 1 、-SeZ 1 ,-Arg-Gly-Asp-Z 3 , connected with the carbonyl group to form lipid derivative groups, amine derivative groups, Z 1 , Z 2 independently selected from alkyl, Z 3 Selected from hydrogen, hydroxyl, amino, ester derivative group formed with the carbon end of Asp, amine derivative group, hydrocarbon group or substituted hydrocarbon; AA2 is selected from one of the structures of Formula 13 to Formula 18: In Formula 13 to Formula 18: the acyl end of AA2 is coupled to the nitrogen end of the main chain, and the acyl end of the main chain is coupled to the nitrogen end of the general formula of AA2; m, e, and n1 are independently selected from integers between 0 and 5; R is selected from hydrogen, -OH, -NH2, a hydrocarbon group or a substituted hydrocarbon group; R1, R2, R3, R4, R5, and R6 are independently selected from hydrogen, alkylene or substituted alkylene, alkylene or alkylene derivatives, alkynylene or alkynylene derivatives, arylene and substituted arylene, heteroarylene or substituted heteroarylene; If R1, R2, R3, R4, R5, and R6 are selected from hydrogen substitution, X, Y1, and Z are unsubstituted; When R1, R2, R3, R4, R5, and R6 are selected from non-hydrogen substitutions, X, Y1, and Z are independently selected from hydrogen, halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio (or seleno), haloalkylthio (or seleno), mercapto (or seleno), alkylthio (or seleno) ether, arylthio (or seleno) ether, hydroxyl, cyano, nitro, carboxyl derivative group, aryloxy, amide, acylamine, amino, hydroxylamine, alkylamine, dialkylamine, trifluoroalkoxy, trifluoromethyl, ester, sulfonyl, alkylsulfonyl, haloalkylsulfonyl, sulfonic acid, sulfonamide, phosphoric acid, phosphoric acid ester, unsubstituted aryl, aryl heterocyclic group, and monocyclic heterocyclic group; In formula V, k, k1 and k2 are independently selected from integers between 0 and 16; R', R'2 and R'3 are independently selected from hydrogen, hydroxyl, amino, hydrocarbon or substituted hydrocarbon; X' is selected from hydrogen, hydrocarbyl or substituted hydrocarbyl; X1, X2 and X3 are independently selected from -H, -OH, -NH2, -NHNZ 1 Z 2 、-NHZ 1 、-NZ 1 Z 2 、-OZ 1 、-NHOZ 1 , -SH, -SeH, -SZ 1 、-SeZ 1 ,-Arg-Gly-Asp-Z 3 , connected with the carbonyl group to form lipid derivative groups, amine derivative groups, Z 1 , Z 2 independently selected from alkyl, Z 3 Selected from hydrogen, hydroxyl, amino, ester derivative group formed with the carbon end of Asp, amine derivative group, hydrocarbon group or substituted hydrocarbon; The selection range of AA3 is consistent with the selection range of AA2 in Formula III described in the above technical solution; In Formula VI, k, k1 and k2 are independently selected from integers between 0 and 16; R', R'1 and R'3 are independently selected from hydrogen, hydroxyl, amino, hydrocarbon or substituted hydrocarbon; X' is selected from hydrogen, hydrocarbyl or substituted hydrocarbyl; X1, X2 and X3 are independently selected from -H, -OH, -NH2, -NHNZ 1 Z 2 、-NHZ 1 、-NZ 1 Z 2 、-OZ 1 、-NHOZ 1 , -SH, -SeH, -SZ 1 、-SeZ 1 ,-Arg-Gly-Asp-Z 3 , connected with the carbonyl group to form lipid derivative groups, amine derivative groups, Z 1 , Z 2 independently selected from alkyl, Z 3 Selected from hydrogen, hydroxyl, amino, ester derivative group formed with the carbon end of Asp, amine derivative group, hydrocarbon group or substituted hydrocarbon; The selection range of AA4 is consistent with the selection range of AA2 in Formula III described in the above technical solution; In Formula VII, k and k1 are independently selected from integers between 0 and 16; R', R'1, R'2 are independently selected from hydrogen, hydroxyl, amino, hydrocarbon or substituted hydrocarbon; X' is selected from hydrogen, hydrocarbyl or substituted hydrocarbyl; X1, X2 are independently selected from -H, -OH, -NH2, -NHNZ 1 Z 2 、-NHZ 1 、-NZ 1 Z 2 、-OZ 1 、-NHOZ 1 , -SH, -SeH, -SZ 1 、-SeZ 1 ,-Arg-Gly-Asp-Z 3 , connected with the carbonyl group to form lipid derivative groups, amine derivative groups, Z 1 , Z 2 independently selected from alkyl, Z 3 Selected from hydrogen, hydroxyl, amino, ester derivative group formed with the carbon end of Asp, amine derivative group, hydrocarbon group or substituted hydrocarbon; AA5 is selected from one of the structures of Formula 19 to Formula 24: In Formulas 19 to 24: the main chain acyl end is coupled to the general nitrogen end of AA5; m, e, and n1 are independently selected from integers between 0 and 5; R is selected from hydrogen, -OH, -NH2, a hydrocarbon group or a substituted hydrocarbon group; R1, R2, R3, R4, R5, and R6 are independently selected from hydrogen, alkylene or substituted alkylene, alkylene or alkylene derivatives, alkynylene or alkynylene derivatives, arylene and substituted arylene, heteroarylene or substituted heteroarylene; If R1, R2, R3, R4, R5, and R6 are selected from hydrogen substitution, X, Y1, and Z are unsubstituted; When R1, R2, R3, R4, R5, and R6 are selected from non-hydrogen substitutions, X, Y1, and Z are independently selected from hydrogen, halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio (or seleno), haloalkylthio (or seleno), mercapto (or seleno), alkylthio (or seleno) ether, arylthio (or seleno) ether, hydroxyl, cyano, nitro, carboxyl derivative group, aryloxy, amide, acylamine, amino, hydroxylamine, alkylamine, dialkylamine, trifluoroalkoxy, trifluoromethyl, ester, sulfonyl, alkylsulfonyl, haloalkylsulfonyl, sulfonic acid, sulfonamide, phosphoric acid, phosphoric acid ester, unsubstituted aryl, aryl heterocyclic group, and monocyclic heterocyclic group; R x Selected from -H, -OH, -NH2, -NHNZ 1 Z 2 、-NHZ 1 、-NZ 1 Z 2 、-OZ 1 、-NHOZ 1 , -SH, -SeH, -SZ 1 、-SeZ 1 ,-Arg-Gly-Asp-Z 3 , connected with the carbonyl group to form a lipid derivative group, an amine derivative group, an olefin group or an olefin derivative, an alkynyl group or an alkynyl derivative, an aryl group and a substituted aryl group, a heteroaryl group or a substituted heteroaryl group, Z 1 , Z 2 independently selected from alkyl, Z 3 It is selected from hydrogen, hydroxyl, amino, an ester derivative group formed with the carbon end of Asp, an amine derivative group, a hydrocarbon group or a substituted hydrocarbon.

7. The polypeptide compound according to any one of claims 5 or 6, and its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, nitrogen oxides, isotope labels, metabolites and prodrugs, characterized in that: The structure of ZT is formula ZT1, where n is 1 or 2; The structure of Linker is shown in the formulas Linker1 to Linker4: In the formulas Linker1 to Linker4, n1, n2, n3, n4, n5, and n6 are independently selected as integers between 0 and 13; Y2 is hydrogen, hydroxyl, carboxyl, sulfonic acid, thiol, amino, amide, sulfonamide, -OMe, -OEt, -SMe, -SEt, -CONHMe, -CONHEt, -SO2NHMe, -SO2NHEt; PD is selected from the following compounds:

8. A polypeptide complex, wherein the polypeptide complex is formed by reacting the polypeptide compound according to any one of claims 1 to 7, and pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotope labels, metabolites and prodrugs thereof with a metal; the metal is selected from rare earth elements, Cu, Ga, In, Bi, Al 18 One of F, At, Ac, Bi or an isotope thereof.

9. A pharmaceutical composition comprising the polypeptide compound according to any one of claims 1 to 7, and pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotope labels, metabolites and prodrugs thereof and / or the polypeptide complex according to claim 8.

10. Use of a polypeptide compound according to any one of claims 1 to 7, and pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotope labels, metabolites and prodrugs thereof, and / or the polypeptide complex according to claim 8, and / or the pharmaceutical composition according to claim 9 in the preparation of drugs for diagnosing and / or treating diseases associated with integrin αvβ5, and / or integrin α5β1, and / or integrin αvβ3, and / or integrin αvβ6.

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