Polypeptide compound and complex thereof, and use

Abstract

The present invention relates to the technical field of pharmaceutical chemistry. Specifically, disclosed are a polypeptide compound and a complex thereof, and a use. The polypeptide compound provided by the present invention can target αvβ5, α5β1 and αvβ3 integrin proteins, are enriched in integrin highly expressed tumor cells, and has an important function in diagnosis and / or treatment of diseases related to integrins αvβ5, α5β1 and αvβ3.

Description

A polypeptide compound and its complex and application

[0001] This application claims priority to the Chinese patent application filed with the China Patent Office on June 21, 2023, with application number 2023107454362 and invention name “A polypeptide compound and its complex and application”, the entire contents of which are incorporated by reference into this application. Technical Field

[0002] The present invention belongs to the technical field of medicinal chemistry, and specifically relates to a class of polypeptide compounds and their complexes and applications. Background Art

[0003] Integrins are a class of transmembrane glycoproteins ubiquitously present in cells. They are members of the cell adhesion molecule family and are the primary mediators of cell-extracellular matrix (ECM) interactions. They are cell membrane surface receptors that recognize and bind to corresponding ligands in the ECM, providing attachment points for cell adhesion, regulating cell motility, proliferation, and apoptosis. They mediate mutual recognition and adhesion between cells and between cells and the ECM, and serve to bridge external cellular processes with internal cellular structures. Integrins are heterodimers composed of two subunits, α and β, linked by non-covalent bonds in a 1:1 ratio. They consist of an extracellular domain, a transmembrane domain, and an intracellular domain. The extracellular domain is connected to form a globular region and contains a divalent cation-binding domain. Based on the specificity of their ligand recognition, integrins can be broadly classified as those that recognize the arginase-glycinase-aspartase peptide (RGD tripeptide) sequence, laminin-binding integrins, leukocyte integrins, and collagen-binding integrins. Integrins bind to ECM proteins—collagen, laminin, vitronectin, fibronectin—or some cell surface molecules through their extracellular domains. Integrins are involved in many important physiological processes, including embryogenesis, blood 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 associated with abnormal integrin regulation.

[0004] Dysregulation of integrin expression on cancer cells has been extensively studied in 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 immunodeficient mouse xenograft models have demonstrated that the loss of integrins in cancer cells or the inhibition of integrin function using blocking antibodies or peptides interferes with tumor growth, metastasis, and resistance to chemotherapy or radiotherapy. β1 integrins have dual roles in growth and metastasis, suggesting their potential therapeutic potential. Integrins, such as αvβ3, αvβ5, and α5β1, are not only expressed on tumor cells but are also induced on endothelial cells during angiogenesis, proving to be targets for anti-angiogenic cancer therapy.

[0005] Recent studies have found that a series of other subtypes of integrins are involved in the development of cancer, including the establishment of pre-metastatic niches, epithelial-mesenchymal transition (EMT), metabolic reorganization, and the stemness and dormancy of cancer cells. Integrin αvβ6 is involved in the activation of TGFβ and is associated with SOX4-mediated cancer immune evasion: 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 blocking of integrin αvβ8 on the surface of regulatory T cells can attenuate TGFβ-mediated responses to CD8 + T cell suppression, thereby restoring CD8 + T cells have tumor-killing ability and are synergistic with radiation or immunotherapy.

[0006] Expression of the integrin αvβ3 is broadly 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, suggesting that αvβ3 may serve as a biomarker for early detection of malignant transformation in prostate cancer. Expression of the integrin αvβ5 has been suggested as a predictive biomarker in several cancer types, including breast, liver, and gastric cancers. Elevated levels of αvβ5 have been detected in patients with glioblastoma or colorectal cancer, and overexpression of αvβ5 is associated with poor overall survival. Integrin α5β1 is involved in tumor-promoting processes such as angiogenesis, proliferation, and metastasis. In patients with early-stage breast cancer, expression of α5β1 in primary tumors correlates with the presence of disseminated tumor cells in bone marrow aspirates and poor metastasis-free survival. Similarly, studies have shown that genetic silencing of α5 or pharmacological inhibition of α5β1 with woximab attenuates bone colonization in mice following 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.

[0007] The abnormal expression of integrin proteins such as αvβ3, αvβ5, and α5β1 in various tumors and their role in tumor development and progression make them promising drug targets for targeted cancer therapy. Drug molecules targeting integrins can either directly kill tumor cells or serve as targeted vectors to precisely deliver cytotoxins and radionuclides to tumor cells, thereby achieving tumor killing. Furthermore, combining radionuclides and fluorescent molecules with integrin-targeting molecules has applications in tumor diagnosis, surgical navigation, and other fields.

[0008] It can be seen that the research on drugs that inhibit integrins is of great significance.

[0009] 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 a 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. The compound is obtained by coupling ZT and PD, or by coupling ZT, a linker, and PD. 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 amino groups and hydroxy groups 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] wherein n is selected from an integer of 1 to 8;

[0024] R a1 、R a2 、R a3 is a substituted or unsubstituted alkylene phosphinate 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;

[0025] R b1 、R b2 、R b3 is hydrogen, hydroxyl, carboxyl, halogen, sulfhydryl, selenoyl, 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, or substituted or unsubstituted C1-C6 phosphate;

[0026] R b1 、R b3 At least one of them is a carboxyl group, an amino group or a hydroxyl group.

[0027] Preferably, n is selected from an integer of 1 to 4;

[0028] R a1 、R a2 、R a3 is a substituted or unsubstituted alkylene phosphinate 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;

[0029] R b1 、R b2 、R b3is hydrogen, hydroxy, carboxyl, halogen, amino, substituted or unsubstituted phosphino, substituted or unsubstituted phosphite, substituted or unsubstituted C1-C6 hydrocarbon, or substituted or unsubstituted C1-C6 alkoxy;

[0030] R b1 、R b3 At least one of them is a carboxyl group.

[0031] More preferably, R a1 、R a2 、R a3 is a C1-C3 alkylene group, a C1-C3 alkyleneoxy group, a C1-C3 alkylenephosphinate group, or a C1-C3 alkylenephosphite group;

[0032] R b1 、R b2 、R b3 is hydrogen, hydroxyl, carboxyl, amino, C1-C3 alkylene phosphinate, C1-C3 alkylene phosphite, C1-C3 hydrocarbon group, C1-C3 alkoxy group;

[0033] R b1 、R b3 At least one of them is a carboxyl group.

[0034] In a specific embodiment of the present invention, the structure of ZT is shown in formulas ZT1 to ZT4:

[0035] In formulae ZT1 to ZT4, n is an integer of 1 to 4.

[0036] In the most preferred embodiment of the present invention, the structure of ZT is formula ZT1, wherein n is 1 or 2.

[0037] The structure of Linker in the above formula is as follows:

[0038] Wherein, d is selected from an integer of 0 to 17;

[0039] R L1 、R L3 -(CH2) d1 COOH, amino, thiol, carboxyl or hydroxyl, d1 is an integer selected from 0 to 13;

[0040] R L2 -Arg-Gly-Asp-, -Arg-Gly-, -Arg-, imino, nitro, imido, substituted or unsubstituted C1-C20 alkylene, substituted or unsubstituted C1-C20 alkylene ether, substituted or unsubstituted C5-C20 arylene ether;

[0041] Preferably, R L1 is an amino group or a carboxyl group;

[0042] R L2 It 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.

[0043] In a specific embodiment of the present invention, the structure of the linker is shown in formulas Linker1 to Linker4:

[0044] In formulas Linker1 to Linker4, n1, n2, n3, n4, n5, and n6 are independently selected from integers between 0 and 13;

[0045] Y2 is hydrogen, hydroxyl, carboxyl, sulfonic acid, mercapto, amino, amide, sulfonamide, -OMe, -OEt, -SMe, -SEt, -CONHMe, -CONHEt, -SO2NHMe, -SO2NHEt.

[0046] In the above formula, PD is a compound and / or its derivative obtained by condensing one or more compounds of Formulae 1 to 6;

[0047] In Formulas 1 to 6, m, e, and n1 are independently selected from integers of 0 to 5;

[0048] 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.

[0049] R1, R2, R3, R4, R5, and R6 are independently selected from substituted or unsubstituted C1-C6 alkylene, substituted or unsubstituted C5-C20 arylene, and 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 group; the q is 1 or 2; the R" is a C1-C6 alkyl group.

[0050] 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 in the substituted alkylene group in R1, R2, R3, R4, R5, and R6 is selected from N, O, SH, or SeH.

[0051] The arylene group in R1, R2, R3, R4, R5 and R6 is selected from an aliphatic ring or an aromatic ring.

[0052] 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.

[0053] 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 group, substituted or unsubstituted C3-C6 heterocyclic group; the substituent in the substituted C1-C6 alkyl, substituted C1-C6 alkyl ether, substituted C5-C20 aryl ether is one or more of -SH, SeH, hydroxyl, amino, carboxyl, sulfonic acid, phosphate, and halogen; q is 1 or 2; and R" is a C1-C6 alkyl;

[0054] Alternatively, R1, R2, and R6 are H. In this case, X, Y1, Z, does not exist;

[0055] 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.

[0056] Preferably, X, Y1, and Z are independently selected from hydrogen, amino, carboxyl, sulfhydryl, -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 group, 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.

[0057] Preferably, PD is formed by condensing one or more amino acids or amino acid-like groups in Formulas 1 to 6 through an amide bond formed by condensing an amino group and a carboxyl group, and / or a sulfonamide bond formed by condensing an amino group and a sulfonic acid group, and / or a sulfinamide bond formed by condensing an amino group and a sulfinic acid group. Preferably, PD is formed by condensing five amino acids or amino acid-like groups, forming four amide bonds, sulfonamide bonds, and / or sulfinamide bonds. Preferably, the amino acid or amino acid-like structure has a nitrogen terminus on the left and a carbon terminus on the right.

[0058] In a preferred embodiment of the present invention, the compounds (amino acids or amino acid-like compounds) of formulas 1 to 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 formulas 1 to 6 preferably include one or both of L-configuration and D-configuration structures.

[0059] More preferably, PD is selected from one of the compounds of formula II to formula VII:

[0060] 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;

[0061] 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 carbonyl 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;

[0062] 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-;

[0063] R3, R4, R5, R6, R7, R8, R9, R 10 、R 11 、R 12 independently selected from hydrogen, hydrocarbyl or substituted hydrocarbyl, heteroatom-substituted hydrocarbyl, alkene or alkene derivative, alkynyl or alkynyl derivative, aryl and substituted aryl, heteroaryl or substituted heteroaryl;

[0064] X, X1, X2, X3, X4, and X5 are independently selected from hydrogen, hydroxy, amino, hydrocarbon, or substituted hydrocarbon.

[0065] In formula III, k1 and k2 are independently selected from integers between 0 and 16;

[0066] R', R'1, R'2 and R'3 are independently selected from hydrogen, hydroxy, amino, hydrocarbon or substituted hydrocarbon;

[0067] 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 carbonyl 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 group;

[0068] AA1 is selected from one of the structures of Formula 7 to Formula 12:

[0069] In formulas 7 to 12: the acyl end of AA1 is coupled to the nitrogen end of the main chain;

[0070] m, e, and n1 are independently selected from integers between 0 and 5;

[0071] R, Z' are independently selected from hydrogen, -OH, -NH2, hydrocarbon or substituted hydrocarbon, acyl derivative group, sulfonyl derivative group;

[0072] R1, R2, R3, R4, R5, and R6 are independently selected from hydrogen, alkylene or substituted alkylene, alkene or alkene derivative, alkynylene or alkynyl derivative, arylene and substituted arylene, heteroarylene or substituted heteroarylene;

[0073] If R1, R2, R3, R4, R5, and R6 are selected from hydrogen, X, Y1, and Z are unsubstituted;

[0074] 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.

[0075] In formula IV, k1 and k2 are independently selected from integers between 0 and 16;

[0076] R', R'1, R'2 and R3 are independently selected from hydrogen, hydroxy, hydrocarbon or substituted hydrocarbon;

[0077] X' is selected from hydrogen, hydrocarbyl or substituted hydrocarbyl;

[0078] 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 carbonyl 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;

[0079] AA2 is selected from one of the structures of Formula 13 to Formula 18:

[0080] In formulas 13 to 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;

[0081] m, e, and n1 are independently selected from integers between 0 and 5;

[0082] R is selected from hydrogen, -OH, -NH2, hydrocarbon or substituted hydrocarbon;

[0083] R1, R2, R3, R4, R5, and R6 are independently selected from hydrogen, alkylene or substituted alkylene, alkene or alkene derivative, alkynylene or alkynyl derivative, arylene and substituted arylene, heteroarylene or substituted heteroarylene;

[0084] If R1, R2, R3, R4, R5, and R6 are selected from hydrogen, X, Y1, and Z are unsubstituted;

[0085] 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.

[0086] In formula V, k, k1 and k2 are independently selected from integers between 0 and 16;

[0087] R', R'2 and R'3 are independently selected from hydrogen, hydroxy, amino, hydrocarbon or substituted hydrocarbon;

[0088] X' is selected from hydrogen, hydrocarbyl or substituted hydrocarbyl;

[0089] 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 carbonyl to form lipid derivative groups, amine derivative groups, Z1 , 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;

[0090] The selection range of AA3 is consistent with the selection range of AA2 in formula III described in the above technical solution.

[0091] In Formula VI, k, k1 and k2 are independently selected from integers between 0 and 16;

[0092] R', R'1 and R'3 are independently selected from hydrogen, hydroxy, amino, hydrocarbon or substituted hydrocarbon;

[0093] X' is selected from hydrogen, hydrocarbyl or substituted hydrocarbyl;

[0094] 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 carbonyl 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;

[0095] The selection range of AA4 is consistent with the selection range of AA2 in formula III described in the above technical solution.

[0096] In Formula VII, k and k1 are independently selected from integers between 0 and 16;

[0097] R', R'1, R'2 are independently selected from hydrogen, hydroxy, amino, hydrocarbon or substituted hydrocarbon;

[0098] X' is selected from hydrogen, hydrocarbyl or substituted hydrocarbyl;

[0099] X1, X2 are independently selected from -H, -OH, -NH2, -NHNZ 1 Z 2 、-NHZ 1 、-NZ1 Z 2 、-OZ 1 、-NHOZ 1 、-SH、-SeH、-SZ 1 、-SeZ 1 ,-Arg-Gly-Asp-Z 3 , connected with carbonyl 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;

[0100] AA5 is selected from one of the structures of Formula 19 to Formula 24:

[0101] In Formulas 19 to 24: the main chain acyl end is coupled to the general nitrogen end of AA5;

[0102] m, e, and n1 are independently selected from integers between 0 and 5;

[0103] R is selected from hydrogen, -OH, -NH2, hydrocarbon or substituted hydrocarbon;

[0104] R1, R2, R3, R4, R5, and R6 are independently selected from hydrogen, alkylene or substituted alkylene, alkene or alkene derivative, alkynylene or alkynyl derivative, arylene and substituted arylene, heteroarylene or substituted heteroarylene;

[0105] If R1, R2, R3, R4, R5, and R6 are selected from hydrogen, X, Y1, and Z are unsubstituted;

[0106] When R1, R2, R3, R4, R5, and R6 are selected from non-hydrogen substituted groups, 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, 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;

[0107] R x Selected from -H, -OH, -NH2, -NHNZ 1 Z 2 、-NHZ 1 、-NZ 1Z 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 alkyne group or an alkyne 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.

[0108] In the most preferred embodiment of the present invention, PD is selected from the compounds of the following structures:

[0109] In a specific embodiment of the present invention, the structure of the polypeptide compound is as follows:

[0110] 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 its pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotope labels, metabolites and prodrugs 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.

[0111] 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).

[0112] Preferably, the metal is 177 Lu, 64 Cu, 68 Ga, 111 In、Al 18 F. 211 At225 Ac, 90 Y. 213 One of Bi and Gd or an isotope thereof.

[0113] In a specific embodiment of the present invention, the structure of the polypeptide complex is as follows:

[0114] The polypeptide complex is preferably formed by the polypeptide compound and the metal chelate; the preparation method thereof preferably comprises the following steps: reacting the polypeptide compound with the metal compound; the reaction is preferably a mixed reaction of the polypeptide compound and the metal chloride, or a mixed reaction of the polypeptide compound and the metal salt; the metal in the metal salt is preferably Al 18 F, Gd, 177 Lu, 64 Cu, 68 Ga, 111 In, 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.

[0115] 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 2-3 hours;

[0116] Alternatively, a polypeptide compound and a 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 a 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.

[0117] Preferably, the preparation method of the polypeptide complex preferably comprises the following steps:

[0118] The polypeptide compound is dissolved in a solvent, mixed with an alkaline solution, and the pH is adjusted to 3-11. Then, a metal chloride is added, and the pH is adjusted to 3-11. The excess metal ions are precipitated to obtain a polypeptide complex.

[0119] Alternatively, the polypeptide compound is dissolved in a solvent, heated to 20-150° C., then mixed with a metal 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 salt solution is preferably water, and the pH is preferably adjusted with KOH or NaOH.

[0120] 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).

[0121] 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.

[0122] Preferably, the pharmaceutical composition further comprises pharmaceutically acceptable excipients and / or carriers.

[0123] 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.

[0124] The diagnosis includes but is not limited to PET / CT and magnetic resonance imaging.

[0125] 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.

[0126] The polypeptide compounds provided by the present invention can target integrin proteins such as αvβ5, α5β1, αvβ3, and αvβ6, 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, thereby enhancing the precise killing of tumors by cytotoxic molecules. In addition, they can also provide targeting carriers for radionuclides 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 in the nanomolar range.

[0127] In the present invention, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0128] In the present invention, the term "alkyl" refers to a straight-chain 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 groups include (but are not limited to) methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like. The alkyl groups in the present invention are optionally substituted with one or more substituents described herein (e.g., halogen).

[0129] In the present invention, the term "haloalkyl" refers to an alkyl group substituted with one or more (e.g., 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 groups include (but are not limited to) -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, -CH2CH2CF3, -CH2Cl, etc. The haloalkyl groups in the present invention are optionally substituted with one or more substituents described herein.

[0130] As used herein, the term "alkoxy" refers to an alkyl group attached to the rest of the molecule via an oxygen atom. Alkoxy groups herein include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, and the like. Alkoxy groups herein are optionally substituted with one or more substituents as described herein.

[0131] 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 groups include (but are not limited to) monocyclic cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclononyl; or bicyclic cycloalkyl groups including fused, bridged, or spirocyclic groups such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, and decalinyl. The cycloalkyl groups in the present invention are optionally substituted with one or more substituents described herein (such as methyl).

[0132] As used herein, the term "heterocycloalkyl" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic group whose ring atoms consist of carbon atoms and at least one heteroatom selected from nitrogen, oxygen, and sulfur. A heterocycloalkyl group may be attached to the rest of the molecule via any one of the ring atoms, provided that valence requirements are met. For example, the term "3- to 8-membered heterocycloalkyl" refers to a heterocycloalkyl group 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.

[0133] 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 groups include (but are not limited to) phenyl, naphthyl, anthracenyl, phenanthrenyl, acenaphthenyl, azulenyl, fluorenyl, indenyl, and pyrenyl. The aryl groups in the present invention are optionally substituted with one or more substituents described herein (e.g., halogen, hydroxyl, cyano, nitro, C1-C6 alkyl, etc.).

[0134] In the present invention, the term "heteroaryl" refers to a monocyclic or fused polycyclic (particularly benzo-fused polycyclic) aromatic group having a conjugated π electron system, wherein the ring atoms consist of carbon atoms and at least one heteroatom selected from nitrogen, oxygen, and sulfur. A heterocycloalkyl group may be attached to the rest of the molecule via any one of the ring atoms, provided that valence requirements are met. For example, the term "C6-C20 heteroaryl" refers to a heteroaryl group having 6 to 20 carbon atoms. In the present invention, heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and their benzo derivatives. The heteroaryl groups in the present invention are optionally substituted with one or more substituents described herein (e.g., halogen, C1-6 alkyl, etc.).

[0135] In the present invention, the term "alkenyl" refers to a straight-chain 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 groups include, but are not limited to, ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, n-octenyl, and n-decenyl. Alkenyl groups in the present invention are optionally substituted with one or more substituents described herein.

[0136] In the present invention, the term "alkynyl" refers to a straight-chain 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 groups include (but are not limited to) ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Alkynyl groups in the present invention are optionally substituted with one or more substituents described herein.

[0137] 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., trifluoromethanesulfonate) 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 if the combination can form a stable compound. If a substituent is described as "optionally substituted by...", the substituent may 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 group list, the one or more hydrogen atoms in the first substituent group may be individually or independently replaced by one or more of the substituents listed in the second substituent group list, or may not be replaced.

[0138] In the present invention, the term "alkylene group" refers to a group obtained by removing two hydrogen atoms from a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon compound.

[0139] 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.

[0140] In the present invention, the term "alkyleneoxy group" refers to a group obtained by removing one hydrogen atom from an alkoxy group.

[0141] In the present invention, the term "alkylene phosphite group" 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 compound, and a phosphite group refers to a group obtained by removing one hydrogen atom connected to a phosphorus atom from hypophosphorous acid; and an "alkylene phosphite group" 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.

[0142] In the present invention, the term "alkylene ether" refers to a group obtained by removing one hydrogen atom from an alkyl ether.

[0143] In the present invention, the term "arylene ether" refers to a group obtained by removing one hydrogen atom from an aryl ether.

[0144] In the present invention, the term "alkylenesulfonyl group" refers to a group in which an alkylene group and a sulfonyl group are linked by a covalent bond, "alkylenesulfonic acid group" refers to a group in which an alkylene group and a sulfonic acid group are linked by a covalent bond, "alkylenesulfonate group" refers to a group in which an alkylene group and a sulfonate group are linked by a covalent bond, and "alkylenephosphate group" refers to a group in which an alkylene group and a phosphate group are linked by a covalent bond.

[0145] In the present invention, the term "each independently" means that at least two groups (or ring systems) present in a structure with the same or similar value ranges can have the same or different meanings in specific circumstances. For example, Substituent 1 and Substituent 2 are each independently hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl. Then, when Substituent 1 is hydrogen, Substituent 2 can be either hydrogen, or halogen, hydroxyl, cyano, alkyl, or aryl. Similarly, when Substituent 2 is hydrogen, Substituent 1 can be either hydrogen, or halogen, hydroxyl, cyano, alkyl, or aryl.

[0146] As used herein, 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 a variety of methods known to 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.

[0147] In the present invention, the term "solvate" refers to a substance formed by the combination of a compound of the present invention (or a pharmaceutically acceptable salt thereof) 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, acetonides, etc.

[0148] 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.

[0149] In the present invention, the term "isotopically labeled" refers to a derivative compound formed by replacing a specific atom in the compound of the present invention with an isotope thereof. Unless otherwise indicated, 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.

[0150] In the present invention, the term "metabolite" refers to a derivative compound formed after metabolism of the compound of the present invention.

[0151] In the present invention, the term "prodrug" refers to a derivative compound that is capable of providing a compound of the present invention directly or indirectly upon administration 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 readily absorbed into the bloodstream), or compounds that promote 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.

[0152] 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 organisms. 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 called acid addition salts or base addition salts.

[0153] In the present invention, the term "pharmaceutically acceptable ester" refers to an ester that is substantially non-toxic to organisms and is hydrolyzed in vivo to form the 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 the compound of the present invention and a pharmaceutically acceptable carboxylic acid or sulfonic acid, such esters being also referred to as carboxylate esters or sulfonate esters.

[0154] In the present invention, the term "isomer" refers to a compound having the same molecular weight due to having the same number of atoms and atom 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 having 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 lead to stereoisomerism, the present invention also includes these stereoisomers and mixtures thereof. Since the compounds of the present invention (or pharmaceutically acceptable salts thereof) include asymmetric carbon atoms, they can exist in the form of single stereoisomers, racemates, enantiomers, and mixtures of diastereomers. Typically, these compounds can be prepared in the form of racemates. However, if desired, such compounds can be prepared or isolated to obtain 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 can be synthesized from optically active starting materials containing the desired chiral center, or by preparing a mixture of enantiomeric products followed by separation or resolution, for example, by 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 can be obtained commercially or prepared by methods well known in the art and resolved by methods well known in the art. The term "enantiomers" refers to a pair of stereoisomers that are non-superimposable mirror images of each other. The term "diastereomer" or "diastereomers" refers to optical isomers that are not mirror images of one another. 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 are interconvertible across a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (or prototropic tautomers) include, but are not limited to, interconversions via proton migration, such as keto-enol isomerization, imine-enamine isomerization, and amide-iminoalcohol isomerization. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

[0155] The present invention has no special restrictions on the preparation method of the polypeptide compound. The solid phase piece-by-piece, fragment synthesis, and liquid phase synthesis methods of the polypeptide compound by those skilled in the art are adopted, and the desired amino acids, quasi-amino acids, or polypeptide substances are 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 of amino acids, and gradual synthesis of the desired polypeptide compound by repeated deprotection group and coupling of amino acids; the connection mode between the PD, ZT, and Linker can form common functional group structures such as amides, carbonates, ureas, sulfonamides, sulfenamides, and amines through the reaction of functional groups in the structure. BRIEF DESCRIPTION OF THE DRAWINGS

[0156] Figure 1 HPLC spectrum of compound TM1;

[0157] Figure 2 HPLC spectrum of compound TM2;

[0158] FIG3 HPLC spectrum of compound TM3;

[0159] FIG4 HPLC spectrum of compound Gd-TM1;

[0160] FIG5 HPLC spectrum of compound Gd-TM2;

[0161] FIG6 HPLC spectrum of compound Gd-TM3;

[0162] FIG7 HPLC spectrum of compound Gd-TM7;

[0163] Figure 8 68 PET / CT imaging of Ga-TM1(2h) (H1975);

[0164] Figure 9 68 PET / CT imaging of Ga-TM7(4h) (H1975);

[0165] Figure 10 68 PET / CT imaging of Ga-TM7(4h) (BxPC-3);

[0166] Figure 11 68 PET / CT imaging of Ga-TM7(4h) (PANC-1);

[0167] Figure 12 MRI images;

[0168] Figure 13. Ratio of tumor and muscle grayscale values ​​on T1 signal of MRI;

[0169] Figure 14 177Lu-TM1 (abbreviated as 177Lu-057) radioactivity purity;

[0170] Figure 15 177 Lu-TM7 (abbreviated as 177Lu-071) radioactivity purity;

[0171] Figure 16 177 SPECT / CT imaging of mice (H1975) bearing Lu-TM1 (abbreviated as 177Lu-057) tumors (1 mCi, MIP image);

[0172] Figure 17 177 SPECT / CT imaging of mice (H1975) bearing Lu-TM7 (abbreviated as 177Lu-071) tumors (1 mCi, MIP image);

[0173] Figure 18 177 Lu-TM1 (abbreviated as 177Lu-057) tumor uptake data within 96 h (H1975);

[0174] Figure 19 177 Lu-TM7 (abbreviated as 177Lu-071) tumor uptake data within 96 hours (H1975). DETAILED DESCRIPTION

[0175] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present invention without making any creative efforts are within the scope of protection of the present invention.

[0176] 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.

[0177] Example 1

[0178] Preparation of polypeptide compound TM1, the compound structure is as follows:

[0179] Step 1: Synthesis of Fmoc-Asn(Trt)-CTC Resin (M1)

[0180] 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) and dissolve it in DCM (10 mL). Add DIEA (0.42 mL, 2.4 mmol) and react for 1 h. Wash the resin three times with DCM (10 mL). Add blocking solution (10 mL, volume ratio DCM: MeOH: DIEA = 75:20:5) and block for 15 min. Wash the resin three times with DMF (15 mL) to obtain intermediate M1, which is directly used in the next reaction.

[0181] Step 2: Synthesis of Fmoc-Asn(Trt)-Asp(tBu)-Aib-Ile-Asn(Trt)-CTC Resin (M2)

[0182] 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 shows dark blue and is directly used in the next reaction.

[0183] Coupling: Fmoc-Ile-OH (1 g, 3 mmol, 3 eq) was dissolved in DMF (15 mL). TBTU (0.96 g, 3 mmol, 3 eq) and DIEA (1 mL, 6 mmol, 6 eq) were added to the reaction mixture under ice-cooling and stirred for 10 min. The activation solution was then added to the Fmoc-depleted resin and allowed to react for 1 h. A small amount of the resin was tested with 5% ninhydrin in ethanol (a small amount of the resin was added to 1 mL of 5% ninhydrin and heated at 110°C for 3 min). The resin was colorless. The reaction mixture was drained and washed three times with DMF (10 mL). The resulting resin was used directly in the next reaction.

[0184] The coupling cycle was repeated, and Fmoc-Aib-OH (0.97 g, 3 eq), Fmoc-Asp(OtBu)-OH (1.23 g, 3 eq), and Fmoc-Asn(Trt)-OH (1.79 g, 3 eq) were coupled in sequence according to the above procedure. The product was washed alternately with 10 mL each of DCM and MeOH three times, dried, transferred to a vacuum oven, and dried at 35°C for 2 h to obtain intermediate M2 (1.36 g), which was used directly in the next reaction.

[0185] 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)

[0186] Intermediate M2 (0.88 g, 0.5 mmol) was subjected to Fmoc removal and coupling in a peptide synthesis tube to obtain M3, which was used directly in the next reaction. (The coupling sequence of monomers is as follows:

[0187] Fmoc-PEG4-OH (0.48g, 1mmol, 2eq, CAS:557756-85-1)

[0188] Alloc-Lys(Fmoc)-OH (0.45g, 1mmol, 2eq, CAS:186350-56-1)

[0189] Fmoc-PEG2-OH (0.39g, 1mmol, 2eq, CAS:166108-71-0)

[0190] Fmoc-PEG2-OH (0.39g, 1mmol, 2eq, CAS:166108-71-0)

[0191] Fmoc-Glu(α-tBu)-OH (0.43g, 1mmol, 2eq, CAS:84793-07-7)

[0192] Octadecanedioic acid 1-tert-butyl ester (0.25g, 1mmol, 2eq, CAS:843666-40-0)

[0193] 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)

[0194] Deprotection: To intermediate M3, DCM (10 mL), PhSiH3 (0.65 g, 6 mmol, 12 eq), and Pd(PPh3)4 (29 mg, 0.025 mmol, 5% mol) were added sequentially. The reaction was allowed to proceed for 2 h under nitrogen sparge. A small amount of the resin was tested with 5% ninhydrin in ethanol (a small amount of the resin was added to 1 mL of 5% ninhydrin and heated at 110°C for 3 min). The resin turned dark blue. The resin was drained and washed three times with DMF (15 mL) to yield intermediate M4, which was used directly in the next reaction.

[0195] 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)

[0196] 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 mixture under ice-cooling and stirred for 10 min. The activation solution was then added to the de-Alloc-protected intermediate M4 and allowed to react for 16 h. A small amount of the resin was tested with 5% ninhydrin in ethanol (a small amount of the resin was added to 1 mL of 5% ninhydrin and heated at 110°C for 3 min). The resin appeared colorless. The reaction mixture was drained and washed three times with DMF (10 mL). The mixture was then washed three times with 10 mL each of DCM and MeOH, alternately, drained, transferred to a vacuum oven, and dried at 35°C for 2 h to yield resin M5 (1 g).

[0197] Step 6: Synthesize TM1

[0198] To 1 g of resin, cleavage solution (10 mL, TFA:Tis:H2O volume ratio of 95:2.5:2.5) was added. The reaction was continued for 1 h, filtered, and the resin was washed with cleavage solution (1 mL). The combined filtrates were dropwise added to -5°C methyl tert-butyl ether (100 mL), allowed to settle for 1 h (refrigerated), centrifuged, and the supernatant removed. MTBE (50 mL) was added, washed, centrifuged, and the supernatant removed. This process was repeated three times to obtain a white solid. The solid was transferred to a vacuum drying oven and dried at 35°C for 2 h to obtain 179 mg of crude peptide. This was purified by HPLC to obtain a purified solution. The purified solution was concentrated to remove most of the organic solvent and lyophilized to obtain 128 mg of 99.80% pure product TM1, with a yield of 12.8%.

[0199] MS (ESI): m / z [M+2H + ] / 2=1019.6.

[0200] 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).

[0201] Example 2

[0202] Preparation of polypeptide compound TM2, the compound structure is as follows:

[0203] Step 1: Synthesis of Fmoc-Asn(Trt)-CTC Resin (M1)

[0204] 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) and dissolve it in DCM (10 mL). Add DIEA (0.42 mL, 2.4 mmol) and react for 1 h. Wash the resin three times with DCM (10 mL). Add blocking solution (10 mL, volume ratio DCM: MeOH: DIEA = 75:20:5) and block for 15 min. Wash the resin three times with DMF (15 mL) to obtain intermediate M1, which is directly used in the next reaction.

[0205] Step 2: Synthesis of Fmoc-Asn(Trt)-Asp(tBu)-Aib-Ile-Asn(Trt)-CTC Resin (M2)

[0206] 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 shows dark blue and is directly used in the next reaction.

[0207] Coupling: Fmoc-Ile-OH (1 g, 3 mmol, 3 eq) was dissolved in DMF (15 mL). TBTU (0.96 g, 3 mmol, 3 eq) and DIEA (1 mL, 6 mmol, 6 eq) were added to the reaction mixture under ice-cooling and stirred for 10 min. The activation solution was then added to the Fmoc-depleted resin and allowed to react for 1 h. A small amount of the resin was tested with 5% ninhydrin in ethanol (a small amount of the resin was added to 1 mL of 5% ninhydrin and heated at 110°C for 3 min). The resin was colorless. The reaction mixture was drained and washed three times with DMF (10 mL). The resulting resin was used directly in the next reaction.

[0208] The coupling cycle was repeated, and Fmoc-Aib-OH (0.97 g, 3 eq), Fmoc-Asp(OtBu)-OH (1.23 g, 3 eq), and Fmoc-Asn(Trt)-OH (1.79 g, 3 eq) were coupled in sequence according to the above procedure. The product was washed alternately with 10 mL each of DCM and MeOH three times, dried, transferred to a vacuum oven, and dried at 35°C for 2 h to obtain intermediate M2 (1.36 g), which was used directly in the next reaction.

[0209] 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)

[0210] Intermediate M2 (0.7 g, 0.5 mmol, batch number YH00047-001) was subjected to Fmoc removal and coupling in a peptide synthesis tube to obtain M3, which was used directly in the next reaction. (The order of coupling monomers is as follows:

[0211] Fmoc-PEG4-OH (0.48g, 1mmol, 2eq, CAS:557756-85-1)

[0212] Alloc-Lys(Fmoc)-OH (0.45g, 1mmol, 2eq, CAS:186350-56-1)

[0213] Fmoc-PEG2-OH (0.39g, 1mmol, 2eq, CAS:166108-71-0)

[0214] Fmoc-PEG2-OH (0.39g, 1mmol, 2eq, CAS:166108-71-0)

[0215] Fmoc-Glu(α-tBu)-OH (0.43g, 1mmol, 2eq, CAS:84793-07-7)

[0216] Palmitic acid (0.25g, 1mmol, 2eq, CAS:57-10-3)

[0217] 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)

[0218] Deprotection: To intermediate M3, DCM (10 mL), PhSiH3 (0.65 g, 6 mmol, 12 eq), and Pd(PPh3)4 (29 mg, 0.025 mmol, 5% mol) were added sequentially. The reaction was allowed to proceed for 2 h under nitrogen sparge. A small amount of the resin was tested with 5% ninhydrin in ethanol (a small amount of the resin was added to 1 mL of 5% ninhydrin and heated at 110°C for 3 min). The resin turned dark blue. The resin was drained and washed three times with DMF (15 mL) to yield intermediate M4, which was used directly in the next reaction.

[0219] 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)

[0220] 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 mixture under ice-cooling and stirred for 10 min. The activation solution was then added to the de-Alloc-protected intermediate M4 and allowed to react for 16 h. A small amount of the resin was tested with 5% ninhydrin in ethanol (a small amount of the resin was added to 1 mL of 5% ninhydrin and heated at 110°C for 3 min). The resin turned colorless. The reaction mixture was drained and washed three times with DMF (10 mL). The mixture was then washed three times with 10 mL each of DCM and MeOH, alternately washed three times. The mixture was drained, transferred to a vacuum oven, and dried at 35°C for 2 h to yield resin M5 (1.2 g).

[0221] Step 6: Synthesize TM2

[0222] To 1 g of resin, cleavage solution (12 mL, TFA:Tis:H2O volume ratio of 95:2.5:2.5) was added. The reaction was continued for 1 h, filtered, and the resin was washed with cleavage solution (1 mL). The combined filtrates were dropwise added to -5°C methyl tert-butyl ether (120 mL), allowed to settle for 1 h (refrigerated), centrifuged, and the supernatant removed. MTBE (50 mL) was added, washed, centrifuged, and the supernatant removed. This process was repeated three times to obtain a white solid. The solid was transferred to a vacuum drying oven and dried at 35°C for 2 h to obtain 540 mg of crude peptide. The purified solution was purified by HPLC. The purified solution was concentrated to remove most of the organic solvent and lyophilized to obtain 233+32 mg of 98.01% pure product TM2, with a yield of 26.8%.

[0223] MS (ESI): m / z [M+2H + ] / 2=990.6.

[0224] 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).

[0225] Example 3

[0226] Preparation of polypeptide compound TM3, the compound structure is as follows:

[0227] The preparation steps were the same as those in Example 1, and the obtained product had a mass of 232 mg and a purity of 92.25%.

[0228] Example 4

[0229] Preparation of polypeptide compound TM4, the compound structure is as follows:

[0230] The preparation steps were the same as those in Example 1, and the obtained product had a mass of 84.4 mg and a purity of 98.35%.

[0231] Example 5

[0232] Preparation of polypeptide compound TM5, the compound structure is as follows:

[0233] The preparation steps were the same as those in Example 1, and the obtained product had a mass of 63.4 mg and a purity of 95.29%.

[0234] Example 6

[0235] Preparation of polypeptide compound TM6, the compound structure is as follows:

[0236] The preparation steps were the same as those in Example 1, and the obtained product had a mass of 18.5 mg and a purity of 97.10%.

[0237] Example 7

[0238] Preparation of polypeptide compound TM7, the compound structure is as follows:

[0239] The preparation steps were the same as those in Example 1, and the obtained product had a mass of 66.6 mg and a purity of 99.77%.

[0240] Example 8

[0241] Preparation of polypeptide complex Gd-TM1, the compound structure is as follows:

[0242] 30.7 mg (0.015 mmol) of TM1 was dissolved in 2 mL of H2O. 0.25 mL of 0.5 M aqueous NaOH (8 eq) was added, and the reaction mixture was kept at a pH between 6 and 8, followed by stirring 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. Purification by preparative HPLC and lyophilization yielded 8.5 mg of the desired product, Gd-TM1, with a purity of 99.02%. Mass spectrometry analysis revealed the following results: MS (ESI): m / z (M+2H + ) / 2=1096.2,(M+3H + ) / 3=730.6.

[0243] Example 9

[0244] Preparation of polypeptide complex Ga-TM2, the compound structure is as follows:

[0245] The preparation method comprises the following steps:

[0246] TM2 (80.01 mg) was weighed and dissolved in 7 ml of purified water. The temperature was raised to 70°C, and 1 ml of an aqueous solution containing 11.22 mg of gallium nitrate was added dropwise. The mixture was stirred and the pH of the aqueous solution was adjusted to 3-5 with 1 mM sodium acetate. The reaction was allowed to proceed for 2 h. After completion of the reaction, the mixture was desalted using a reverse purification system to obtain the desired target compound, Ga-TM2 (17.12 mg), with a purity of 95.36%. The mass spectrometry results were: MS (ESI): m / z (M+2H + ) / 2=1023.0,(M+3H + ) / 3=682.3.

[0247] Example 10

[0248] Preparation of polypeptide complex Ga-TM3, the compound structure is as follows:

[0249] The preparation steps were the same as those in Example 9, and the product was obtained in a mass of 25 mg with a purity of 98.62%.

[0250] The results of mass spectrometry are: MS (ESI): (M+2H + ) / 2=1027.8,(M+3H + ) / 3=685.7.

[0251] Example 11

[0252] Preparation of polypeptide complex Gd-TM7, the compound structure is as follows:

[0253] The preparation steps were the same as those in Example 8, and the product was obtained in a mass of 4.5 mg with a purity of 98.58%.

[0254] The results of mass spectrometry are: MS (ESI): (M+2H + ) / 2=912.5,(M+3H + ) / 3=615.2.

[0255] Test Example 1 Target Affinity Test

[0256] Surface Plasmon Resonance (SPR) technology was used to test the affinity of the example compounds with the target proteins integrin α5β1, αvβ3, αvβ5, and αvβ6. The specific steps are as follows:

[0257] Recombinant integrin α5β1, αvβ3, αvβ5, and αvβ6 proteins were immobilized on a CM5 chip (Biacore). An SPR instrument (Biacore T200) was used to measure the binding constants (Ka) and dissociation constants (Kd) of the compounds with integrin α5β1, αvβ3, αvβ5, and αvβ6 at 25°C with an injection volume of 30 μL of the test solution and a flow rate of 30 μL / min. The affinity constants KD of the compounds for the target proteins integrin α5β1, αvβ3, αvβ5, and αvβ6 were calculated according to the formula KD = Kd / Ka (the lower the KD value, the higher the affinity of the example compound for 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.

[0258] The in vitro affinity data are shown in Table 1:

[0259] Table 1 KD values ​​of compounds for integrin α5β1, αvβ3, αvβ5 or αvβ6

[0260] Experimental Example 2 Radioactive compound labeling experiment

[0261] Radioactivity of compound TM1 68 Ga labeling

[0262] Add the aqueous solution of TM1 (20ug) into the prepared 68The GaCl3 solution is then adjusted to a pH of 3-5 with sodium acetate aqueous solution and acetic acid, and reacted at 70-95°C for 15 minutes. After the reaction is complete, the product is purified to obtain the labeled product. 68 Solution of Ga-TM1.

[0263] All compounds prepared by the present invention 68 The Ga labeling method was the same as above.

[0264] PET / CT experiments

[0265] 1) Evaluation of lung adenocarcinoma model

[0266] M-NSG mice inoculated with H1975 were injected with about 100 μCi of 68 Ga-TM1 and 68 PET / CT imaging was performed 1, 2, and 4 hours after the injection of Ga-TM7 solution, and the experimental data in Table 2 were obtained through image post-processing.

[0267] Table 2 PET / CT experimental results

[0268] 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 from the values ​​of various tissues over time. Judging from the slow accumulation in the tumor, its ligands TM1 and TM7 were used 68 Chelated Ga has the potential to diagnose and / or treat lung adenocarcinoma.

[0269] PCT / CT imaging images are shown in Figures 8-9.

[0270] 2) Evaluation of pancreatic cancer model

[0271] Nude mice inoculated with BxPC-3 and PANC-1 were injected with about 100 μCi of 68 PET / CT imaging was performed 1 and 4 hours after the injection of Ga-TM7 solution, and the experimental data in Table 3 were obtained through image post-processing.

[0272] Table 3 PET / CT experimental results

[0273] The above animal experiment results show that 68Ga-TM7 was significantly enriched in the tumors of nude mice inoculated with BxPC-3 and PANC-1, and the uptake value (%ID / g) of the tumor site gradually increased with time. The drug was gradually eliminated from the values ​​of various tissues over 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.

[0274] PCT / CT imaging images are shown in Figures 10-11.

[0275] 3) Comparison of MRI data

[0276] Gd-dota, Gd-TM1 (represented as 7013-001 in the figure) and Gd-TM7 (represented as 7013-002 in the figure) were dissolved in physiological saline to a concentration of 0.1 mmol / ml and filtered into a sterile EP tube using a 0.22 μm sterile filter. BALB / c nude mice with the MD-MB-231 breast cancer model were anesthetized by intraperitoneal injection of chloral hydrate (100 μL). Cross-sectional MR imaging of the mice was collected before drug injection in all experimental groups, and the acquisition time was recorded. The breast cancer model was injected with drugs at a dose of 0.1 mmol / kg through the tail vein, and the injection time was recorded. MR images (T1 signal, T2 signal) were collected 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70 minutes, 24 hours, and 48 hours after drug injection. After each MR image acquisition, the mice were kept warm. The imaging data MR image is shown in FIG12 , and the ratio of the grayscale value of the tumor to the muscle T1 signal of the MR image is shown in FIG13 .

[0277] Animal MR image data analysis: First, using Image J, we circled the grayscale values ​​of the entire tumor (T) and muscle (M) in both T1 and T2 images, excluding the tumor capsule. This was repeated three times and the average was calculated. Statistical analysis of the T1 signal within the breast cancer tumor was performed (see Figure 13 below), using the formula: tumor-to-muscle grayscale ratio = T / M. Analysis of the T1 signal ratio revealed that Gd-TM1 was optimal between 10 and 30 minutes, while both Gd-TM1 and Gd-TM7 were superior to Gd-Dota between 40 and 60 minutes. After 24 hours, the tumor-to-muscle grayscale ratios of Gd-TM1 and Gd-TM7 were higher than before injection. Both the ratios and the images indicate specific tumor uptake of Gd-TM1 and Gd-TM7.

[0278] 4) 177Lu treatment evaluation

[0279] 1. Labeling method

[0280] 1.1 Precursor aliquoting: Dissolve the precursor in pure water to a concentration of 1 mg / mL, aliquot 50 μL into each tube, and store in a freezer at -20°C.

[0281] 1.2 Sodium acetate preparation: Weigh 2.04642 g of sodium acetate and dissolve it in 50 mL of pure water. Adjust the pH to 5.5 with 37% concentrated hydrochloric acid.

[0282] 1.3 Labeling: Add 200 μL of 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 After the mixture is shaken, heat it at 95°C for 30 min and cool it to room temperature.

[0283] 1.4 Nuclide purification and quality testing

[0284] Analysis and Identification

[0285] 1.4.1 Instrument: Waters 1525 / 2489, Raytest radioactivity detector

[0286] 1.4.2 Flow rate: 1 mL / min

[0287] 1.4.3 Column temperature: room temperature

[0288] 1.4.4 Elution procedure

[0289] Table 4

[0290] 1.4.5 The test results are as follows

[0291] 177 Lu-TM1 (abbreviated as 177Lu-057) has a radioactivity purity of 100% (as shown in Figure 14 ) and its structural formula is as follows:

[0292] 177 Lu-TM7 (abbreviated as 177Lu-071) has a radioactivity purity of 100% (as shown in Figure 15 ) and its structural formula is as follows:

[0293] 2. 177 SPECT / CT study of mice with Lu-057 / 071 tumors

[0294] 2.1 Tumor mouse model: M-NSG mice inoculated with H1975

[0295] 2.2 Mouse condition: good

[0296] 2.3 Test substance preparation: When administering to animals, dilute the test substance to 5 mCi / mL with sodium chloride injection.

[0297] 2.4 Experimental Grouping:

[0298] Table 5

[0299] 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 the tumor-bearing mice, and the injection time, dose and measurement time were recorded. 177 SPECT / CT scans were performed 1 h, 4 h, 24 h, 48 h, 72 h, and 96 h after Lu-057 / 071. One frame of image was acquired every 20 s at the 1-4 h time point, every 35 s at the 24-48 h time point, and every 50 s at the 72-96 h time point. During the scan, the animals continued to inhale isoflurane to maintain the anesthesia effect.

[0300] 3. SPECT / CT imaging

[0301] Figure 16 shows two M-NSG mice inoculated with H1975 and injected with 37MBq of 177 Lu-057 was imaged within 96 hours, and specific uptake was clearly observed in the tumor. As time went on, other tissues that had taken up the drug were gradually cleared through the kidneys.

[0302] Figure 17 shows two M-NSG mice inoculated with H1975 and injected with 37MBq of 177 Lu-071 imaging within 96 hours clearly shows specific uptake in the tumor, with other tissues gradually cleared through the kidneys over time. Since the M1 mouse died after 48 hours of imaging, corresponding data were not obtained at 72 and 96 hours.

[0303] 4. Quantitative SPECT / CT imaging

[0304] For SPECT / CT imaging, 1% of the injected dose was retained in each mouse at the time of dosing. This 1% of the injected dose was then used together with the mouse for SPECT / CT imaging quantification. Total uptake in each tissue was determined using this semi-quantitative method. The corresponding uptake is shown in Tables 6-7 below. The % ID total for each tissue was highest 4 hours after dosing. Rapid clearance was observed in the heart, liver, muscle, lung, brain, and intestines 4 hours later, while the clearance rate for tumors was much lower than that for normal tissues, indicating tumor-specific uptake.

[0305] The uptake values ​​of the tumor portion were calculated by measuring the tumor volume, as shown in Figures 18 and 19. In Figures 18 and 19, the left side of each bar graph is M1 and the right side is M2.

[0306] Table 6

[0307] Table 7

[0308] 5. Efficacy evaluation

[0309] 177 Lu-057 and 177 Pharmacodynamic Study on Lu-071 Tumor-bearing Mice

[0310] 5.1 Tumor mouse model: M-NSG mice inoculated with H1975

[0311] 5.2 Mouse condition: good

[0312] 5.3 Test substance preparation: When administering to animals, dilute the test substance to 5 mCi / mL with sodium chloride injection (1 mCi / ml per mouse).

[0313] 5.4 Experimental Grouping:

[0314] Table 8

[0315] 5.5 Tumor Data Monitoring

[0316] The tumor volume monitoring of the drug-treated group and the normal saline group showed that the drug-treated group significantly inhibited tumor growth. The relevant detailed data are shown in Table 9 below.

[0317] Table 9

[0318] Representative data of TM1 and TM7 The above data fully demonstrate that its chelated 68Ga, Gd and 177Lu can be used for the diagnosis and treatment of lung adenocarcinoma and pancreatic cancer models.

[0319] 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. The data showed that there was specific uptake at the tumor site, and the uptake value was increasing at 4 hours. Gd-TM1 and Gd-TM7 compounds were subjected to MR imaging in breast cancer model mice. The imaging data showed that the compounds were specifically enriched at the tumor site and the data was better than Gd-DOTA, and the tumor was significantly taken up and enriched at 48 hours. 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 that receive radioactivity or their isotopes such as 177Lu, 64Cu, 68Ga, 111In, Al18F, 211At, 225Ac, 90Y, 213Bi.

[0320] The results of PET / CT and MR imaging animal experiments show 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, radionuclides, etc. to tumor cells.

[0321] The results of in vitro enzymology 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.

[0322] 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 above embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the above 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 derivatives 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 alkyl, ester, sulfonyl, alkylsulfonyl, halogenated alkylsulfonyl, sulfonic acid, sulfonamide, phosphoric acid, phosphate ester, unsubstituted aromatic, aromatic heterocyclic, monocyclic heterocyclic, N, O, SH, SeH, hydrogen, carboxyl, methyl thio (or seleno) ether, ethyl thio (or seleno) ether, -SOMe, -SO2Me, -CONH2, -COOMe, -COOEt, -NHOCH, -NHOCCH3, -NHSO2Me, p-toluenesulfonamide, sulfonic acid ester; q is 1 or 2; R" is a C1-C6 alkyl; 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), haloalkylthio (or seleno), thiol (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, haloalkylsulfonyl, 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 groups formed with the carbon end of Asp amino acid, amine derivative groups Biogroup, 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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