Fibroblast activating protein ligand and application thereof

Abstract

The invention relates to a fibroblast activating protein ligand and application thereof, in particular to a compound shown in a formula (I) or pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound, and application of the compound or the pharmaceutically acceptable salt in diagnosis or treatment of diseases related to fibroblast activating protein, such as tumors or cancers.

Description

A fibroblast activation protein ligand and its use Technical Field

[0001] The present disclosure relates to a fibroblast activation protein ligand and uses thereof, and belongs to the field of pharmaceuticals. Background Art

[0002] In recent years, the tumor microenvironment (TME) has garnered significant interest as a therapeutic target for cancer treatment. The TME can encompass a significant portion of the tumor: for example, in pancreatic ductal carcinoma, it has been reported to comprise up to 80% of the tumor mass. Cancer-associated fibroblasts (CAFs) are a component of the TME and are abundantly present in the stroma of tumors such as breast and colon cancer. Fibroblast activation protein (FAP), a type II transmembrane serine protease, serves as a marker for tumor-associated fibroblasts. FAP is absent or expressed at low levels in normal tissues but is highly expressed in over 90% of epithelial tumors, such as breast, colorectal, lung, ovarian, and pancreatic cancers. Because FAP expression is limited in normal tissues, it has been identified as a potential pan-tumor target for cancer treatment. In mesenchymal cancer indications, particularly sarcomas and mesotheliomas, FAP is expressed on tumor cells in addition to CAFs. FAP expression is also observed in chronic inflammatory diseases such as rheumatoid arthritis and osteoarthritis, as well as in cardiac remodeling after myocardial infarction.

[0003] The first approach to targeting FAP as a cancer therapy was the application of the monoclonal antibody sibrozumab, which was tested in both unconjugated and 131I-conjugated forms against colorectal cancer. Other approaches targeting FAP, including bispecific antibodies or antibody fragment constructs, chimeric antigen receptor T cells, and antibody-drug conjugates, are currently under investigation, most of which are in preclinical development or phase 1 clinical trials. Small molecule FAP inhibitors (FAPIs) have also been discovered and conjugated to radioactivity to create excellent imaging agents for various cancer indications (J Nucl Med 2022;63:415–423).

[0004] FAP-2286, a peptide that potently and selectively binds to FAP and is linked to DOTA via a linker, is currently in the clinical stage. The development of more FAP inhibitors holds great promise for future applications.

[0005] Summary of the Invention

[0006] The present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0007] Among them, the R 1a 、R 1b are each independently selected from hydrogen or methyl;

[0008] The v is selected from 0 or 1;

[0009] The G1 is selected from -(CO)-LR 1c , wherein L is selected from C 3-20 Alkylene, the R 1c Selected from methyl or -NH-(C=NH)-NR 1d R 1f , the R 1d 、R 1f Each independently selected from hydrogen or methyl; or said G1 is selected from The u is selected from an integer from 1 to 5;

[0010] The R 2a 、R 2b 、R 2c are each independently selected from hydrogen or C 1-3 alkyl;

[0011] The R 3a 、R 3b are each independently selected from hydrogen, C 1-3 Alkyl, or R 3a 、R 3b Together with the atoms to which they are attached, they form a 5- to 6-membered nitrogen-containing heterocyclic alkyl group, wherein the C 1-3 Alkyl or 5 to 6 membered nitrogen-containing heterocyclic alkyl optionally substituted by 1, 2 or 3 R A Substituted, the R A the same or different, selected from hydroxy, amino, halogen, C 1-3 Alkyl or halogenated C 1-3 alkyl;

[0012] The R 4a 、R 4b 、R 4c 、R 4d Each independently selected from hydrogen, hydroxy, amino, halogen, C 1-3 Alkyl or halogenated C 1-3 alkyl;

[0013] The R 5a is selected from hydrogen or methyl;

[0014] The R 5b Selected from C 1-6 alkyl, 6 to 10-membered aryl or 5 to 6-membered heteroaryl, the C 1-6 Alkyl, 6 to 10 membered aryl or 5 to 6 membered heteroaryl are optionally substituted by 1 or 2 R B Substituted, the R B the same or different, selected from hydroxy, amino, halogen, -CONH2;

[0015] The m is selected from 1, 2 or 3; the hydrogen on CH2 is optionally replaced by one or more selected from hydroxyl, halogen, C 1- 3-membered alkyl, 6- to 10-membered aryl, or 5- to 6-membered heteroaryl substituted (i.e. wherein m is selected from 1, 2 or 3, and the hydrogen on CH2 is optionally replaced by one or more selected from hydroxyl, halogen, C1 -3 alkyl, 6- to 10-membered aryl, or 5- to 6-membered heteroaryl);

[0016] The R 6a Selected from hydroxyl or amino;

[0017] Said n is selected from 1, 2 or 3;

[0018] The R 7a 、R 7b are each independently selected from hydrogen, C 1-3 alkyl;

[0019] Said q is selected from 0 or 1;

[0020] The ring A is selected from phenyl, pyridyl, naphthyl or thienyl;

[0021] The R 7c Each independently selected from halogen, nitro, amino, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, trifluoromethyl, difluoromethyl, trifluoroethyl;

[0022] Said p is selected from 0, 1, 2 or 3;

[0023] The R 8a 、R 8b Each independently selected from hydrogen, -COOH, -CONH2, CH2-OH, -CONHR 8c 、-(CO)-(NR 8c )-R 8d , the R 8c 、R 8d Each place is independently selected from C 1-6 alkyl;

[0024] Said r is selected from 0 or 1;

[0025] The s is selected from 0 or 1;

[0026] The X is selected from O, S or NR 9 , the R 9 Selected from hydrogen or C 1-6 alkyl;

[0027] The t is selected from 1, 2, 3, 4, 5 or 6;

[0028] The R 10 Selected from hydrogen or C 1-6 alkyl;

[0029] The Y is a chelating agent or hydrogen, and the chelating agent optionally complexes nuclides.

[0030] In an optional embodiment, Y is a chelating agent, which optionally complexes nuclides.

[0031] In an alternative embodiment, said Y is hydrogen.

[0032] In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,

[0033] The R 1a 、R 1b ,v,G1,R 2a 、R 2b 、R 2c 、R 3a 、R 3b 、R 4a 、R 4b 、R 4c 、R 4d , R5a, R 5b ,m,R 6a 、n、R 7a 、R 7b ,q,ring A,R 7c ,p,R 8a 、R 8b ,r,s,X,t,R 10 , Y are as defined in formula (I).

[0034] In an optional embodiment, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, or the compound of formula (II) or a pharmaceutically acceptable salt thereof provided by the present disclosure, the R 2a is hydrogen or methyl, R 2b 、R 2c are each independently selected from hydrogen or methyl; optionally, the R 2b is hydrogen, the R 2c is methyl, or the R 2b 、R 2c All are methyl.

[0035] In an optional embodiment, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, or the compound of formula (II) or a pharmaceutically acceptable salt thereof provided by the present disclosure, the R 4a 、R 4b Each independently selected from hydrogen, hydroxyl; optionally, the R 4a is hydrogen, the R4b It is a hydroxyl group.

[0036] In an optional embodiment, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, or the compound of formula (II) or a pharmaceutically acceptable salt thereof provided by the present disclosure, the R 2a is hydrogen or methyl; said R 2b 、R 2c are each independently selected from hydrogen or methyl, and at least one is methyl; the R 4a is hydrogen, the R 4b is a hydroxyl group; the R 4c 、R 4d are each independently selected from hydrogen.

[0037] In an optional embodiment, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, or the compound of formula (II) or a pharmaceutically acceptable salt thereof provided by the present disclosure, the R 3a 、R 3b are each independently selected from hydrogen, C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R A Substituted, the R A the same or different, selected from hydroxy, amino, halogen, C 1-3 Alkyl or halogenated C 1-3 alkyl.

[0038] In an optional embodiment, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, or the compound of formula (II) or a pharmaceutically acceptable salt thereof provided by the present disclosure, the R 3a is methyl, the R 3b For hydrogen.

[0039] In an optional embodiment, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, or the compound of formula (II) or a pharmaceutically acceptable salt thereof provided by the present disclosure, the R 3a 、R 3b Together with the atoms to which they are attached, they form a 5-membered nitrogen-containing heterocycloalkyl group, which is optionally substituted by 1, 2 or 3 R A Substituted, the R A the same or different, selected from hydroxy, amino, halogen, C 1-3 Alkyl or halogenated C 1-3 alkyl.

[0040] In an optional embodiment, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, or the compound of formula (II) or a pharmaceutically acceptable salt thereof provided by the present disclosure, the R 3a 、R 3b Together with the atoms to which they are attached, they form a 5-membered nitrogen-containing heterocycloalkyl group, which is not substituted.

[0041] In an optional embodiment, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, or the compound of formula (II) or a pharmaceutically acceptable salt thereof provided by the present disclosure, the R 7a 、R 7b are each independently selected from hydrogen, C 1-3 alkyl;

[0042] Said q is selected from 0 or 1;

[0043] The ring A is selected from phenyl or naphthyl;

[0044] The R 7c Each independently selected from halogen, nitro, amino, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, trifluoromethyl, difluoromethyl, trifluoroethyl;

[0045] The p is selected from 0, 1, 2 or 3.

[0046] In an optional embodiment, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, or the compound of formula (II) or a pharmaceutically acceptable salt thereof provided by the present disclosure, the R 7a 、R 7b are each independently selected from hydrogen;

[0047] The q is 0;

[0048] The ring A is a phenyl group;

[0049] The R 7c Each independently selected from fluorine, chlorine, bromine, iodine or trifluoromethyl, difluoromethyl, trifluoroethyl;

[0050] The p is selected from 0, 1 or 2.

[0051] In an optional embodiment, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, or the compound of formula (II) or a pharmaceutically acceptable salt thereof provided by the present disclosure, the R 1a 、R 1b are each independently selected from hydrogen or methyl;

[0052] The v is selected from 0 or 1;

[0053] The G1 is selected from -(CO)-LR 1c , wherein L is selected from C 3-20 Alkylene, the R 1c Selected from methyl.

[0054] In an optional embodiment, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, or the compound of formula (II) or a pharmaceutically acceptable salt thereof provided by the present disclosure, the R 1a、R 1b are each independently selected from hydrogen;

[0055] The v is selected from 0;

[0056] The G1 is selected from -(CO)-LR 1c , wherein L is selected from C 4-14 Alkylene, the R 1c selected from methyl;

[0057] In an optional embodiment, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, or the compound of formula (II) or a pharmaceutically acceptable salt thereof provided by the present disclosure, the R 1a 、R 1b are each independently selected from hydrogen or methyl;

[0058] The v is selected from 0 or 1;

[0059] The G1 is selected from -(CO)-LR 1c , wherein L is selected from C 3-20 Alkylene, the R 1c Selected from -NH-(C=NH)-NR 1d R 1f Right now The R 1d 、R 1f are each independently selected from hydrogen or methyl.

[0060] In an optional embodiment, the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,

[0061] The R 1a 、R 1b are each independently selected from hydrogen;

[0062] The v is selected from 0;

[0063] The G1 is selected from -(CO)-LR 1c , wherein L is selected from C 4-14 Alkylene, the R 1c Selected from -NH(C=NH)-NR 1d R 1f , the R 1d 、R 1f are each independently selected from hydrogen or methyl.

[0064] In an optional embodiment, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, or the compound of formula (II) or a pharmaceutically acceptable salt thereof provided by the present disclosure, the R 1a 、R 1b are each independently selected from hydrogen or methyl;

[0065] The v is selected from 0 or 1;

[0066] The G1 is selected from The u is selected from integers of 1 to 5.

[0067] In an optional embodiment, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, or the compound of formula (II) or a pharmaceutically acceptable salt thereof provided by the present disclosure, the R 1a 、R 1b are each independently selected from hydrogen;

[0068] The v is selected from 0;

[0069] The G1 is selected from

[0070] The u is selected from 1 or 2.

[0071] In an optional embodiment, the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,

[0072] The R 5a selected from hydrogen;

[0073] The R 5b Selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with 1 or 2 R B Substituted, the R B the same or different, selected from hydroxyl or halogen;

[0074] The m is selected from 0 or 1; the hydrogen on CH2 is optionally replaced by one or more selected from hydroxyl, halogen, hydroxyl, C 1-3 Alkyl substitution;

[0075] The n is 2;

[0076] The R 6a It is amino;

[0077] The R 8a 、R 8b Each is independently selected from hydrogen, -COOH, and -CONH2, and at least one is -COOH or -CONH2, and r is 1.

[0078] In an optional embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound of formula (II) or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound of formula (III) or a pharmaceutically acceptable salt thereof,

[0079] The R 2a is hydrogen or methyl;

[0080] The R 2b 、R 2c are each independently selected from hydrogen or methyl, and at least one is methyl;

[0081] The R 3a 、R 3b are each independently selected from hydrogen, C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R A Substituted, the R A the same or different, selected from hydroxy, amino, halogen, C 1-3 Alkyl or halogenated C 1-3 Alkyl; or said R 3a 、R 3b Together with the atoms to which they are attached, they form a 5-membered nitrogen-containing heterocycloalkyl group, which is optionally substituted by 1, 2 or 3 R A Substituted, the R A the same or different, selected from hydroxy, amino, halogen, C 1-3 Alkyl or halogenated C 1-3 alkyl;

[0082] The R 4a is hydrogen, fluorine or trifluoromethyl, said R 4b For fluorine, hydroxyl;

[0083] The R 4c 、R 4d are each independently selected from hydrogen;

[0084] The R 7c Each independently selected from fluorine, chlorine, bromine, iodine or trifluoromethyl, difluoromethyl, trifluoroethyl;

[0085] Said p is selected from 0, 1 or 2;

[0086] G1, s, X, t, R 10 , Y are as defined in formula (I).

[0087] In an optional embodiment, in the compound of formula (III) or a pharmaceutically acceptable salt thereof provided by the present disclosure, the R 4a is hydrogen, the R 4b It is a hydroxyl group.

[0088] In an optional embodiment, in the compound of formula (III) or a pharmaceutically acceptable salt thereof provided by the present disclosure, the R 3a is hydrogen, the R 3b It is a methyl group.

[0089] In an optional embodiment, in the compound of formula (III) or a pharmaceutically acceptable salt thereof provided by the present disclosure, the R 3a、R 3b Together with the atoms to which they are attached, they form a 5-membered nitrogen-containing heterocycloalkyl group, which is not substituted.

[0090] In an optional embodiment, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, a compound of formula (II) or a pharmaceutically acceptable salt thereof, or a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein s is 1; X is S; R 10 For hydrogen.

[0091] In an optional embodiment, in the compound of formula (III) or a pharmaceutically acceptable salt thereof provided by the present disclosure, the G1 is selected from -(CO)-LR 1c , wherein L is selected from C 4-14 Alkylene, the R 1c is selected from methyl, and the L can be selected from C4 alkylene, C6 alkylene, C8 alkylene, C 10 Alkylene, C 12 Alkylene or C 14 Alkylene.

[0092] In an optional embodiment, in the compound of formula (III) or a pharmaceutically acceptable salt thereof provided by the present disclosure, the G1 is selected from -(CO)-LR 1c , wherein L is selected from -(CO)-LR 1c , wherein L is selected from C 4-14 Alkylene, the R 1c Selected from -NH-(C=NH)-NR 1d R 1f , the R 1d 、R 1f Each is independently selected from hydrogen or methyl, and the L can be, for example, C4 alkylene, C5 alkylene or C6 alkylene.

[0093] In an optional embodiment, in the compound of formula (III) or a pharmaceutically acceptable salt thereof provided by the present disclosure, the G1 is selected from The u is selected from 1 or 2.

[0094] The present disclosure provides compounds, wherein the fragment connected to Y specifically refers to:

[0095] Corresponding fragments, selected from:

[0096] Group 1:

[0097] Group 2:

[0098] Group 3:

[0099] The present disclosure provides compounds, wherein the fragment connected to Y specifically refers to:

[0100] Corresponding fragments, selected from:

[0101] Group 1'

[0102] Group 2':

[0103] Group 3':

[0104] The chelating agent in the present disclosure is selected from DOTA, DOTAGA, NOTA, NODAGA, NODA-MPAA, HBED, TETA, CB-TE2A, DTPA, DFO, Macropa, HOPO, TRAP, THP, DATA, NOTP, sarcophagine, FSC, NETA, H4octapa, Pycup, NxS4-x(N4, N2S2, N3S), Hynic, 99mTc(CO)3-chelating agent.

[0105] In an alternative embodiment, the chelating agent is selected from

[0106] In some embodiments, the chelating agent is selected from DOTA, DOTAGA, NOTA, NODAGA, NODA-MPAA, HBED, CB-TE2A, DFO, THP, N4.

[0107] In some embodiments, the chelating agent is selected from the group consisting of DOTA, DOTAGA, NOTA, and NODAGA.

[0108] The present disclosure provides the following compounds or pharmaceutically acceptable salts thereof, which are selected from:

[0109] Group 4:

[0110] Hex-[Cys-(tMeBn(DOTA-AET))-Ala-Pro-(4-OH-Pro)-Thr-Gln-Phe-Cys]-OH,

[0111] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-Pro-Thr-Gln-Phe-Cys]-OH、

[0112] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Sar-(4-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0113] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0114] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、

[0115] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(3-F-Phe)-Cys]-OH、

[0116] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(4-F-Phe)-Cys]-OH、

[0117] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(2-Cl-Phe)-Cys]-OH、

[0118] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(3-Cl-Phe)-Cys]-OH、

[0119] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(4-Cl-Phe)-Cys]-OH、

[0120] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、

[0121] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(3-CF3-Phe)-Cys]-OH、

[0122] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(4-CF3-Phe)-Cys]-OH、

[0123] Oct-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0124] Dec-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0125] Dod-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0126] Tet-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0127] Pal-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0128] {2-[2-(2-Methoxyethoxy)ethoxy]-Ace}-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0129] [2-(2-Methoxyethoxy)-Ace]-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0130] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-F-Pro)-Thr-Gln-Phe-Cys]-OH、

[0131] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-F-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、

[0132] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-F-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、

[0133] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-(4-OH-Pro)-(4-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0134] (5-guanidineValy)-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0135] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(2-Nal)-Cys]-OH、

[0136] Hex-[Cys-(tMeBn(DOTA-AET))-Ala-Pro-Pro-Thr-Gln-Phe-Cys]-OH、

[0137] Hex-[Cys-(tMeBn(DOTA-AET))-Ala-Pro-Pro-Thr-Gln-(2-F-Phe)-Cys]-OH、

[0138] Hex-[Cys-(tMeBn(DOTA-AET))-Ala-Pro-Pro-Thr-Gln-(2-CF3-Phe)-Cys]-OH、

[0139] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Sar-(4-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0140] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0141] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、

[0142] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(3-F-Phe)-Cys]-OH、

[0143] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(4-F-Phe)-Cys]-OH、

[0144] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(2-Cl-Phe)-Cys]-OH、

[0145] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(3-Cl-Phe)-Cys]-OH、

[0146] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(4-Cl-Phe)-Cys]-OH、

[0147] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH,

[0148] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(3-CF3-Phe)-Cys]- OH,

[0149] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(4-CF3-Phe)-Cys]-OH,

[0150] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-(4-F-Pro)-Thr-Gln-Phe-Cys]-OH,

[0151] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-(4-F-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH,

[0152] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-(4-F-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH,

[0153] Hex-[Cys-(tMeBn(NOTA-AET))-Ala-Pro-Pro-Thr-Gln-(2-F-Phe)-Cys]-OH,

[0154] Hex-[Cys-(tMeBn(NOTA-AET))-Ala-Pro-Pro-Thr-Gln-(2-CF3-Phe)-Cys]-OH;

[0155] Group 5:

[0156] Hex-[Cys-(tMeBn(DOTA-AET))-Ala-Pro-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH,

[0157] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Sar-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0158] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0159] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、

[0160] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(3-F-Phe)-Cys]-OH、

[0161] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(4-F-Phe)-Cys]-OH、

[0162] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-Cl-Phe)-Cys]-OH、

[0163] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(3-Cl-Phe)-Cys]-OH、

[0164] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(4-Cl-Phe)-Cys]-OH、

[0165] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、

[0166] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(3-CF3-Phe)-Cys]-OH、

[0167] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(4-CF3-Phe)-Cys]-OH、

[0168] Oct-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0169] Dec-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0170] Dod-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0171] Tet-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0172] Pal-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0173] {2-[2-(2-Methoxyethoxy)ethoxy]-Ace}-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0174] [2-(2-Methoxyethoxy)-Ace]-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0175] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-Phe-Cys]-OH、

[0176] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、

[0177] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、

[0178] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-((4R)-OH-Pro)-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0179] (5-guanidineValy)-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0180] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-Nal)-Cys]-OH、

[0181] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Sar-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0182] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0183] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、

[0184] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(3-F-Phe)-Cys]-OH、

[0185] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(4-F-Phe)-Cys]-OH、

[0186] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-Cl-Phe)-Cys]-OH、

[0187] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(3-Cl-Phe)-Cys]-OH、

[0188] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(4-Cl-Phe)-Cys]-OH、

[0189] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、

[0190] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(3-CF3-Phe)-Cys]-OH、

[0191] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(4-CF3-Phe)-Cys]-OH,

[0192] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-Phe-Cys]-OH,

[0193] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH,

[0194] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-(xCF3-Phe)-Cys]-OH;

[0195] and Group 6:

[0196] Hex-[Cys-(tMeBn(DOTA-AET))-Ala-Pro-((4S)-OH-Pro)-Thr-Gln-Phe-Cys]-OH,

[0197] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Sar-((4S)-OH-Pro)-Thr-Gln-Phe-Cys]-OH,

[0198] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-Phe-Cys]-OH,

[0199] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH,

[0200] Note: There seems to be a typo in the original text where "xCF3" is likely a mistake, and I've translated it as "2-F" in the translation following the pattern of the text. If this is not correct, please provide the correct information.Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(3-F-Phe)-Cys]-OH、

[0201] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(4-F-Phe)-Cys]-OH、

[0202] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(2-Cl-Phe)-Cys]-OH、

[0203] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(3-Cl-Phe)-Cys]-OH、

[0204] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(4-Cl-Phe)-Cys]-OH、

[0205] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、

[0206] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(3-CF3-Phe)-Cys]-OH、

[0207] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(4-CF3-Phe)-Cys]-OH、

[0208] Oct-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0209] Dec-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0210] Dod-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0211] Tet-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0212] Pal-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0213] {2-[2-(2-Methoxyethoxy)ethoxy]-Ace}-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0214] [2-(2-Methoxyethoxy)-Ace]-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0215] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-F-Pro)-Thr-Gln-Phe-Cys]-OH、

[0216] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-F-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、

[0217] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-F-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、

[0218] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-((4R)-OH-Pro)-((4S)-OH-Pro)-Thr-Gln-Phe-

[0219] Cys]-OH、

[0220] (5-guanidineValy)-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0221] Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(2-Nal)-Cys]-OH、

[0222] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Sar-((4S)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0223] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0224] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、

[0225] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(3-F-Phe)-Cys]-OH、

[0226] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(4-F-Phe)-Cys]-OH、

[0227] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(2-Cl-Phe)-Cys]- OH、

[0228] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(3-Cl-Phe)-Cys]-OH、

[0229] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(4-Cl-Phe)-Cys]-OH、

[0230] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、

[0231] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(3-CF3-Phe)-Cys]- OH、

[0232] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(4-CF3-Phe)-Cys]-OH、

[0233] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4S)-F-Pro)-Thr-Gln-Phe-Cys]-OH、

[0234] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4S)-F-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、

[0235] Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4S)-F-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH.

[0236] In the compound or pharmaceutically acceptable salt thereof provided by the present disclosure, the chelating agent complexes the nuclide, the nuclide is a diagnostically active nuclide, and the diagnostically active nuclide is selected from 43 Sc, 44 Sc, 51 Mn, 52 Mn, 64 Cu, 67 Ga, 68 Ga, 86 Y. 89 Zr, 94m Tc, 99m Tc, 111 In, 152 Tb, 155 Tb, 201 Tl, 203 Pb, 18 F. 76 Br, 77 Br, 123 I. 124 I. 125 I.

[0237] In some embodiments, the diagnostically active nuclide is selected from 43 Sc, 44 Sc, 64 Cu, 67 Ga, 68 Ga, 86 Y. 89 Zr, 99m Tc, 111 In, 152 Tb, 155 Tb, 203 Pb, 18 F. 76 Br, 77 Br, 123 I. 124 I. 125 I.

[0238] In some embodiments, the diagnostically active nuclide is selected from 64 Cu, 68 Ga, 89 Zr, 99m Tc, 111 In, 18F. 123 I and 124 I.

[0239] In the compound or pharmaceutically acceptable salt thereof provided by the present disclosure, the chelating agent complexes the nuclide, and the nuclide is a therapeutically active nuclide selected from 47 Sc, 67 Cu, 89 Sr. 90 Y. 153 Sm, 149 Tb, 161 Tb, 177 Lu, 186 Re、 188 Re、 212 Pb, 213 Bi, 223 Ra, 225 Ac, 226 Th, 227 Th, 131 I. 211 A.

[0240] In an optional embodiment, the therapeutically active radionuclide is selected from 47 Sc, 67 Cu, 90 Y. 177 Lu, 188 Re、 212 Pb, 213 Bi, 225 Ac, 227 Th, 131 I. 211 At.

[0241] In an optional embodiment, the therapeutically active radionuclide is selected from 90 Y. 177 Lu, 225 Ac, 227 Th, 131 I and 211 At.

[0242] The present disclosure provides the following compounds or pharmaceutically acceptable salts thereof,

[0243] Hex-[Cys-(tMeBn( 68 Ga-DOTA-AET))-Aib-Sar-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH,

[0244] Hex-[Cys-(tMeBn( 68Ga-DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0245] Hex-[Cys-(tMeBn( 68 Ga-DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、

[0246] Hex-[Cys-(tMeBn( 68 Ga-DOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-Phe-Cys]-OH、

[0247] Hex-[Cys-(tMeBn( 68 Ga-DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、

[0248] Hex-[Cys-(tMeBn( 68 Ga-DOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-(2-F-Phe)- Cys]-OH、

[0249] Hex-[Cys-(tMeBn( 68 Ga-DOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、

[0250] Hex-[Cys-(tMeBn( 68 Ga-DOTA-AET))-Ala-Pro-Pro-Thr-Gln-(2-F-Phe)-Cys]-OH、

[0251] Hex-[Cys-(tMeBn( 68 Ga-DOTA-AET))-Ala-Pro-Pro-Thr-Gln-(2-CF3-Phe)-Cys]-OH、

[0252] Hex-[Cys-(tMeBn( 177 Lu-DOTA-AET))-Aib-Sar-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]- OH、

[0253] Hex-[Cys-(tMeBn( 177 Lu-DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0254] Hex-[Cys-(tMeBn( 177 Lu-DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、

[0255] Hex-[Cys-(tMeBn( 177 Lu-DOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-Phe-Cys]-OH、

[0256] Hex-[Cys-(tMeBn( 177 Lu-DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、

[0257] Hex-[Cys-(tMeBn( 177 Lu-DOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、

[0258] Hex-[Cys-(tMeBn( 177 Lu-DOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、

[0259] Hex-[Cys-(tMeBn( 177 Lu-DOTA-AET))-Ala-Pro-Pro-Thr-Gln-(2-F-Phe)-Cys]-OH、

[0260] Hex-[Cys-(tMeBn( 177 Lu-DOTA-AET))-Ala-Pro-Pro-Thr-Gln-(2-CF3-Phe)-Cys]-OH、

[0261] Hex-[Cys-(tMeBn( 64 Cu-DOTA-AET))-Aib-Sar-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0262] Hex-[Cys-(tMeBn( 64 Cu-DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0263] Hex-[Cys-(tMeBn( 64 Cu-DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH

[0264] Hex-[Cys-(tMeBn( 64 Cu-DOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-Phe-Cys]-OH、

[0265] Hex-[Cys-(tMeBn( 64 Cu-DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、

[0266] Hex-[Cys-(tMeBn( 64 Cu-DOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、

[0267] Hex-[Cys-(tMeBn( 64Cu-DOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、

[0268] Hex-[Cys-(tMeBn( 64 Cu-DOTA-AET))-Ala-Pro-Pro-Thr-Gln-(2-F-Phe)-Cys]-OH、

[0269] Hex-[Cys-(tMeBn( 64 Cu-DOTA-AET))-Ala-Pro-Pro-Thr-Gln-(2-CF3-Phe)-Cys]-OH、

[0270] Hex-[Cys-(tMeBn( 64 Cu-DOTA-AET))-Aib-Sar-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0271] Hex-[Cys-(tMeBn( 64 Cu-DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0272] Hex-[Cys-(tMeBn( 64 Cu-DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH

[0273] Hex-[Cys-(tMeBn( 64 Cu-DOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-Phe-Cys]-OH、

[0274] Hex-[Cys-(tMeBn( 64 Cu-DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、

[0275] Hex-[Cys-(tMeBn(64 Cu-DOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、

[0276] Hex-[Cys-(tMeBn( 64 Cu-DOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、

[0277] Hex-[Cys-(tMeBn( 64 Cu-DOTA-AET))-Ala-Pro-Pro-Thr-Gln-(2-F-Phe)-Cys]-OH、

[0278] Hex-[Cys-(tMeBn( 64 Cu-DOTA-AET))-Ala-Pro-Pro-Thr-Gln-(2-CF3-Phe)-Cys]-OH、

[0279] Hex-[Cys-(tMeBn(Al 18 F-NOTA-AET))-Aib-Sar-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0280] Hex-[Cys-(tMeBn(Al 18 F-NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0281] Hex-[Cys-(tMeBn(Al 18 F-NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、

[0282] Hex-[Cys-(tMeBn(Al 18 F-NOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-Phe-Cys]-OH、

[0283] Hex-[Cys-(tMeBn(Al 18 F-NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、

[0284] Hex-[Cys-(tMeBn(Al 18 F-NOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、

[0285] Hex-[Cys-(tMeBn(Al 18 F-NOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、

[0286] Hex-[Cys-(tMeBn(Al 18 F-NOTA-AET))-Ala-Pro-Pro-Thr-Gln-(2-F-Phe)-Cys]-OH、

[0287] Hex-[Cys-(tMeBn(Al 18 F-NOTA-AET))-Ala-Pro-Pro-Thr-Gln-(2-CF3-Phe)-Cys]-OH、

[0288] Hex-[Cys-(tMeBn( 68 Ga-NOTA-AET))-Aib-Sar-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0289] Hex-[Cys-(tMeBn( 68 Ga-NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0290] Hex-[Cys-(tMeBn( 68 Ga-NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、

[0291] Hex-[Cys-(tMeBn( 68 Ga-NOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-Phe-Cys]-OH、

[0292] Hex-[Cys-(tMeBn( 68 Ga-NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、

[0293] Hex-[Cys-(tMeBn( 68 Ga-NOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、

[0294] Hex-[Cys-(tMeBn( 68 Ga-NOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、

[0295] Hex-[Cys-(tMeBn( 68 Ga-NOTA-AET))-Ala-Pro-Pro-Thr-Gln-(2-F-Phe)-Cys]-OH、

[0296] Hex-[Cys-(tMeBn( 68 Ga-NOTA-AET))-Ala-Pro-Pro-Thr-Gln-(2-CF3-Phe)-Cys]-OH、

[0297] Hex-[Cys-(tMeBn( 64 Cu-NOTA-AET))-Aib-Sar-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0298] Hex-[Cys-(tMeBn( 64 Cu-NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、

[0299] Hex-[Cys-(tMeBn( 64 Cu-NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH

[0300] Hex-[Cys-(tMeBn( 64 Cu-NOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-Phe-Cys]-OH,

[0301] Hex-[Cys-(tMeBn( 64 Cu-NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH,

[0302] Hex-[Cys-(tMeBn( 64 Cu-NOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH,

[0303] Hex-[Cys-(tMeBn( 64 Cu-NOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH,

[0304] Hex-[Cys-(tMeBn( 64 Cu-NOTA-AET))-Ala-Pro-Pro-Thr-Gln-(2-F-Phe)-Cys]-OH,

[0305] Hex-[Cys-(tMeBn( 64 Cu-NOTA-AET))-Ala-Pro-Pro-Thr-Gln-(2-CF3-Phe)-Cys]-OH.

[0306] The aforementioned compounds provided by the present disclosure can be used as medicines.

[0307] Another aspect of the present disclosure provides a pharmaceutical composition comprising the aforementioned compound or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents, and excipients.

[0308] Another aspect of the present disclosure provides a method for preparing the aforementioned compound or its pharmaceutically acceptable salt or the aforementioned pharmaceutical composition, the method comprising the step of complexing the compound or its pharmaceutically acceptable salt with a nuclide.

[0309] In another aspect, the present disclosure provides use of the aforementioned compound or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition for preparing a medicament for diagnosing or treating a disease, wherein the disease is a disease involving fibroblast activation protein (FAP).

[0310] In an optional embodiment, the disease involving fibroblast activation protein (FAP) is a disease associated with up-regulation of fibroblast activation protein (FAP) expression.

[0311] In alternative embodiments, the disease involves cells that display upregulated expression of fibroblast activation protein (FAP).

[0312] In alternative embodiments, the disease comprises diseased tissue comprising cells that display upregulated expression of fibroblast activation protein (FAP).

[0313] In an alternative embodiment, the disease is a disease involving tumor-associated fibroblasts.

[0314] In another aspect, the present disclosure further provides use of the aforementioned compound or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition in the preparation of a drug for diagnosing or treating a disease, wherein the disease is a tumor or cancer.

[0315] In another aspect, the present disclosure provides use of the aforementioned compound or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition in the preparation of a medicament for diagnosing or treating a disease selected from inflammatory diseases, cardiovascular diseases, autoimmune diseases, and fibrotic diseases.

[0316] In alternative embodiments, the disease is an inflammatory disease, such as atherosclerosis, arthritis, or rheumatoid arthritis.

[0317] In an alternative embodiment, the disease is cardiovascular disease.

[0318] In alternative embodiments, the disease is a cardiovascular disease involving atherosclerotic plaques.

[0319] In alternative embodiments, the disease is atherosclerotic lesions due to plaque rupture, acute coronary syndrome, myocardial infarction, thrombosis or vascular occlusion.

[0320] In alternative embodiments, the disease is a fibrotic disease, such as idiopathic pulmonary fibrosis, Crohn's disease, and liver fibrosis.

[0321] The tumor or cancer described in the present disclosure is selected from solid tumors, epithelial tumors, bladder cancer, breast cancer, cervical cancer, colorectal cancer, bile duct cancer, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, head and neck cancer, liver cancer, lung cancer, melanoma, mesothelioma, neuroendocrine tumors and carcinomas, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, salivary gland cancer, sarcoma, squamous cell carcinoma, glioma (e.g., human brain astrocytoblastoma cells), and thyroid cancer (e.g., medullary thyroid carcinoma).

[0322] In alternative embodiments, the tumor or cancer of the present disclosure is selected from breast cancer, colorectal cancer, bile duct cancer, head and neck cancer, lung cancer, mesothelioma, neuroendocrine tumors and carcinomas, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, and squamous cell carcinoma.

[0323] The present disclosure further provides a method for diagnosing or treating a disease, comprising administering to a patient a diagnostically effective amount or a therapeutically effective amount of the aforementioned compound or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, wherein the disease is selected from diseases involving fibroblast activation protein (FAP), tumors or cancers, inflammatory diseases, cardiovascular diseases, autoimmune diseases, and fibrotic diseases.

[0324] The patient described in the present disclosure can be a mammal, such as a human, dog, cat, horse, and cow.

[0325] In some embodiments, the compounds provided herein are used in a method of diagnosing a disease by imaging, wherein the imaging method is selected from scintigraphy, single photon emission computed tomography (SPECT), and positron emission tomography (PET).

[0326] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0327] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution.

[0328] In certain embodiments, the pharmaceutical composition comprises 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1% to 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of a pharmaceutically acceptable excipient.

[0329] The present disclosure further provides a method for preparing the aforementioned compound or its pharmaceutically acceptable salt or the aforementioned pharmaceutical composition, which comprises the steps of complexing the compound represented by formula (I) or its pharmaceutically acceptable salt with a nuclide,

[0330] The Y is a chelating agent, the chelating agent complexes the nuclide, the R 1a 、R 1b ,v,G1,R 2a 、R 2b 、R 2c 、R 3a 、R 3b 、R 4a 、R 4b 、R 4c 、R 4d 、R 5a 、R 5b ,m,R 6a 、n、R 7a 、R 7b ,q,ring A,R 7c ,p,R 8a 、R 8b ,r,s,X,t,R 10 As defined in formula (I).

[0331] The present disclosure further provides a method for preparing the aforementioned compound or its pharmaceutically acceptable salt or the aforementioned pharmaceutical composition, comprising the steps of reacting the compound represented by formula (I-1) with a chelating agent,

[0332] The R 1a 、R 1b ,v,G1,R 2a 、R 2b 、R 2c 、R 3a 、R 3b 、R 4a 、R 4b 、R 4c 、R 4d 、R5a 、R 5b ,m,R 6a 、n、R 7a 、R 7b ,q,ring A,R 7c ,p,R 8a 、R 8b ,r,s,X,t,R 10 As defined in formula (I).

[0333] The present disclosure further provides a compound represented by formula (I-2) or a pharmaceutically acceptable salt thereof,

[0334] The R 1a 、R 1b ,v,G1,R 2a 、R 2b 、R 2c 、R 3a 、R 3b 、R 4a 、R 4b 、R 4c 、R 4d 、R 5a 、R 5b ,m,R 6a 、n、R 7a 、R 7b ,q,ring A,R 7c ,p,R 8a 、R 8b , r are as defined in formula (I).

[0335] The present disclosure further provides a method for preparing the compound of formula (III) or a pharmaceutically acceptable salt thereof, comprising the steps of reacting the compound of formula (III-1) or a pharmaceutically acceptable salt thereof with 2-aminoethanethiol and 1,3,5-tris(bromomethyl)benzene.

[0336] Said Y is hydrogen; R 10 is hydrogen; t is 1; X is a sulfur atom; s is 1;

[0337] The R 2a 、R 2b 、R 2c 、R 3a 、R 3b 、R 4a 、R 4b 、R 4c 、R 4d 、R 7c , p, and G1 are as defined in formula (III).

[0338] Optionally, the preparation method of the compound of formula (I) or a pharmaceutically acceptable salt thereof provided in the present disclosure further comprises the steps in the preparation method of the compound of formula (III) or a pharmaceutically acceptable salt thereof.

[0339] The present disclosure further provides a compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof,

[0340] The R 2a 、R 2b 、R 2c 、R 3a 、R 3b 、R 4a 、R 4b 、R 4c 、R 4d 、R 7c , p, and G1 are as defined in formula (III).

[0341] The present disclosure discloses that the chelating agent and the radioactive element in the structure of the compound labeled with radioactive element are not limited to one way of presentation. 177 Take Lu-DOTA-09 as an example,

[0342] The structural formula can also be expressed as:

[0343] in Both represent chelating agents and 177 Lu forms a coordination bond between them.

[0344] The pharmaceutically acceptable salts of the compounds described in the present disclosure may be selected from inorganic salts or organic salts.

[0345] The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present disclosure. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure form or in racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

[0346] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0347] In the chemical structures of the compounds disclosed herein, the bond " " indicates that the configuration is not specified, i.e. if chiral isomers exist in the chemical structure, the bond " ” can be "or" ”, or both "and" " Two configurations. In the chemical structure of the compound disclosed in the present invention, the bond " " does not specify the configuration, i.e. the bond" The configuration of " can be E-type or Z-type, or contain both E and Z configurations.

[0348] The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are encompassed within the scope of the present disclosure.

[0349] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123I. 125 I and 36 Cl et al.

[0350] Unless otherwise stated, when a position is specifically designated as deuterium (D), the position is understood to have at least 1000 times the abundance of deuterium greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). In the example, the compound has a natural abundance greater than deuterium that can be at least 1000 times the abundance of deuterium, at least 2000 times the abundance of deuterium, at least 3000 times the abundance of deuterium, at least 4000 times the abundance of deuterium, at least 5000 times the abundance of deuterium, at least 6000 times the abundance of deuterium or more abundant deuterium. The disclosure also includes various deuterated forms of formula (I) compounds. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of formula (I) compounds with reference to relevant literature. Commercially available deuterated starting materials may be used in the preparation of deuterated forms of the compounds of formula (I), or they may be synthesized using conventional techniques using deuterated reagents, including but not limited to deuterated borane, trideuterated borane in tetrahydrofuran, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.

[0351] Terminology

[0352] "Optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "C 1-6 The term "alkyl" means that halogen or cyano may but need not be present, and the description includes both the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen and cyano.

[0353] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0354] "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the U.S. Food and Drug Administration (FDA) for use by humans or domestic animals.

[0355] As used herein, an "effective amount" or "therapeutically effective amount" encompasses an amount sufficient to ameliorate or prevent the symptoms or conditions of a medical condition. An effective amount also refers to an amount sufficient to permit or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. An effective amount can be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.

[0356] The term "alkyl" refers to a saturated aliphatic hydrocarbon group. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, and various branched chain isomers thereof.

[0357] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like.

[0358] The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon containing 3 to 20 ring atoms, wherein one or more ring atoms is a heteroatom selected from nitrogen, oxygen or S(O)m (wherein m is an integer from 0 to 2), but excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.

[0359] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy.

[0360] The term "alkylene" refers to the portion remaining after removing two hydrogen atoms from an alkane molecule, including straight and branched subgroups of 1 to 20 carbon atoms. Non-limiting examples include methylene (-CH2-), ethylene (such as -CH2CH2- or -CH(CH3)-).

[0361] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings which share adjacent pairs of carbon atoms) group having a conjugated pi electron system, preferably 6- to 12-membered, such as phenyl and naphthyl.

[0362] The aryl ring may be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, wherein the ring that is attached to the parent structure is the aryl ring, non-limiting examples of which include:

[0363] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 6 to 12-membered, more preferably 5-membered or 6-membered. Non-limiting examples include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, triazolyl, indazolyl, benzimidazolyl, wait.

[0364] The heteroaryl ring may be fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0365] The term "hydroxy" refers to -OH.

[0366] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0367] The term "cyano" refers to -CN.

[0368] The term "amino" refers to -NH2.

[0369] The term "nitro" refers to -NO2.

[0370] The term "oxo" refers to =0.

[0371] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently replaced by a corresponding number of substituents. When the substituent is keto or oxo (i.e., =O), then two (2) hydrogen atoms on the atom are replaced.

[0372] Abbreviations, names, and structures of unnatural amino acids and other chemical structures in structures BRIEF DESCRIPTION OF THE DRAWINGS

[0373] FIG1 shows the uptake of the disclosed compounds in tumors and various tissues.

[0374] FIG2 is a graph showing the compounds disclosed herein and 68 Tumor / kidney uptake ratio curve of Ga-FAP-2286 (** indicates statistically significant difference).

[0375] FIG3 is a graph showing the compounds disclosed herein and 68 Ga-FAP-2286 uptake values ​​in tumors at different time points.

[0376] FIG4 is a graph showing the compounds disclosed herein and 68Tumor / kidney uptake ratio of Ga-FAP-2286 at different time points.

[0377] FIG5 shows the compounds disclosed herein and 177 Lu-FAP-2286 uptake values ​​in tumors at different time points.

[0378] FIG6 shows the compounds disclosed herein and 177 Tumor / kidney uptake ratio of Lu-FAP-2286 at different time points.

[0379] FIG. 7 shows the compounds disclosed herein and 68 Ga-FAP-2286 uptake values ​​in tumors at different time points.

[0380] FIG8 shows the compounds disclosed herein and 68 The tumor / kidney uptake ratio of Ga-FAP-2286 at different time points.

[0381] FIG9 shows the compound of the present disclosure and Al 18 F-NOTA-2286 uptake values ​​in tumors at different time points.

[0382] FIG10 is a graph showing the relationship between the compounds disclosed herein and Al 18 F-NOTA-2286 uptake values ​​in tumors and kidneys at different time points.

[0383] Figure 11 shows the different radioactive doses 177 Tumor growth curve of U-87MG model mice after Lu-DOTA-09 administration (n=8, mean ± SD).

[0384] Figure 12 shows the different radioactive doses 177 Body weight changes of mice during Lu-DOTA-09 administration (n=8, mean ± SD).

[0385] Figure 13 shows different radioactive doses 177 Survival of U-87MG model mice after Lu-DOTA-09 administration. DETAILED DESCRIPTION

[0386] Example

[0387] The following synthetic descriptions or specific examples are for illustrative purposes only and should not be construed as limiting in any way the preparation of the disclosed compounds by other methods.

[0388] HPLC / MS analysis chromatographic conditions are as follows:

[0389] 10 μl of each sample was automatically injected. Mobile phase: A: 0.1% formic acid in water, B: 0.1% formic acid in acetonitrile. Flow rate: 1.5 ml / min. Gradient: B increased from 10% to 95% over 0-6 min, from 95% to 100% over 6-8 min, from 100% to 10% over 8-8.10 min, and maintained at 10% B over 8.10-11.0 min.

[0390] Equipment model: Thermo Fisher ULTIMATE3000 ISQEM.

[0391] Chromatographic column: Eclipse Plus C18, 3.5 nm, 4.6 × 100 mm.

[0392] UV detection wavelength: 220nM.

[0393] Compound purity data were obtained by manual integration and molecular weight [M+1] was collected. + or [M-1] - .

[0394] The chromatographic conditions for the preparative liquid phase were as follows:

[0395] Mobile phase: A: 0.1% trifluoroacetic acid in water, B: 0.1% trifluoroacetic acid in acetonitrile. Flow rate: 60 ml / min. Gradient: B increased from 25% to 45% over 0-20.0 min, from 45% to 70% over 20.0-30.0 min, and maintained at 70% B over 30.0-40.0 min.

[0396] Equipment model: Agilent AGILENT1260Ⅱ.

[0397] Chromatographic column: HPLCONE, 5.0 μm, 30 × 250 mm.

[0398] UV detection wavelength: 220nM.

[0399] The radio-HPLC analysis chromatographic conditions are as follows:

[0400] 5-20 μl of each sample was automatically injected. Mobile phase: A: 0.1% formic acid in water, B: 0.1% formic acid in acetonitrile. Flow rate: 0.8 ml / min. Gradient: B increased from 10% to 50% over 0-24 min, from 50% to 10% over 24-25 min, and maintained at 10% B for 25-35 min.

[0401] Equipment model: Thermo Fisher ULTIMATE3000 ISQEM.

[0402] Chromatographic column: XBridge C18 3.5 μm, 4.6*150 mm.

[0403] UV detection wavelength: 225nM.

[0404] Radioactivity detector: 30000cps / V.

[0405] Radiochemical purity was obtained by manual integration.

[0406] The abbreviations in the examples correspond to the full Chinese names:

[0407] Example 1. Preparation of DOTA-01

[0408] It can be prepared by either of two solid-phase synthesis schemes.

[0409] Option 1

[0410] a. Solid phase carrier loaded with the first amino acid

[0411] CTC resin (degree of substitution = 1.09 mmol / g) was selected as the solid support and the resin was swollen with DMF for 1 hour. An amino acid solution was then prepared: 3.00 eq Fmoc-Cys(Trt)-OH and 6.00 eq DIPEA dissolved in 8 times the mass of the resin in DMF. Stir thoroughly and allow the solution to react with the resin for 3 hours. The resin was washed, capped with methanol and DIPEA, and washed 4-6 times with 8 times the mass of the resin in DMF. The resin was then washed sequentially with 8 times the mass of isopropyl ether, DCM, and 8 times the mass of the resin. The resin was then dried after shrinkage and the degree of substitution was measured before use.

[0412] b. Amino acid coupling

[0413] The coupling was performed using the general coupling method described below for each amino acid in the synthesis.

[0414] The Fmoc-Cys(Trt)-CTC resin obtained in the previous step was swelled with 8 times the resin's mass in DMF for 1 hour. The Fmoc protecting group was removed twice with 8 times the resin's mass in 20% piperidine / DMF solution (first 5 minutes, second 20 minutes). After deprotection, the resin was washed 4-6 times with 8 times the resin's mass in DMF. An amino acid activation solution was prepared: 3.0 eq of amino acid and 3.0 eq of HOBT were dissolved in 8 vol of DMF. Activated with 3.0 eq of DIC for 2-5 minutes, followed by reaction. After deprotection, the resin was washed 4-6 times with 8 times the resin's mass in DMF. Following linear peptide resin coupling using the above method, the resin was washed, shrunk, and dried for later use.

[0415] c. lysis

[0416] The obtained peptide resin was cleaved using a cleavage solution with a ratio of TFA / DTT / H2O / Tips = 94 / 2.5 / 2.5 / 1. The amount of cleavage solution added was 8 to 10 times the mass of the peptide resin. After 2 hours of cleavage, the filtrate was filtered to obtain a filtrate. The filtrate was poured into 80 to 100 times the mass of the peptide resin in isopropyl ether for crystallization, filtered, washed with isopropyl ether, and dried to obtain a linear crude peptide.

[0417] d. Cyclization

[0418] The resulting crude linear peptide was dissolved in a 1 / 1 mixture of acetonitrile and purified water (400 times the mass of the crude peptide). 7.2 eq of DIPEA was added first, followed by 1.2 eq of 1,3,5-tris(bromomethyl)benzene. After the reaction was complete, 3.6 eq of mercaptoethylamine was added directly to the system. After completion of the reaction, preparative liquid phase purification was performed and lyophilization was performed to obtain the cyclic peptide intermediate.

[0419] e. Connect to DOTA

[0420] The resulting lyophilized cyclic peptide powder was dissolved in 10 times the mass of DMF, and 4.0 eq of DIPEA and 2.0 eq of DOTA-NHS were added. The reaction was monitored by LCMS until completion. The product was purified by preparative liquid phase and lyophilized to obtain the target product. Purity: 98.2%, MS m / z (ESI): 1540.72 [MH] - .

[0421] Option 2

[0422] 1: Solid phase carrier loaded with the first amino acid

[0423] Wang resin (degree of substitution = 1.08 mmol / g) was selected as the solid support. The resin was swollen with 8 times the resin mass of DMF for 1 hour. An amino acid solution was then prepared: 3.00 eq Fmoc-Cys(Mmt)-OH and 3.00 eq HOBT were dissolved in 8 times the resin mass of DMF. After stirring, 3.00 eq DIC was added to activate the amino acid. After activation, the solution was added to the swollen resin, swirled evenly, and 0.3 eq DMAP was added as a catalyst. The reaction was allowed to proceed for 3 hours. After the reaction, the resin was washed 4-6 times with 8 times the resin mass of DMF. 3.00 eq acetic anhydride and 6.00 eq DIPEA were dissolved in 8 times the resin mass of DMF for 1 hour. The resin was washed 4-6 times with 8 times the resin mass of DMF. The resin was then shrunk with 8 times the resin mass of isopropyl ether, DCM, and isopropyl ether. The resin was then dried and the degree of substitution was measured before use.

[0424] 2: Amino acid coupling

[0425] The coupling was performed using the general coupling method described below for each amino acid in the synthesis.

[0426] The Fmoc-Cys(Mmt)-Wang resin obtained in the previous step was swollen with 8 times the resin's weight of DMF for 1 hour. The Fmoc protecting group was removed twice with 8 times the resin's weight of 20% piperidine / DMF solution (first 5 minutes, second 20 minutes). After deprotection, the resin was washed 4-6 times with 8 times the resin's weight of DMF. An amino acid activation solution was prepared: 3.0 eq of amino acid and 3.0 eq of HOBT were dissolved in 8 vol of DMF. 3.0 eq of DIC was added for activation for 2-5 minutes, followed by reaction. After completion of the reaction and deprotection, the resin was washed 4-6 times with 8 times the resin's weight of DMF. Following the above method, the linear peptide resin was coupled, washed, and the resin was shrunk and dried for later use.

[0427] 3: Solid-phase cyclization

[0428] The side chain protecting group Mmt of Cys was removed with 1% TFA / DCM (8 times the mass of the resin), the resin was washed 4 to 6 times with DMF (8 times the mass of the resin), and then DMF (8 times the mass of the resin) was added as a solvent. 7.2 eq of DIPEA was added, followed by 1.2 eq of 1,3,5-tris(bromomethyl)benzene. After the cyclization was completed, 3.6 eq of mercaptoethylamine was directly added to the system. After the reaction was completed, the resin was washed 4 to 6 times with DMF (8 times the mass of the resin).

[0429] 4: Connect to DOTA

[0430] Dissolve 4.0eq DIPEA and 2.0eq DOTA-NHS in 8 times the mass of the resin in DMF to prepare a reaction solution, and add it to the solid phase column for reaction. After the reaction is completed, wash the resin 4 to 6 times with 8 times the mass of the resin in DMF. Contract the peptide resin with 8 times the mass of the resin in isopropyl ether, DCM, and isopropyl ether, dry it, and set aside.

[0431] 5: Cracking

[0432] The resulting peptide resin was cleaved using a cleavage solution with a ratio of TFA / DTT / H₂O / Tips = 94 / 2.5 / 2.5 / 1. The amount of cleavage solution added was 8-10 times the mass of the peptide resin. After 2 hours of cleavage, the filtrate was filtered and poured into 80-100 times the mass of isopropyl ether for crystallization. The filtrate was filtered, washed with isopropyl ether, and dried to obtain a linear crude peptide. The product was then purified by preparative liquid phase and lyophilized to obtain a lyophilized powder. Purity: 96.7%, MS m / z (ESI): 1540.72 [MH] - .

[0433] Example 2. Preparation of DOTA-02

[0434] The target compound DOTA-02 was obtained in a manner similar to that of Example 1, Scheme 1, with a purity of 97.7% and MS m / z (ESI): 1556.34 [MH] - .

[0435] Example 3. Preparation of DOTA-03

[0436] The target compound DOTA-03 was obtained in a manner similar to that of Example 1, Scheme 1, with a purity of 96.3% and MS m / z (ESI): 1555.08 [M+H] + .

[0437] Example 4. Preparation of DOTA-04

[0438] The target compound DOTA-04 was obtained in a manner similar to that of Example 1, Scheme 1, with a purity of 95.2% and MS m / z (ESI): 1545.01 [M+H] + .

[0439] Example 5. Preparation of DOTA-05

[0440] The target compound DOTA-05 was obtained in a manner similar to that of Scheme 1 of Example 1;

[0441] a. Solid phase carrier loaded with the first amino acid

[0442] CTC resin (substitution degree = 1.09 mmol / g) was selected as the solid phase carrier, and the resin was swollen with DMF for 1 hour. Then, an amino acid solution was prepared: 3.00eq Fmoc-Cys(Trt)-OH, 6.00eq DIPEA was dissolved in 8 times the mass of the resin in DMF, stirred evenly and reacted with the resin for 3 hours, the resin was washed, and methanol and DIPEA were capped. The resin was washed 4 to 6 times with DMF 8 times the mass of the resin, and washed with isopropyl ether, DCM, and isopropyl ether 8 times the mass of the resin in turn. The resin was shrunk and dried, and the degree of substitution was measured for later use.

[0443] b. Amino acid coupling

[0444] The coupling was performed using the general coupling method described below for each amino acid in the synthesis.

[0445] The Fmoc-Cys(Trt)-CTC resin obtained in the previous step was swelled with 8 times the resin's mass in DMF for 1 hour. The Fmoc protecting group was removed twice with 8 times the resin's mass in 20% piperidine / DMF (5 minutes for the first time, 20 minutes for the second time). After deprotection, the resin was washed 4-6 times with 8 times the resin's mass in DMF. An amino acid activation solution was prepared: 3.0 eq of amino acid and 3.0 eq of HBTU dissolved in 8 vol of DMF. Activation was performed with 3.0 eq of DEPEA for 2-5 minutes, followed by reaction. After completion of the reaction, deprotection was performed, and the resin was washed 4-6 times with 8 times the resin's mass in DMF. Following the above method, the linear peptide resin was coupled, washed, and the resin was shrunk. Drying was then performed for later use.

[0446] c. lysis

[0447] The obtained peptide resin was cleaved using a cleavage solution with a ratio of TFA / DTT / H2O / Tips = 94 / 2.5 / 2.5 / 1. The amount of cleavage solution added was 8 to 10 times the mass of the peptide resin. After 2 hours of cleavage, the filtrate was filtered to obtain a filtrate. The filtrate was poured into 80 to 100 times the mass of the peptide resin in isopropyl ether for crystallization, filtered, washed with isopropyl ether, and dried to obtain a linear crude peptide.

[0448] d. Cyclization

[0449] The resulting crude linear peptide was dissolved in a 1 / 1 mixture of acetonitrile and purified water (400 times the mass of the crude peptide). 7.2 eq of DIPEA was added first, followed by 1.2 eq of 1,3,5-tribromomethylbenzene. After the reaction was complete, 3.6 eq of mercaptoethylamine was added directly to the system. After completion of the reaction, preparative liquid phase purification was performed and lyophilization was performed to obtain the cyclic peptide intermediate.

[0450] e. Connect to DOTA

[0451] The obtained cyclic peptide freeze-dried powder was dissolved in 10 times the mass of DMF, and 4.0eq DIPEA and 2.0eq DOTA-NHS were added. The reaction was monitored by LCMS until the end, and the target product was purified by preparative liquid phase and freeze-dried.

[0452] Purity: 97.8%, MS m / z (ESI): 1571.10 [M+H] + .

[0453] Example 6. Preparation of DOTA-06

[0454] a. Solid phase carrier loaded with the first amino acid

[0455] CTC resin (degree of substitution = 1.09 mmol / g) was selected as the solid support. The resin was swollen with DMF for 1 hour. An amino acid solution was then prepared: 3.00 eq Fmoc-Cys(Trt)-OH and 6.00 eq DIPEA dissolved in 8 times the mass of the resin in DMF. The mixture was stirred and allowed to react with the resin for 3 hours. The resin was washed, capped with methanol and DIPEA, and washed 4-6 times with 8 times the mass of the resin in DMF. The resin was then washed sequentially with 8 times the mass of the resin in isopropyl ether, DCM, and 8 times the mass of the resin in isopropyl ether. The resin was then shrunk and dried. The degree of substitution was measured and set aside.

[0456] b. Amino acid coupling

[0457] The coupling was performed using the general coupling method described below for each amino acid in the synthesis.

[0458] The Fmoc-Cys(Trt)-CTC resin obtained in the previous step was swelled with 8 times the resin's mass in DMF for 1 hour. The Fmoc protecting group was removed twice with 8 times the resin's mass in 20% piperidine / DMF solution (first 5 minutes, second 20 minutes). After deprotection, the resin was washed 4-6 times with 8 times the resin's mass in DMF. An amino acid activation solution was prepared: 3.0 eq of amino acid and 3.0 eq of HBTU dissolved in 8 vol of DMF. Activation was performed with 3.0 eq of DIPEA for 2-5 minutes, followed by reaction. After completion of the reaction, the resin was deprotected and washed 4-6 times with 8 times the resin's mass in DMF. Following the above method, the linear peptide resin was coupled, washed, and the resin was shrunk and dried for later use.

[0459] c. lysis

[0460] The obtained peptide resin was cleaved using a cleavage solution with a ratio of TFA / DTT / H2O / Tips = 94 / 2.5 / 2.5 / 1. The amount of cleavage solution added was 8 to 10 times the mass of the peptide resin. After 2 hours of cleavage, the filtrate was filtered to obtain a filtrate. The filtrate was poured into 80 to 100 times the mass of the peptide resin in isopropyl ether for crystallization, filtered, washed with isopropyl ether, and dried to obtain a linear crude peptide.

[0461] d. Cyclization

[0462] The resulting crude linear peptide was dissolved in a 1 / 1 mixture of acetonitrile and purified water (400 times the mass of the crude peptide). 7.2 eq of DIPEA was added first, followed by 1.2 eq of 1,3,5-tris(bromomethyl)benzene. After the reaction was complete, 3.6 eq of mercaptoethylamine was added directly to the system. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was purified by preparative liquid phase and lyophilized to obtain the cyclic peptide intermediate.

[0463] e. Connect to DOTA

[0464] The obtained cyclic peptide freeze-dried powder was dissolved in 10 times the mass of DMF, and 4.0eq DIPEA and 2.0eq DOTA-NHS were added. The reaction was monitored by LCMS until the end, and the target product was purified by preparative liquid phase and freeze-dried.

[0465] Purity: 96.9%, MS m / z (ESI): 1587.88 [MH] - .

[0466] Example 7. Preparation of DOTA-07

[0467] The target compound DOTA-07 was obtained in a manner similar to that of Example 1, Scheme 1, with a purity of 96.9% and MS m / z (ESI): 1587.84 [MH] - .

[0468] Example 8. Preparation of DOTA-08

[0469] The target compound DOTA-08 was obtained in a manner similar to that of Example 1, Scheme 1, with a purity of 96.9% and MS m / z (ESI): 1587.93 [MH] - .

[0470] Example 9. Preparation of DOTA-09

[0471] a. Solid phase carrier loaded with the first amino acid

[0472] CTC resin (substitution degree = 1.09 mmol / g) was selected as the solid phase carrier, and the resin was swollen with DMF for 1 hour. Then, an amino acid solution was prepared: 3.00eq Fmoc-Cys(Trt)-OH, 6.00eq DIPEA was dissolved in 8 times the mass of the resin in DMF, stirred evenly and reacted with the resin for 3 hours, the resin was washed, and methanol and DIPEA were capped. The resin was washed 4 to 6 times with DMF 8 times the mass of the resin, and washed with isopropyl ether, DCM, and isopropyl ether 8 times the mass of the resin in turn. The resin was shrunk and dried, and the degree of substitution was measured for later use.

[0473] b. Amino acid coupling

[0474] The coupling was performed using the general coupling method described below for each amino acid in the synthesis.

[0475] The Fmoc-Cys(Trt)-CTC resin obtained in the previous step was swollen with 8 times the resin's mass of DMF for 1 hour. The Fmoc protecting group was removed twice with 8 times the resin's mass of 20% piperidine / DMF solution (first 5 minutes, second 20 minutes). After deprotection, the resin was washed 4-6 times with 8 times the resin's mass of DMF. An amino acid activation solution was prepared: 3.0 eq of amino acid and 3.0 eq of HBTU were dissolved in 8 vol of DMF. Activation was performed with 3.0 eq of DIPEA for 2-5 minutes, followed by reaction. After completion of the reaction, the resin was deprotected and washed 4-6 times with 8 times the resin's mass of DMF. Following the above method, the linear peptide resin was coupled, washed, shrunk, and dried for later use.

[0476] c. lysis

[0477] The obtained peptide resin was cleaved using a cleavage solution with a ratio of TFA / DTT / H2O / Tips = 94 / 2.5 / 2.5 / 1. The amount of cleavage solution added was 8 to 10 times the mass of the peptide resin. After 2 hours of cleavage, the filtrate was filtered to obtain a filtrate. The filtrate was poured into 80 to 100 times the mass of the peptide resin in isopropyl ether for crystallization, filtered, washed with isopropyl ether, and dried to obtain a linear crude peptide.

[0478] d. Cyclization

[0479] The resulting crude linear peptide was dissolved in a 1 / 1 mixture of acetonitrile and purified water (400 times the mass of the crude peptide). 7.2 eq of DIPEA was added first, followed by 1.2 eq of 1,3,5-tris(bromomethyl)benzene. After the reaction was complete, 3.6 eq of mercaptoethylamine was added directly to the system. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was purified by preparative liquid phase and lyophilized to obtain the cyclic peptide intermediate.

[0480] e. Connect to DOTA

[0481] The resulting lyophilized cyclic peptide powder was dissolved in 10 times the mass of DMF, and 4.0 eq of DIPEA and 2.0 eq of DOTA-NHS were added. The reaction was monitored by LCMS until completion. The product was purified by preparative liquid phase and lyophilized to obtain the target product. Purity: 98.9%, MS m / z (ESI): 1637.78 [MH] - .

[0482] Example 10. Preparation of DOTA-10

[0483] The target compound DOTA-10 was obtained in a manner similar to that of Example 1, Scheme 1, with a purity of 99.3% and MS m / z (ESI): 1637.79 [MH] - .

[0484] Example 11. Preparation of DOTA-11

[0485] The target compound DOTA-11 was obtained in a manner similar to that of Example 1, Scheme 1, with a purity of 99.4% and MS m / z (ESI): 1603.76 [MH] - .

[0486] Example 12. Preparation of DOTA-12

[0487] The target compound DOTA-12 was obtained in a manner similar to that of Example 1, Scheme 1, with a purity of 99.1% and MS m / z (ESI): 1572.31 [MH] - .

[0488] Example 13. Preparation of DOTA-13

[0489] The target compound DOTA-13 was obtained in a manner similar to that of Example 1, Scheme 1, with a purity of 98.9% and MS m / z (ESI): 1590.01 [MH] - .

[0490] Example 14. Preparation of DOTA-14

[0491] The target compound DOTA-14 was obtained in a manner similar to that of Example 1, Scheme 1, with a purity of 97.4% and MS m / z (ESI): 1589.87 [MH] - .

[0492] Example 15. Preparation of NOTA-04

[0493] a. Solid phase carrier loaded with the first amino acid

[0494] CTC resin (degree of substitution = 1.09 mmol / g) was selected as the solid support. The resin was swollen with DMF for 1 hour. An amino acid solution was then prepared: 3.00 eq Fmoc-Cys(Trt)-OH and 6.00 eq DIPEA dissolved in 8 times the mass of the resin in DMF. The mixture was stirred and allowed to react with the resin for 3 hours. The resin was washed, capped with methanol and DIPEA, and washed 4-6 times with 8 times the mass of the resin in DMF. The resin was then washed sequentially with 8 times the mass of the resin in isopropyl ether, DCM, and 8 times the mass of the resin in isopropyl ether. The resin was then shrunk and dried. The degree of substitution was measured and set aside.

[0495] b. Amino acid coupling

[0496] The coupling was performed using the general coupling method described below for each amino acid in the synthesis.

[0497] The Fmoc-Cys(Trt)-CTC resin obtained in the previous step was swelled with 8 times the resin's mass in DMF for 1 hour. The Fmoc protecting group was removed twice with 8 times the resin's mass in 20% piperidine / DMF solution (first 5 minutes, second 20 minutes). After deprotection, the resin was washed 4-6 times with 8 times the resin's mass in DMF. An amino acid activation solution was prepared: 3.0 eq of amino acid and 3.0 eq of HBTU dissolved in 8 vol of DMF. Activated with 3.0 eq of DEPEA for 2-5 minutes, followed by reaction. After deprotection, the resin was washed 4-6 times with 8 times the resin's mass in DMF. Following linear peptide resin coupling using the above method, the resin was washed, shrunk, and dried for later use.

[0498] c. lysis

[0499] The obtained peptide resin was cleaved using a cleavage solution with a ratio of TFA / DTT / H2O / Tips = 94 / 2.5 / 2.5 / 1. The amount of cleavage solution added was 8 to 10 times the mass of the peptide resin. After 2 hours of cleavage, the filtrate was filtered to obtain a filtrate. The filtrate was poured into 80 to 100 times the mass of the peptide resin in isopropyl ether for crystallization, filtered, washed with isopropyl ether, and dried to obtain a linear crude peptide.

[0500] d. Cyclization

[0501] The resulting crude linear peptide was dissolved in a 1 / 1 mixture of acetonitrile and purified water (400 times the mass of the crude peptide). 7.2 eq of DIPEA was added first, followed by 1.2 eq of 1,3,5-tris(bromomethyl)benzene. After the reaction was complete, 3.6 eq of mercaptoethylamine was added directly to the system. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was purified by preparative liquid phase and lyophilized to obtain the cyclic peptide intermediate.

[0502] e. Connect NOTA

[0503] The obtained cyclic peptide lyophilized powder was dissolved in 10 times the mass of DMF, 4.0eq DIPEA and 2.0eq NOTA-NHS were added, and the reaction was monitored by LCMS until the end. The product was purified by preparative liquid phase and lyophilized to obtain the target product.

[0504] Purity: 97.20%, MS m / z (ESI): 1442.89 [MH] - .

[0505] Example 16. Preparation of NOTA-05

[0506] The target compound NOTA-05 was obtained in a similar manner to Example 15 with a purity of 97.20% and MS m / z (ESI): 1470.33 [M+H] + .

[0507] Example 17. Preparation of NOTA-06

[0508] The target compound NOTA-06 was obtained in a similar manner to Example 15 with a purity of 99.2% and MS m / z (ESI): 1486.94 [MH] - .

[0509] Example 18. Preparation of NOTA-07

[0510] The target compound NOTA-07 was obtained in a similar manner to Example 15 with a purity of 99.0% and MS m / z (ESI): 1486.91 [MH] - .

[0511] Example 19. Preparation of NOTA-08

[0512] The target compound NOTA-08 was obtained in a similar manner to Example 15 with a purity of 99.6% and MS m / z (ESI): 1486.86 [MH] - .

[0513] Example 20. Preparation of NOTA-09

[0514] a. Solid phase carrier loaded with the first amino acid

[0515] CTC resin (degree of substitution = 1.09 mmol / g) was selected as the solid support. The resin was swollen with DMF for 1 hour. An amino acid solution was then prepared: 3.00 eq Fmoc-Cys(Trt)-OH and 6.00 eq DIPEA dissolved in 8 times the mass of the resin in DMF. The mixture was stirred and allowed to react with the resin for 3 hours. The resin was washed, capped with methanol and DIPEA, and washed 4-6 times with 8 times the mass of the resin in DMF. The resin was then washed sequentially with 8 times the mass of the resin in isopropyl ether, DCM, and 8 times the mass of the resin in isopropyl ether. The resin was then shrunk and dried. The degree of substitution was measured and set aside.

[0516] b. Amino acid coupling

[0517] The coupling was performed using the general coupling method described below for each amino acid in the synthesis.

[0518] The Fmoc-Cys(Trt)-CTC resin obtained in the previous step was swollen with 8 times the resin's mass of DMF for 1 hour. The Fmoc protecting group was removed twice with 8 times the resin's mass of 20% piperidine / DMF solution (first 5 minutes, second 20 minutes). After deprotection, the resin was washed 4-6 times with 8 times the resin's mass of DMF. An amino acid activation solution was prepared: 3.0 eq of amino acid and 3.0 eq of HBTU dissolved in 8 vol of DMF. Activation was performed with 3.0 eq of DEPEA for 2-5 minutes, followed by reaction. Deprotection was then performed, and the resin was washed 4-6 times with 8 times the resin's mass of DMF. Following the linear peptide resin coupling, the resin was washed, shrunk, and dried for later use.

[0519] c. lysis

[0520] The obtained peptide resin was cleaved using a cleavage solution with a ratio of TFA / DTT / H2O / Tips = 94 / 2.5 / 2.5 / 1. The amount of cleavage solution added was 8 to 10 times the mass of the peptide resin. After 2 hours of cleavage, the filtrate was filtered to obtain a filtrate. The filtrate was poured into 80 to 100 times the mass of the peptide resin in isopropyl ether for crystallization, filtered, washed with isopropyl ether, and dried to obtain a linear crude peptide.

[0521] d. Cyclization

[0522] The resulting crude linear peptide was dissolved in a 1 / 1 mixture of acetonitrile and purified water (400 times the mass of the crude peptide). 7.2 eq of DIPEA was added first, followed by 1.2 eq of 1,3,5-tris(bromomethyl)benzene. After the reaction was complete, 3.6 eq of mercaptoethylamine was added directly to the system. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was purified by preparative liquid phase and lyophilized to obtain the cyclic peptide intermediate.

[0523] e. Connect NOTA

[0524] The resulting lyophilized cyclic peptide powder was dissolved in 10 times the mass of DMF, and 4.0 eq of DIPEA and 2.0 eq of NOTA-NHS were added. The reaction was monitored by LCMS until completion. The product was purified by preparative liquid phase and lyophilized to obtain the target product. Purity: 99.7%, MS m / z (ESI): 1536.65 [MH] - .

[0525] Example 21. Preparation of NOTA-12

[0526] The target compound NOTA-12 was obtained in a similar manner to Example 15 with a purity of 98.8% and MS m / z (ESI): 1470.88 [MH] - .

[0527] Example 22. Preparation of NOTA-13

[0528] The target compound NOTA-13 was obtained in a similar manner to Example 15 with a purity of 98.6% and MS m / z (ESI): 1488.96 [MH] - .

[0529] Example 23. Preparation of NOTA-14

[0530] The target compound NOTA-14 was obtained in a similar manner to Example 15 with a purity of 97.9% and MS m / z (ESI): 1538.94 [MH] - .

[0531] Example 24. Preparation of NOTA-15

[0532] The target compound NOTA-15 was obtained in a similar manner to Example 15 with a purity of 97.3% and MS m / z (ESI): 1456.95 [MH] - .

[0533] Example 25. Preparation of NOTA-16

[0534] The target compound NOTA-16 was obtained in a similar manner to Example 15 with a purity of 97.8% and MS m / z (ESI): 1506.90 [MH] - .

[0535] Example 26. 68 Preparation of Ga-DOTA-05

[0536] Elute with 0.1N hydrochloric acid 68 GaCl3 solution, add 0.1ml 1mM sodium acetate aqueous solution to the reaction vessel; then add 0.9ml of the above 68 Add 5 μl of DOTA-05 (1 mg / ml) and 67 μl of gentisic acid (15 mg / ml) to the GaCl solution, mix well, adjust the reaction mixture to pH 3.5-5.0, and heat at 95°C for 15 minutes. Radio-HPLC analysis revealed a radiochemical purity of 97.54%.

[0537] If the radiochemical purity is not less than 90%, it can be used directly. If the radiochemical purity is less than 90%, it should be purified using C18 artridge, rinsed with ethanol, and diluted with saline to an ethanol content of less than 10%.

[0538] Example 27. 68 Preparation of Ga-DOTA-06

[0539] The target compound was obtained in a similar manner to Example 26. 68 Ga-DOTA-06, radiochemical purity 92.64%.

[0540] Example 28. 68 Preparation of Ga-DOTA-07

[0541] The target compound was obtained in a similar manner to Example 26. 68 Ga-DOTA-07, radiochemical purity 94.76%.

[0542] Example 29. 68 Preparation of Ga-DOTA-08

[0543] The target compound was obtained in a similar manner to Example 26. 68 Ga-DOTA-08, radiochemical purity 93.99%.

[0544] Example 30. 68 Preparation of Ga-DOTA-09

[0545] Elute with 0.1N hydrochloric acid 68 GaCl3 solution, add 0.1ml 1mM sodium acetate aqueous solution to the reaction vessel; then add 0.9ml of the above 68 Add 5 μl of DOTA-09 (1 mg / ml) and 67 μl of gentisic acid (15 mg / ml) to the GaCl solution, mix well, adjust the reaction mixture to pH 3.5-5.0, and heat at 95°C for 15 minutes. Radio-HPLC analysis revealed a radiochemical purity of 93.38%.

[0546] Example 31. 68 Preparation of Ga-DOTA-12

[0547] The target compound was obtained in a similar manner to Example 26. 68 Ga-DOTA-12, radiochemical purity 97.57%.

[0548] Example 32. 68 Preparation of Ga-DOTA-13

[0549] The target compound was obtained in a similar manner to Example 26. 68 Ga-DOTA-13, radiochemical purity 95.81%.

[0550] Example 33. 177 Preparation of Lu-DOTA-05

[0551] To a reaction vessel, 75 μl of 0.4 M acetic acid / sodium acetate buffer, 7.5 μl of DOTA-05 solution (1 mg / ml), 31.5 μl of gentisic acid solution (15 mg / ml), and 7-15 mCi of Lu-177 were added sequentially and mixed thoroughly. The reaction solution was heated at 90-95°C for 15 minutes to a pH of 4.0-4.5. Cool to room temperature, and add 1.4 ml of diluent (10 mg / ml vitamin C solution in saline). Radiochemical purity was determined by radio-HPLC, yielding a radiochemical purity of 96.28%.

[0552] Example 34. 177 Preparation of Lu-DOTA-06

[0553] The target compound was obtained in a similar manner to Example 33. 177 Lu-DOTA-06, radiochemical purity 96.18%.

[0554] Example 35. 177 Preparation of Lu-DOTA-09

[0555] To a reaction vessel, 75 μl of 0.4 M acetic acid / sodium acetate buffer, 7.5 μl of DOTA-09 solution (1 mg / ml), 31.5 μl of gentisic acid solution (15 mg / ml), and 7-15 mCi of Lu-177 were added, mixed thoroughly, and the reaction solution was heated at 90-95°C for 15 minutes to a pH of 4.0-4.5. Cool to room temperature, and add 1.4 ml of diluent (10 mg / ml vitamin C solution in saline). Radio-HPLC analysis revealed a radiochemical purity of 94.20%.

[0556] Example 36. 177 Preparation of Lu-DOTA-13

[0557] The target compound was obtained in a similar manner to Example 33. 177 Lu-DOTA-13, radiochemical purity 95.95%.

[0558] Example 37.177 Preparation of Lu-DOTA-14

[0559] The target compound was obtained in a similar manner to Example 33. 177 Lu-DOTA-14, radiochemical purity 97.45%.

[0560] Example 38. 68 Preparation of Ga-NOTA-05

[0561] Elute with 0.1N hydrochloric acid 68 GaCl3 solution, add 0.1ml 1mM sodium acetate aqueous solution to the reaction vessel; then add 0.9ml of the above 68 Add 5 μl of NOTA-05 aqueous solution (1 mg / ml) and 67 μl of gentisic acid aqueous solution (15 mg / ml) to the GaCl3 solution, mix well, adjust the reaction solution to pH 3.5-5.0, and react at room temperature for 15 minutes. Radio-HPLC analysis revealed a radiochemical purity of 91.07%.

[0562] If the radiochemical purity is not less than 90%, it can be used directly. If the radiochemical purity is less than 90%, it should be purified using a C18 cartridge, eluted with ethanol, and diluted with saline to an ethanol content of less than 10%.

[0563] Example 39. 68 Preparation of Ga-NOTA-06

[0564] The target compound was obtained in a similar manner to Example 38. 68 Ga-NOTA-06, radiochemical purity 91.38%.

[0565] Example 40. 68 Preparation of Ga-NOTA-07

[0566] The target compound was obtained in a similar manner to Example 38. 68 Ga-NOTA-07, radiochemical purity 92.54%.

[0567] Example 41. 68 Preparation of Ga-NOTA-09

[0568] Elute with 0.1N hydrochloric acid 68 GaCl3 solution, add 0.1ml 1mM sodium acetate aqueous solution to the reaction vessel; then add 0.9ml of the above 68Add 5 μl of NOTA-09 aqueous solution (1 mg / ml) and 67 μl of gentisic acid aqueous solution (15 mg / ml) to the GaCl3 solution, mix well, adjust the reaction solution to pH 3.5-5.0, and react at room temperature for 15 minutes. Radio-HPLC analysis revealed a radiochemical purity of 92.36%.

[0569] Example 42.A1 18 Preparation of F-NOTA-05

[0570] Dissolve 1 μl of 10 mM NOTA-05 aqueous solution in 50-100 μl of 0.5 M acetic acid / sodium acetate buffer at pH 4.0-4.4, then add 2 mM AlCl3 aqueous solution at a molar ratio of 2:1, and add 1850 MBq of QMA-purified 18F - 50 μl of the solution was reacted at 100°C for 10-15 minutes. Purification was performed using an HLB cartridge, eluting with ethanol / water (1:1 ratio). The solution was diluted with saline to a concentration of less than 10% ethanol. Radio-HPLC analysis revealed a radiochemical purity of 92.37%.

[0571] Example 43.A1 18 Preparation of F-NOTA-09

[0572] Dissolve 1 μl of 10 mM NOTA-09 aqueous solution in 50-100 μl of 0.5 M acetic acid / sodium acetate buffer at pH 4.0-4.4, then add 2 mM AlCl3 aqueous solution at a molar ratio of 2:1, and add 1850 MBq of QMA-purified 18F - 50 μl of the solution was reacted at 100°C for 10-15 minutes. Purification was performed using an HLB cartridge, eluting with ethanol / water (1:1 ratio). The solution was diluted with saline to a concentration of less than 10% ethanol. Radio-HPLC analysis revealed a radiochemical purity of 91.57%.

[0573] Example 44.A1 18 Preparation of F-NOTA-14

[0574] The target compound Al was obtained in a similar manner to Example 42. 18 F-NOTA-14, radiochemical purity 90.33%.

[0575] Example 45.A1 18 Preparation of F-NOTA-15

[0576] The target compound Al was obtained in a similar manner to Example 42. 18 F-NOTA-15, radiochemical purity 92.94%.

[0577] Example 46.A1 18 Preparation of F-NOTA-16

[0578] The target compound Al was obtained in a similar manner to Example 42. 18 F-NOTA-16, radiochemical purity 91.60%.

[0579] Example 47. 64 Preparation of Cu-DOTA-09

[0580] Dissolve 5 μl of 10 mM DOTA-09 aqueous solution in 100 μl of sodium acetate solution at pH = 3.5-6.5, then add 1850 MBq of DOTA-09 dissolved in 0.1 M hydrochloric acid. 64 50 μl of CuCl2 solution was reacted at 80°C for 15 min, purified using a C18 column, and diluted with saline to a concentration of less than 10% ethanol. Radio-HPLC analysis revealed a radiochemical purity of 98.59%.

[0581] Example 48. 64 Preparation of Cu-NOTA-09

[0582] Dissolve 5 μl of 10 mM NOTA-09 aqueous solution in 100 μl of sodium acetate solution at pH = 3.5-6.5, then add 1850 MBq of 0.1 M hydrochloric acid solution. 64 50 μl of CuCl2 solution was reacted at 80°C for 15 min, purified using a C18 column, and diluted with saline to a concentration of less than 10% ethanol. Radio-HPLC analysis revealed a radiochemical purity of 97.37%.

[0583] Example 49. 225 Preparation of Ac-DOTA-09

[0584] 318 μl of Tris buffer (pH 8, 0.25 M), 5 μl of DOTA-09 solution (1 μmol / ml) and 20-50 μCi were added to the reaction vessel in sequence. 225Mix the Ac nuclide thoroughly. Add an appropriate amount of 0.1N hydrochloric acid to adjust the pH of the reaction system to 6.0-8.0. Heat at 90-95°C for 10-20 minutes. After heating, cool to room temperature and add 0.65 ml of 10 mg / ml sodium ascorbate in saline. Assay by radio-HPLC to determine radiochemical purity, which should be greater than 90%.

[0585] Comparative Example 1. Preparation of NOTA-2286

[0586] The target compound NOTA-2286 was obtained in a similar manner to Example 15 with a purity of 97.35% and MS m / z (ESI): 1367.78 [MH] - .

[0587] Comparative Example 2.Al 18 Preparation of F-NOTA-2286

[0588] The target compound Al was obtained in a similar manner to Example 42. 18 F-NOTA-2286, radiochemical purity 95.37%.

[0589] Comparative Example 3. 68 Preparation of Ga-NOTA-2286

[0590] The target compound was obtained in a similar manner to Example 38. 68 Ga-NOTA-2286, radiochemical purity 96.29%.

[0591] Comparative Example 4. 68 Preparation of Ga-FAP-2286

[0592] The target compound was obtained in a similar manner to Example 26. 68 Ga-FAP-2286, radiochemical purity 94.98%.

[0593] Comparative Example 5. 177 Preparation of Lu-FAP-2286

[0594] The target compound was obtained in a similar manner to Example 33. 177 Lu-FAP-2286, radiochemical purity 97.76%.

[0595] Biological evaluation

[0596] The present disclosure is further described and explained below in conjunction with test examples, but these test examples are not intended to limit the scope of the present disclosure.

[0597] Test Example 1: FAPα enzyme activity test

[0598] 1.1 Experimental materials and instruments

[0599] Table 1. Source information of experimental materials and instruments

[0600] 1.2 Experimental steps

[0601] Dilute the substrate (Z-Gly-Pro-AMC) to a 0.5 mM stock solution with DMSO. Dilute the 0.5 mM stock solution to 50 μM with PBS before each experiment. Dilute FAPα protein to 0.5 ng / μl with PBS. Dilute the test compound and positive control to a concentration of 100 nM or 200 nM with PBS for single-point inhibition determination. For single-point inhibition rates comparable to those of the positive compound, further IC values ​​were determined. 50 Values. Test compounds and positive controls were diluted in PBS to a maximum concentration of 10 μM and a minimum concentration of 0 nM. A five-fold serial dilution series was performed, with a total of eight steps. Testing method: 85 μl of FAPα dilution and 10 μl of compound dilution were added to the microplate, mixed thoroughly, and incubated at 37°C for 10 minutes. Then, 5 μl of 50 μM substrate was added, mixed thoroughly, and incubated at 37°C for 10 minutes. Read the plate using a microplate reader with excitation at 380 nm and emission at 465 nm.

[0602] 1.3 Experimental Results

[0603] Table 2. IC values ​​of the compounds disclosed herein for FAPα 50 value

[0604] Note: The structure of FAP-2286 is as follows:

[0605] Reference: European Journal of Nuclear Medicine and Molecular Imaging(2022)49:3651–3667

[0606] Test Example 2: PET / SPECT Imaging Test of Labeled Compounds

[0607] 2.1 Experimental Materials

[0608] Cell information: U-87MG cells (Wuhan Punosai Life Science Co., Ltd.); culture conditions: U-87MG cell-specific culture medium (MEM+10% FBS+1% P / S); passage number: 6-9 generations.

[0609] Experimental animals: strain: B-NDG (Biocytogen Jiangsu Gene Biotechnology Co., Ltd.); age: 5-8 weeks; body weight: 20-24 g.

[0610] Reagents: PBS (Solarbau, P1020); Matrigel (ABW, 0827045); Trypsin-EDTA (Gibco, 25200-072); U-87MG special culture medium (Pnosel, CM-0238).

[0611] Instruments: small animal PET / CT (ediso, nanoScan PET / CT 4 heads); actimeter (Capintec, actimeter); electronic balance (Changzhou Shuangjie, DT100).

[0612] 2.2 Experimental steps

[0613] Model building

[0614] Prepare sufficient amount of U-87MG cells and inoculate them into the posterior part of the right forelimb of B-NDG mice. The inoculation volume is 100 μl containing 50% Matrigel and 5×10 6 After inoculation, the tumor volume and animal weight were monitored twice a week, and the tumor volume of 200-500 m 3 Model mice between 2 and 3 months old were enrolled in this experiment, and each group was randomly divided according to tumor volume.

[0615] Steps

[0616] 1) Wipe the work surface with 75% medical alcohol and lay a disposable sterile tablecloth;

[0617] 2) Prepare a 0.5mL insulin syringe, alcohol pad, cotton swab, and marker in the injection chamber. Place the syringe in the mouse holder and disinfect the mouse's tail with an alcohol pad.

[0618] 3) Inject the prepared test sample into the tail vein of each mouse, and record the time of each injection, the activity of the syringe, and the activity of the empty needle;

[0619] 4) Tumor-bearing mice were anesthetized with isoflurane and placed in a prone position on the small animal PET / SPECT table and fixed;

[0620] 5) Acquire static PET / SPECT images at various time points after drug administration. Perform a full-body CT scan before each static scan to obtain images of the systemic distribution of the labeled compound in the tumor-bearing mice. Obtain PET / SPECT images for each experimental animal at various time points after drug administration. Select and outline major organs, including the tumor, muscle, bone, lung, brain, liver, and kidney.

[0621] 6) Observe the radioactive accumulation and clearance of the labeled compound in the tumor and non-target tissues of tumor-bearing mice.

[0622] 2.3 Experimental Results

[0623] Table 3. Compounds of the present disclosure and 68 Ga-FAP-2286 uptake in tumors and various tissues and tumor / kidney ratio

[0624] 68 Ga-DOTA-05 and positive control 68 The tumor uptake of Ga-FAP-2286 in model mice is close to that of 68 The uptake of Ga-DOTA-06 in tumors was significantly higher than that in 68 Ga-FAP-2286. 68 Ga-DOTA-05 and 68 Ga-DOTA-06 has lower kidney uptake and higher tumor / kidney uptake ratio (Figure 1). 68 Ga-DOTA-05 and 68 The tumor / kidney uptake ratio of Ga-DOTA-06 was increased, while 68 The tumor / kidney uptake ratio of Ga-FAP-2286 was reduced ( FIG. 2 ).

[0625] Table 4. Compounds of the present disclosure and 68 Ga-FAP-2286 uptake in tumors and tumor / kidney ratio

[0626] In mouse models, 68 Ga-DOTA-06, 68 Ga-DOTA-07, 68 Ga-DOTA-08, 68 Ga-DOTA-09, 68 Ga-DOTA-12 and 68 The uptake of Ga-DOTA-13 in tumors (Figure 3) and the tumor / kidney ratio (Figure 4) were significantly higher than those in controls. 68 Ga-FAP-2286.

[0627] Table 5. Compounds of the present disclosure and 177 Lu-FAP-2286 uptake in tumors and tumor / kidney ratio

[0628] In mouse models, 177 Lu-DOTA-09 and 177 Lu-DOTA-14 slowly decreases in the tumor and maintains a relatively stable intratumoral retention. 177 The intratumoral retention of Lu-FAP-2286 decreased rapidly after 4 hours (Figure 5). 177 Lu-DOTA-09 and 177 The tumor / kidney ratio of Lu-DOTA-14 (Figure 6) was higher than that of the control 177 Lu-FAP-2286.

[0629] Table 6. Compounds of the present disclosure and 68 Ga-NOTA-2286 uptake in tumors and tumor / kidney ratio

[0630] In mouse models, 68 Ga-NOTA-05、 68 Ga-NOTA-06、 68 Ga-NOTA-07 and 68 The uptake of Ga-DOTA-09 in tumors (Figure 7) and the tumor / kidney ratio (Figure 8) were significantly higher than those in controls. 68 Ga-NOTA-2286.

[0631] Table 7. Compounds of the present disclosure and Al 18 F-NOTA-2286 uptake in tumors and tumor / kidney ratio.

[0632] In mouse models, Al 18 F-NOTA-09 and Al 18 The uptake of F-NOTA-14 in tumors (Figure 9) and the tumor / kidney ratio (Figure 10) were significantly higher than those in the control group. 18 F-NOTA-2286.

[0633] Test Example 3 177 Lu-labeled compound blood concentration experiment

[0634] 3.1 Experimental Materials

[0635] Experimental animals: strain: SD rats (Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.); age: 5-6 weeks old; body weight: 100-150 g.

[0636] Reagent: Sodium chloride injection (Shandong Qidu Pharmaceutical).

[0637] Instruments: Activity meter (Capintec); 1 / 10,000 balance (Sartorius Scientific Instruments Co., Ltd.); low-energy γ-counter (PerkinElmer, USA).

[0638] 3.2 Experimental steps

[0639] 1) Weigh and mark the empty tubes for γ-counting determination in advance.

[0640] 2) After the rats were injected with the test article through the tail vein, blood was collected from the animals by orbital bleeding at 2 min, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 24 h, 48 h and 72 h, and the sample tubes containing blood were weighed.

[0641] 3) Calculate the net weight of the blood and count the radioactivity of the blood using a γ-counter.

[0642] 4) Determine the distribution of the labeled compound in the blood of rats at different time points. Dilute the test sample accurately 100-fold and place 0.5 ml in a counting tube as a 1% ID standard (i.e., 1% of the injected dose). Measure the radioactivity counts of the 1% ID standard and the organism simultaneously on a gamma counter.

[0643] 5) Calculate pharmacokinetic parameters using DAS software.

[0644] The data in rat blood are expressed as the percentage of radioactive counts per gram of blood to the total dose (radioactive counts) (%ID / g). Specific calculation formula:

[0645] %ID / g = CPM organ or tissue / (CPM total dose × W organ or tissue) × 100%

[0646] The data of each sampling point were expressed as mean ± standard deviation (mean ± SD).

[0647] At the same time, the drug concentration in the blood is calculated based on the radioactive count in the blood. The specific calculation formula is:

[0648] 3.3 Experimental Results

[0649] Table 8. Compounds of the present disclosure and 177 Pharmacokinetic parameters of Lu-FAP-2286

[0650] In vivo pharmacokinetic studies showed that 177 Lu-DOTA-09, 177 Lu-DOTA-06,177 Lu-DOTA-13, 177 The half-life of Lu-DOTA-14 in rats (t 1 / 2 ) and mean residence time (MRTlast) were significantly longer than 177 Lu-FAP-2286, consistent with its longer intratumoral residence time in mouse imaging studies.

[0651] Test Example 4: In vivo efficacy study of the disclosed compounds in U-87MG model mice

[0652] 4.1 Cell Information

[0653] Name: U-87MG cells

[0654] Source: Wuhan Prosai Life Science Technology Co., Ltd.

[0655] Item No.: CL-0238

[0656] Batch number: YBMIL8BQH0

[0657] Culture conditions: U-87MG cell culture medium (90% MEM + 10% FBS + 1% P / S)

[0658] Passage times: 23-36 generations

[0659] 4.2 Experimental Animals

[0660] Lineage: B-NDG

[0661] Level: SPF level

[0662] Age: 5 weeks

[0663] Weight: 21-24g

[0664] Gender and number: Male, 90 were introduced for the construction of U-87MG model, and 40 were selected for inclusion.

[0665] Source: Biocytogen Jiangsu Gene Biotechnology Co., Ltd.

[0666] Production license: SCXK(Su)2021-0005.

[0667] Certificate number: B202311200038

[0668] 4.3 Experimental Drugs

[0669] name: 177 Lu-DOTA-09 (preparation see Example 35)

[0670] Specifications and ingredients: 31mCi / 2.5mL / 37.5nmol

[0671] 177 Lu-FAP-2286 (reference comparative example 5)

[0672] Specifications and ingredients: 15.87mCi / 1.25mL / 18.75nmol

[0673] 4.4. Instrument and equipment information

[0674] Table 9. Instrument and equipment information

[0675] 4.5 Reagent Information

[0676] Table 10. Reagent information

[0677] 4.6 Experimental Design

[0678] Prepare about 4.5 × 10 8 A suspension of 100 μL of U-87MG cells was inoculated into the posterior position of the right forelimb of B-NDG mice. The inoculation volume was 100 μL, containing 50% Matrigel and 5×10 6 A total of 90 cells were inoculated and the mice were allowed to grow until their tumors grew to 150 cm 3 About 40 mice with uniform tumor size were selected for inclusion in the group.

[0679] The dosing regimen is as follows:

[0680] Administration route: tail vein injection;

[0681] Dosing volume: 0.03-0.07 mL / animal;

[0682] Frequency and dosage of administration: The control group was given PBS, 177 Lu-FAP-2286 group received a single dose of 0.8 mCi / mouse. 177 Lu-DOTA-09 0.4mCi group received a single dose of 0.4mCi per mouse. 177 Lu-DOTA-09 0.8mCi group received a single dose of 0.8mCi per mouse. 177 Lu-DOTA-09 0.8 mCi × 2 components were administered twice, 0.8 mCi per mouse, with an interval of 35 days between administrations. Each group consisted of 8 mice. The administration time and activity of each mouse were recorded in detail.

[0683] 4.7 Operation steps

[0684] After tumor modeling, the tumor size was observed. The tumor volume and animal weight were measured using a digital caliper one day before or on the day of administration. The animals were evenly divided into 5 groups according to the tumor volume, namely: control group,177 Lu-FAP-2286 0.8mCi group, 177 Lu-DOTA-09 0.4mCi group, 177 Lu-DOTA-09 0.8mCi group, 177 Lu-DOTA-09 0.8mCi*2 groups, 8 mice in each group.

[0685] On the day of administration, prepare the test sample after receiving it (use the original test sample solution directly) and measure the activity of the prepared solution. Wipe the work surface with 75% medical alcohol and lay a disposable sterile tablecloth. Prepare a 0.5mL insulin syringe, alcohol pad, cotton swab, and marker in the injection room. Place the mouse in the holder and disinfect the mouse's tail with an alcohol pad. Administer the prepared test sample to each mouse through the tail vein, and record the time of each injection.

[0686] The tumor and body weight measurement phase begins on the second day after administration. Tumors are measured and weighed at least twice a week. The long and short diameters of the tumor are recorded each time. Measurements are made at the same location as much as possible. Abnormalities and deaths of animals are recorded in a timely manner. Animals need to be sacrificed when the average tumor diameter is greater than 20 mm or when the tumor ruptures or necrotizes. The calculation method for tumor volume is: tumor volume (mm 3 ) = major diameter × minor diameter × minor diameter × 0.52.

[0687] 4.8 Experimental Results and Discussion

[0688] Tumor growth curve

[0689] The experimental results showed that different doses of 177 Lu-DOTA-09 showed a certain inhibitory effect on tumor growth in U-87MG model mice ( FIG. 11 ).

[0690] The growth rate of U-87MG tumors was faster. The tumor size of the control group reached 3057.58±715.73mm on the 20th day after administration. 3 , 177 The tumor size of the Lu-FAP-2286 0.8 mCi group was 1833.89 ± 338.00 mm 3 , 177 The tumor size of the Lu-DOTA-09 0.4 mCi group was 790.09 ± 618.40 mm 3 , 177 Lu-DOTA-09 0.8mCi group and 177 The tumor sizes of the Lu-DOTA-09 0.8mCi*2 group were 314.25±65.57mm 3 and 326.04±82.5mm 3The tumor inhibition rates of the four drug-administered groups 20 days after administration were 40.02%, 74.16%, 89.72% and 89.34%, respectively.

[0691] 35 days after the first dose, 177 The second administration of Lu-DOTA-09 0.8mCi*2 group continued to inhibit tumor growth.

[0692] On the 46th day after taking the medicine, 177 The tumor size in the Lu-DOTA-09 0.8mCi group was 3605.05±803.40mm 3 , 177 The tumor size of the Lu-DOTA-09 0.8mCi*2 group was 1735±482.69mm 3 .

[0693] Mouse weight

[0694] 177 During the administration of Lu-DOTA-09, the body weight of mice was tested simultaneously, and it was found that there was no significant change in body weight in the mice in the four dose groups. 177 Lu-DOTA-09 did not cause any toxic side effects such as weight loss in tumor-bearing animals ( FIG. 12 ).

[0695] Mouse survival

[0696] Statistics show that 177 Lu-DOTA-09 significantly improved the survival rate of U-87MG model mice (Figure 13). In the control group, tumors began to overload on the 20th day after administration, and all died of tumors on the 42nd day, with a median survival of 35 days. 177 In the Lu-DOTA-09 0.8mCi*2 group, about half of the mice were still alive 59 days after administration. 177 Lu-DOTA-09 significantly improved the survival of tumor-bearing mice. 177 Lu-FAP-2286 0.8mCi group, 177 Lu-DOTA-09 0.4mCi group, 177 Lu-DOTA-09 0.8mCi group and 177 The median survival times of the Lu-DOTA-09 0.8mCi*2 groups were 35 days, 39 days, 42 days, 49 days and 57.5 days, respectively.

[0697] Experimental Conclusion

[0698] 177 Lu-DOTA-09 as 177Lu-labeled radioactive targeted drugs can significantly inhibit the growth of FAP-positive tumors in U-87MG model mice and prolong the survival of mice.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, in, The R 1a , R 1b are each independently selected from hydrogen or methyl; The v is selected from 0 or 1; The G1 is selected from -(CO)-LR 1c , wherein L is selected from C 3-20 Alkylene, the R 1c Selected from methyl or -NH-(C=NH)-NR 1d R 1f , the R 1d , R 1f Each independently selected from hydrogen or methyl; or said G1 is selected from The u is selected from an integer from 1 to 5; The R 2a , R 2b , R 2c are each independently selected from hydrogen or C 1-3 alkyl; The R 3a , R 3b are each independently selected from hydrogen, C 1-3 Alkyl, or R 3a , R 3b Together with the atoms to which they are attached, they form a 5- to 6-membered nitrogen-containing heterocycloalkyl group, wherein the C 1-3 The alkyl group or the 5- to 6-membered nitrogen-containing heterocycloalkyl group is optionally substituted with 1, 2 or 3 R A Substitute, the R A the same or different, selected from hydroxyl, amino, halogen, C 1-3 Alkyl or halogenated C 1-3 alkyl; The R 4a , R 4b , R 4c , R 4d are each independently selected from hydrogen, hydroxy, amino, halogen, C 1-3 Alkyl or halogenated C 1-3 alkyl; The R 5a is selected from hydrogen or methyl; The R 5b Selected from C 1-6 alkyl, 6 to 10-membered aryl or 5 to 6-membered heteroaryl, the C 1-6 alkyl, 6 to 10 membered aryl or 5 to 6 membered heteroaryl optionally substituted with 1 or 2 R B Substitute, the R B are the same or different and are selected from hydroxy, amino, halogen, -CONH2; The m is selected from 1, 2 or 3; the hydrogen on CH2 is optionally replaced by one or more selected from hydroxyl, halogen, C 1- 3-membered alkyl, 6- to 10-membered aryl, or 5- to 6-membered heteroaryl; The R 6a Selected from hydroxyl or amino; The n is selected from 1, 2 or 3; The R 7a , R 7b are each independently selected from hydrogen, C 1-3 alkyl; The q is selected from 0 or 1; The ring A is selected from phenyl, pyridyl, naphthyl or thienyl; The R 7c Each is independently selected from halogen, nitro, amino, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, trifluoromethyl, difluoromethyl, trifluoroethyl; Said p is selected from 0, 1, 2 or 3; The R 8a , R 8b Each independently selected from hydrogen, -COOH, -CONH2, CH2-OH, -CONHR 8c 、-(CO)-(NR 8c )-R 8d , the R 8c , R 8d Each region is independently selected from C 1-6 alkyl; The r is selected from 0 or 1; The s is selected from 0 or 1; The X is selected from O, S or NR 9 , the R 9 Selected from hydrogen or C 1-6 alkyl; The t is selected from 1, 2, 3, 4, 5 or 6; The R 10 Selected from hydrogen or C 1-6 alkyl; The Y is a chelating agent or hydrogen, and the chelating agent is optionally a complexing nuclide; preferably, the Y is a chelating agent.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound of formula (II) or a pharmaceutically acceptable salt thereof, The R 1a , R 1b ,v,G1,R 2a , R 2b , R 2c , R 3a , R 3b , R 4a , R 4b , R 4c , R 4d , R 5a , R 5b ,m,R 6a ,n,R 7a , R 7b ,q,ring A,R 7c , p, R 8a , R 8b , r, s, X, t, R 10 , Y as defined in claim 1.

3. The compound represented by formula (I) according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 2a is hydrogen or methyl, R 2b , R 2c Each is independently selected from hydrogen or methyl; preferably, the R 2b is hydrogen, the R 2c is methyl, or said R 2b , R 2c All are methyl.

4. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R 4a , R 4b Each independently selected from hydrogen, hydroxyl; preferably, the R 4a is hydrogen, the R 4b It is hydroxyl.

5. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 3 or 4, wherein R 2a is hydrogen or methyl; said R 2b , R 2c are each independently selected from hydrogen or methyl, and at least one is methyl; the R 4a is hydrogen, the R 4b is a hydroxyl group; said R 4c , R 4d are each independently selected from hydrogen.

6. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R 3a , R 3b are each independently selected from hydrogen, C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R A Substitute, the R A the same or different, selected from hydroxyl, amino, halogen, C 1-3 Alkyl or halogenated C 1-3 Alkyl; preferably, the R 3a is methyl, the R 3b For hydrogen.

7. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R 3a , R 3b The atoms to which they are attached form a 5-membered nitrogen-containing heterocycloalkyl group, which may be optionally substituted by 1, 2 or 3 R A Substitute, the R A the same or different, selected from hydroxyl, amino, halogen, C 1-3 Alkyl or halogenated C 1-3 Alkyl; preferably, the 5-membered nitrogen-containing heterocycloalkyl is not substituted.

8. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein: The R 7a , R 7b are each independently selected from hydrogen, C 1-3 alkyl; The q is selected from 0 or 1; The ring A is selected from phenyl or naphthyl; The R 7c Each is independently selected from halogen, nitro, amino, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, trifluoromethyl, difluoromethyl, trifluoroethyl; Said p is selected from 0, 1, 2 or 3; Preferably, The R 7a , R 7b are each independently selected from hydrogen; The q is 0; The ring A is selected from phenyl; The R 7c Each independently selected from fluorine, chlorine, bromine, iodine or trifluoromethyl, difluoromethyl, trifluoroethyl; The p is selected from 0, 1 or 2.

9. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein The R 1a , R 1b are each independently selected from hydrogen or methyl; The v is selected from 0 or 1; The G1 is selected from -(CO)-LR 1c , wherein L is selected from C 3-20 Alkylene, the R 1c Selected from methyl; Preferably, the R 1a , R 1b are each independently selected from hydrogen; The v is selected from 0; The G1 is selected from -(CO)-LR 1c , wherein L is selected from C 4-14 Alkylene, the R 1c Selected from methyl.

10. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein: The R 1a , R 1b are each independently selected from hydrogen or methyl; The v is selected from 0 or 1; The G1 is selected from -(CO)-LR 1c , wherein L is selected from C 3-20 Alkylene, the R 1c Selected from -NH-(C=NH)-NR 1d R 1f , the R 1d , R 1f are each independently selected from hydrogen or methyl; Preferably, The R 1a , R 1b are each independently selected from hydrogen; The v is selected from 0; The G1 is selected from -(CO)-LR 1c , wherein L is selected from C 4-14 Alkylene, the R 1c Selected from -NH-(C=NH)-NR 1d R 1f , the R 1d , R 1f are each independently selected from hydrogen or methyl.

11. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein: The R 1a , R 1b are each independently selected from hydrogen or methyl; The v is selected from 0 or 1; The G1 is selected from The u is selected from an integer from 1 to 5; Preferably, The R 1a , R 1b are each independently selected from hydrogen; The G1 is selected from The v is selected from 0; The u is selected from 1 or 2.

12. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein: The R 5a Selected from hydrogen; The R 5b Selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with 1 or 2 R B Substitute, the R B are the same or different and are selected from hydroxyl or halogen; The m is selected from 0 or 1; the hydrogen on CH2 is optionally replaced by one or more selected from hydroxyl, halogen, C 1-3 Alkyl substitution; The n is 2; The R 6a It is amino group; The R 8a , R 8b Each is independently selected from hydrogen, -COOH, and -CONH2, and at least one of them is -COOH or -CONH2, and r is 1.

13. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound of formula (III) or a pharmaceutically acceptable salt thereof, The R 2a is hydrogen or methyl; The R 2b , R 2c Each is independently selected from hydrogen or methyl, and at least one is methyl; The R 3a , R 3b are each independently selected from hydrogen, C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R A Substitute, the R A the same or different, selected from hydroxyl, amino, halogen, C 1-3 Alkyl or halogenated C 1-3 Alkyl; or said R 3a , R 3b The atoms to which they are attached form a 5-membered nitrogen-containing heterocycloalkyl group, which may be optionally substituted by 1, 2 or 3 R A Substitute, the R A the same or different, selected from hydroxyl, amino, halogen, C 1-3 Alkyl or halogenated C 1-3 alkyl; The R 4a is hydrogen, fluorine or trifluoromethyl, said R 4b Fluorine and hydroxyl groups; The R 4c , R 4d are each independently selected from hydrogen; The R 7c Each independently selected from fluorine, chlorine, bromine, iodine or trifluoromethyl, difluoromethyl, trifluoroethyl; Said p is selected from 0, 1 or 2; G1, s, X, t, R 10 , Y as defined in claim 1.

14. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 13, wherein R 4a is hydrogen, the R 4b It is hydroxyl.

15. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 14, wherein R 3a is methyl, the R 3b For hydrogen.

16. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 14, wherein R 3a , R 3b Together with the atoms to which they are attached, they form a 5-membered nitrogen-containing heterocycloalkyl group, which is not substituted.

17. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein s is 1; X is S; R 10 For hydrogen.

18. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 17, wherein G1 is selected from -(CO)-LR 1c , wherein L is selected from C 4-14 Alkylene, the R 1c is selected from methyl; preferably, L is selected from C4 alkylene, C6 alkylene, C8 alkylene, C 10 Alkylene, C 12 Alkylene or C 14 Alkylene.

19. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 17, wherein G1 is selected from -(CO)-LR 1c , wherein L is selected from -(CO)-LR 1c , wherein L is selected from C 4-14 Alkylene, the R 1c Selected from -NH(C=NH)-NR 1d R 1f , the R 1d , R 1f Each is independently selected from hydrogen or methyl; preferably, L is selected from C4 alkylene, C5 alkylene or C6 alkylene.

20. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 17, wherein: The G1 is selected from The u is selected from 1 or 2.

21. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, wherein the fragment connected to Y is selected from Group 1: Group 2: Group 3:

22. The compound of formula (I) according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, wherein the chelating agent is selected from DOTA, DOTAGA, NOTA, NODAGA, NODA-MPAA, HBED, TETA, CB-TE2A, DTPA, DFO, Macropa, HOPO, TRAP, THP, DATA, NOTP, sarcophagine, FSC, NETA, H4octapa, Pycup, NxS4-x (N4, N2S2, N3S), Hynic, 99mTc (CO) 3-chelating agent, Preferred are DOTA, DOTAGA, NOTA, NODAGA, NODA-MPAA, HBED, CB-TE2A, DFO, THP, N4; most preferred are DOTA, DOTAGA, NOTA and NODAGA.

23. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 22, selected from: Group 4: Hex-[Cys-(tMeBn(DOTA-AET))-Ala-Pro-(4-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-Pro-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Sar-(4-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(3-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(4-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(2-Cl-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(3-Cl-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(4-Cl-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(3-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(4-CF3-Phe)-Cys]-OH、 Oct-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Dec-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Dod-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Tet-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Pal-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 {2-[2-(2-Methoxyethoxy)ethoxy]-Ace}-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 [2-(2-Methoxyethoxy)-Ace]-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-F-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-F-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-F-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-(4-OH-Pro)-(4-OH-Pro)-Thr-Gln-Phe-Cys]-OH (5-guanidineValy)-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(2-Nal)-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Ala-Pro-Pro-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Ala-Pro-Pro-Thr-Gln-(2-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Ala-Pro-Pro-Thr-Gln-(2-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Sar-(4-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(3-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(4-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(2-Cl-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(3-Cl-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(4-Cl-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(3-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-(4-OH-Pro)-Thr-Gln-(4-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-(4-F-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-(4-F-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-(4-F-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Ala-Pro-Pro-Thr-Gln-(2-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Ala-Pro-Pro-Thr-Gln-(2-CF3-Phe)-Cys]-OH; Group 5: Hex-[Cys-(tMeBn(DOTA-AET))-Ala-Pro-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Sar-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(3-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(4-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-Cl-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(3-Cl-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(4-Cl-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(3-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(4-CF3-Phe)-Cys]-OH、 Oct-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Dec-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Dod-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Tet-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Pal-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 {2-[2-(2-Methoxyethoxy)ethoxy]-Ace}-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 [2-(2-Methoxyethoxy)-Ace]-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-((4R)-OH-Pro)-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 (5-guanidineValy)-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-Nal)-Cys]-OH Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Sar-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(3-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(4-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-Cl-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(3-Cl-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(4-Cl-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(3-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(4-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH; Group 6: Hex-[Cys-(tMeBn(DOTA-AET))-Ala-Pro-((4S)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Sar-((4S)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(3-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(4-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(2-Cl-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(3-Cl-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(4-Cl-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(3-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(4-CF3-Phe)-Cys]-OH、 Oct-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Dec-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Dod-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Tet-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Pal-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 {2-[2-(2-Methoxyethoxy)ethoxy]-Ace}-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 [2-(2-Methoxyethoxy)-Ace]-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-F-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-F-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-F-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-((4R)-OH-Pro)-((4S)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 (5-guanidineValy)-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn(DOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(2-Nal)-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Sar-((4S)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(3-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(4-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(2-Cl-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(3-Cl-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(4-Cl-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(3-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4S)-OH-Pro)-Thr-Gln-(4-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4S)-F-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4S)-F-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(NOTA-AET))-Aib-Pro-((4S)-F-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH.

24. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 23, wherein the chelating agent complexes a nuclide, the nuclide comprises a diagnostically active nuclide or a therapeutically active nuclide, the diagnostically active nuclide is selected from 43 Sc, 44 Sc, 51 Mn, 52 Mn, 64 Cu, 67 Ga, 68 Ga, 86 Y. 89 Zr, 94m Tc, 99m Tc, 111 In, 152 Tb, 155 Tb, 201 Tl, 203 Pb, 18 F. 76 Br, 77 Br, 123 I. 124 I. 125 I; preferred 43 Sc, 44 Sc, 64 Cu, 67 Ga, 68 Ga, 86 Y. 89 Zr, 99m Tc, 111 In, 152 Tb, 155 Tb, 203 Pb, 18 F. 76 Br, 77 Br, 123 I. 124 I. 125 I; Most preferably 64 Cu, 68 Ga, 89 Zr, 99m Tc, 111 In, 18 F. 123 I and 124 I; the therapeutically active nuclide is selected from 47 Sc, 67 Cu, 89 Sr. 90 Y. 153 Sm, 149 Tb, 161 Tb, 177 Lu, 186 Re, 188 Re, 212 Pb, 213 Bi, 223 Ra, 225 Ac, 226 Th, 227 Th, 131 I. 211 At; preferred 47 Sc, 67 Cu, 90 Y. 177 Lu, 188 Re, 212 Pb, 213 Bi, 225 Ac, 227 Th, 131 I. 211 At; best 90 Y. 177 Lu, 225 Ac, 227 Th, 131 I and 211 At.

25. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 24, selected from: Hex-[Cys-(tMeBn( 68 Ga-DOTA-AET))-Aib-Sar-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn( 68 Ga-DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn( 68 Ga-DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn( 68 Ga-DOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn( 68 Ga-DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn( 68 Ga-DOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn( 68 Ga-DOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn( 68 Ga-DOTA-AET))-Ala-Pro-Pro-Thr-Gln-(2-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn( 68 Ga-DOTA-AET))-Ala-Pro-Pro-Thr-Gln-(2-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn( 177 Lu-DOTA-AET))-Aib-Sar-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn( 177 Lu-DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn( 177 Lu-DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH Hex-[Cys-(tMeBn( 177 Lu-DOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn( 177 Lu-DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn( 177 Lu-DOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn( 177 Lu-DOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn( 177 Lu-DOTA-AET))-Ala-Pro-Pro-Thr-Gln-(2-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn( 177 Lu-DOTA-AET))-Ala-Pro-Pro-Thr-Gln-(2-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn( 64 Cu-DOTA-AET))-Aib-Sar-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn( 64 Cu-DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn( 64 Cu-DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH Hex-[Cys-(tMeBn( 64 Cu-DOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn( 64 Cu-DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn( 64 Cu-DOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn( 64 Cu-DOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn( 64 Cu-DOTA-AET))-Ala-Pro-Pro-Thr-Gln-(2-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn( 64 Cu-DOTA-AET))-Ala-Pro-Pro-Thr-Gln-(2-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn( 225 Ac-DOTA-AET))-Aib-Sar-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn( 225 Ac-DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn( 225 Ac-DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH Hex-[Cys-(tMeBn( 225 Ac-DOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn( 225 Ac-DOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn( 225 Ac-DOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-(2-F-Phe)- Cys]-OH、 Hex-[Cys-(tMeBn( 225 Ac-DOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn( 225 Ac-DOTA-AET))-Ala-Pro-Pro-Thr-Gln-(2-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn( 64 Cu-DOTA-AET))-Ala-Pro-Pro-Thr-Gln-(2-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(Al 18 F-NOTA-AET))-Aib-Sar-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn(Al 18 F-NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn(Al 18 F-NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(Al 18 F-NOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn(Al 18 F-NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(Al 18 F-NOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(Al 18 F-NOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(Al 18 F-NOTA-AET))-Ala-Pro-Pro-Thr-Gln-(2-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn(Al 18 F-NOTA-AET))-Ala-Pro-Pro-Thr-Gln-(2-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn( 68 Ga-NOTA-AET))-Aib-Sar-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn( 68 Ga-NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn( 68 Ga-NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH Hex-[Cys-(tMeBn( 68 Ga-NOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn( 68 Ga-NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn( 68 Ga-NOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn( 68 Ga-NOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn( 68 Ga-NOTA-AET))-Ala-Pro-Pro-Thr-Gln-(2-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn( 68 Ga-NOTA-AET))-Ala-Pro-Pro-Thr-Gln-(2-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn( 64 Cu-NOTA-AET))-Aib-Sar-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn( 64 Cu-NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn( 64 Cu-NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH Hex-[Cys-(tMeBn( 64 Cu-NOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-Phe-Cys]-OH、 Hex-[Cys-(tMeBn( 64 Cu-NOTA-AET))-Aib-Pro-((4R)-OH-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn( 64 Cu-NOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-(2-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn( 64 Cu-NOTA-AET))-Aib-Pro-((4R)-F-Pro)-Thr-Gln-(2-CF3-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn( 64 Cu-NOTA-AET))-Ala-Pro-Pro-Thr-Gln-(2-F-Phe)-Cys]-OH、 Hex-[Cys-(tMeBn( 64 Cu-NOTA-AET))-Ala-Pro-Pro-Thr-Gln-(2-CF3-Phe)-Cys]-OH。 26. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 25 and one or more pharmaceutically acceptable carriers, diluents or excipients.

27. A method for preparing a compound of formula (I) according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26, comprising the step of complexing the compound or the pharmaceutically acceptable salt thereof with a nuclide.

28. Use of a compound of formula (I) according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26, in the preparation of a medicament for diagnosing or treating a disease, wherein the disease is a disease involving fibroblast activation protein (FAP); preferably, the disease involving fibroblast activation protein (FAP) is a disease associated with upregulated expression of fibroblast activation protein (FAP); more preferably, the disease involves cells showing upregulated expression of fibroblast activation protein (FAP) or diseased tissue containing cells showing upregulated expression of fibroblast activation protein (FAP), such as a tumor or cancer.

29. according to the compound shown in the formula (I) described in any one of claims 1 to 25 or its pharmaceutically acceptable salt or the purposes of the pharmaceutical composition described in claim 26 in the preparation of the medicine for diagnosing or treating disease, described disease is tumor or cancer, described tumor or cancer is selected from solid tumor, epithelioma, bladder cancer, breast cancer, cervical cancer, colorectal cancer, bile duct cancer, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumor, head and neck cancer, liver cancer, lung cancer, melanoma, mesothelioma, neuroendocrine tumor and cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, salivary gland cancer, sarcoma, squamous cell carcinoma, glioma (such as human brain astrocytoma glioblastoma cell), and thyroid cancer (such as medullary thyroid carcinoma).

30. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 25 or a pharmaceutical composition according to claim 26 in the preparation of a medicament for diagnosing or treating a disease selected from inflammatory diseases, cardiovascular diseases, autoimmune diseases and fibrotic diseases.

31. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 24 or 25, or a pharmaceutical composition according to claim 26, comprising the steps of complexing the compound of formula (I) or a pharmaceutically acceptable salt thereof with a nuclide, The Y is a chelating agent, the chelating agent complexes the nuclide, and the R 1a , R 1b ,v,G1,R 2a , R 2b , R 2c , R 3a , R 3b , R 4a , R 4b , R 4c , R 4d , R 5a , R 5b ,m,R 6a ,n,R 7a , R 7b ,q,ring A,R 7c , p, R 8a , R 8b , r, s, X, t, R 10 As defined in claims 1 to 25.

32. A method for preparing a compound of formula (I) according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 26, the method comprising the step of reacting a compound of formula (I-1) with a chelating agent, The R 1a , R 1b ,v,G1,R 2a , R 2b , R 2c , R 3a , R 3b , R 4a , R 4b , R 4c , R 4d , R 5a , R 5b ,m,R 6a ,n,R 7a , R 7b ,q,ring A,R 7c , p, R 8a , R 8b , r, s, X, t, R 10 As defined in claims 1 to 25.

33. A compound represented by formula (I-2) or a pharmaceutically acceptable salt thereof, The R 1a , R 1b ,v,G1,R 2a , R 2b , R 2c , R 3a , R 3b , R 4a , R 4b , R 4c , R 4d , R 5a , R 5b ,m,R 6a ,n,R 7a , R 7b ,q,ring A,R 7c , p, R 8a , R 8b , r as defined in claims 1 to 25.

34. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 13 to 25, comprising the steps of reacting a compound of formula (III-1) or a pharmaceutically acceptable salt thereof with 2-aminoethanethiol and 1,3,5-tris(bromomethyl)benzene, Y is hydrogen; R 10 is hydrogen; t is 1; X is a sulfur atom; s is 1; The R 2a , R 2b , R 2c , R 3a , R 3b , R 4a , R 4b , R 4c , R 4d , R 7c , p, G1 as defined in claims 13 to 25.

35. The preparation method according to claim 31 or 32, further comprising the steps in the preparation method according to claim 34.

36. A compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof, The R 2a , R 2b , R 2c , R 3a , R 3b , R 4a , R 4b , R 4c , R 4d , R 7c , p, G1 as defined in claims 13 to 25.

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