Radioactive compounds targeting sstr receptors and uses thereof

Abstract

This application generally relates to the field of radioactive compounds that target cell surface receptors (such as somatostatin receptors). In particular, this application relates to compounds comprising radionuclides. This application also relates to methods of using the compound or its salts to target and / or kill target cells.

Description

[0001] Cross-referencing

[0002] This application claims priority to International Patent Application No. PCT / CN2023 / 135488, filed November 30, 2023; International Patent Application No. PCT / CN2024 / 121427, filed September 26, 2024; and International Patent Application No. PCT / CN2024 / 130720, filed November 8, 2024, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This application generally relates to the field of compounds that target cell surface receptors, such as somatostatin receptors. In particular, the present invention relates to compounds comprising radionuclides. This application also relates to methods of using the compound or a pharmaceutically acceptable salt thereof to target and / or kill tumor cells expressing somatostatin receptor 2 (SSTR2). Background Technology

[0004] Somatostatin, also known as growth hormone-inhibiting hormone (GHIH), is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation through interaction with a G protein-coupled somatostatin receptor and inhibition of the release of various secondary hormones. Somatostatin receptor type 2 (SSTR2) can be activated by somatostatin and is encoded by the SSTR2 gene in humans. SSTR2 is most highly expressed in the pancreas (both α and β cells), but is also expressed in other tissues such as the brain and kidneys, and at lower levels in the jejunum, colon, and liver. Abnormalities in the SSTR2 signaling pathway have been found to be associated with various diseases, including cancer.

[0005] Studies have shown that high expression of somatostatin type 2 receptor (SSTR2) is a key characteristic of neuroendocrine tumors. Therefore, SSTR2 has been extensively explored as a therapeutic target for delivering radionuclides containing SSTR2-binding peptide complexes to tumor tissue, enabling PET or SPECT / CT-based diagnostics and internal α or β radiotherapy. However, new methods with higher tumor cell selectivity and robust efficacy remain needed. This application addresses these needs. Invention Overview

[0007] In one respect, this article provides compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0008] (I)

[0009] in:

[0010] T is the trivalent component.

[0011] Z is the somatostatin receptor 2 (SSTR2) binding site, where Z is located via the linker L Z Combined with T,

[0012] E is the effector part, where E is connected via the connector L. E Combined with T,

[0013] A is the unsubstituted or substituted fatty acid moiety, wherein A is via the linker L A With T, and

[0014] L Z L E and L A Each is an independent key or a binary connector.

[0015] In some implementations, L A Is it a key or a binary connector: –(Y) n - where n is an integer from 1 to 20, and each Y is independently selected from amino acid residues and -N(R N (C2 alkylene Y) a ) y1 Y b The group consisting of C(O)-, where R N Is it H or C? 1- C6 alkyl, wherein Y a It is -O-, -S-, -NH- or -N(C 1- C6 alkyl)-, where y1 is an integer from 1 to 10, and where Y b It is C 1- C3 alkylene. In some embodiments, L A It contains one or more amino acid residues. In some embodiments, L A Contains one or more amino acid residues, each independently selected from the group consisting of: alanine (Ala, A), asparagine (Asn, N), aspartic acid (Asp, D), glutamine (Gln, Q), glutamic acid (Glu, E), γGlu, glutamine (Gln), glycine (Gly, G), isoleucine (Ile, I), leucine (Leu, L), εLys, methionine (Met, M), phenylalanine (Phe, F), proline (Pro, P), serine (Ser, S), threonine (Thr, T), tryptophan (Trp, W), tyrosine (Tyr, Y), valine (Val, V), pyrrolidone (Pyl, O), pyrrolidone-carboxy-lysine (PCL), γ-carboxyglutamic acid (Gla), NR 5C5 alkylene C(O)(Ahx), cysteine ​​(Cya), leucine (Nle), valine (Nva), 2-aminooctanoic acid (Aoc), 2-naphthylalanine (2-Nal), 3-(trifluoromethyl)phenylalanine (TFP), homophenylalanine (hPhe), cyclohexylalanine (Cha), 1-naphthylalanine (1-Nal), 4-benzoyl-L-phenylalanine (Bpa), 2-methoxy-4-vinylphenylalanine (MvF), 4-fluorophenylalanine (Bpa), 4-phenyl-2, 3-Dihydroxy-6-nitrophenylalanine (pNIPA), 2-(2-naphthyl)alanine (2-Nal-ala), 4-(4-propoxyphenyl)alanine (Ppa), 4-carboxyphenylalanine (4-CPA), 4-butylphenylalanine (Bua), 2-nitrophenylalanine (2-Npa), 4-azidophenylalanine (4-AzF), 2-(4-nitrophenyl)ethylalanine (2-Npe), 3-iodo-L-tyrosine (Ity), 5,5,5-trifluoroleucine (TFL), or their D enantiomers. In some embodiments, L A It comprises one or more negatively charged amino acid residues, wherein each negatively charged amino acid residue is independently and optionally selected from the group consisting of: D-Asp, Asp, D-Glu, Glu, D-γGlu, γGlu, and Cya. In some embodiments, L A It includes one or more D-Asp, Asp, or any combination thereof. In some implementations, L A It comprises one or more neutral amino acid residues, wherein each amino acid residue is independently and optionally selected from the group consisting of: Gly, D-Pro, Pro, D-Ser, and Ser. In some embodiments, L A It contains one or more neutral amino acid residues, wherein each amino acid residue is independently and optionally selected from the group consisting of Gly and Ser.

[0016] In some implementations, L A Includes -N(R) N (C2-alkyleneO) y1 Y b C(O)-, where R N Let H be an integer from 1 to 10, and Y be a integer from 1 to 10. b It is C 1- C3 alkylene. In some embodiments, -N(R N (C2 alkylene Y) a ) y1 Y bC(O)- is -NH(C2alkyleneO)2C1alkyleneC(O) (OEG), -NH(C2alkyleneO)C2alkyleneC(O) (PEG1), -NH(C2alkyleneO)3C2alkyleneC(O) (PEG3), or -NH(C2alkyleneO)6C2alkyleneC(O) (PEG6). In some embodiments, each Y is independently selected from the group consisting of: Ahx, Cya, Gla, Gly, D-Ala, Ala, D-Val, Val, D-Leu, Leu, D-Phe, Phe, D-Pro, Pro, D-Met, Met, D-Trp, Trp, D-Thr, Thr, D-Tyr, Tyr, D-Nle, Nle, D-Ser, Ser, D-Asp, Asp, D-Glu, Glu, D-γGlu, γGlu, OEG, and PEG1. In some implementations, each Y is independently selected from the following group: Gly, D-Asp, Asp, D-Glu, Glu, D-γGlu, γGlu, and OEG. In some implementations, n is an integer from 1 to 10. In some implementations, n is an integer from 1 to 5.

[0017] In some implementations, L A It is a bivalent connector containing 1 to 5 Asp. In some implementations, L A It includes –(Asp) 2-5 – a bivalent connector. In some implementations, L A It contains –(D-Asp) 2-5 – a bivalent connector. In some implementations, L A It contains 2 to 5 Asp, and 2 to 5 of these Asp are in L A The middle part is discontinuous. In some implementations, L A It is a key, -γGlu-γGlu-, -Glu-γGlu-, -Asp-, -Asp-Asp-, -γGlu-, -Gly-Ser-Gly-, -Asp-Asp-Asp-, -γGlu-γGlu-OEG-OEG-, -Asp-Asp-Gly-Gly-Gly-, -Asp-, -Glu-Glu-, -(D-Asp)-(D-Asp)-, -Gly-Gly-, -Asp-Asp-Asp-Asp-, -Cya-, -Gla-, -eLys-eLys-, -Ahx-Ahx-, -Gly-Ser-Gly-, or -Asp-Asp-OEG-. In some implementations, L A Is -Asp-Asp-, -Asp-Asp-Asp-, -(D-Asp)-(D-Asp)-, or -Asp-Asp-Asp-Asp-.

[0018] In some embodiments, T comprises one or more amino acid residues, each independently selected from the group consisting of: Lys, D-Lys, ornithine (Orn), homolysine, 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab), cysteine, homocysteine, glutamine, glutamic acid, asparagine, aspartic acid, 3,5-bis(aminomethyl)benzoic acid (Bab), 4-aminomethylphenylalanine (Amp), 4R-4-aminoproline (Apr), 4-(2-aminoethoxy)phenylalanine, 4-aminopiperidin-4-carboxylic acid (Apc), and 2-((1,3-diaminopropyl-2-yl)oxy)acetic acid (Dpa). In some embodiments, T is Lys, D-Lys, Amp, Apr, or Bab. In some embodiments, T comprises Lys or D-Lys. In some embodiments, when T contains any of the amino acid residues selected from the group consisting of Lys, D-Lys, Orn, homolysine, 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab), cysteine, homocysteine, glutamine, glutamic acid, asparagine, aspartic acid, 4R-4-aminoproline (Apr), and 4-(2-aminoethoxy)phenylalanine, then A is conjugated to the α-amino group of T. In some embodiments, when T contains Lys or D-Lys, then A is conjugated to the α-amino group of Lys or D-Lys.

[0019] In some embodiments, A is a fatty acid moiety. In some embodiments, A is a saturated fatty acid moiety. In some embodiments, A is a fatty monocarboxylic acid moiety; in some embodiments, A is an unsubstituted or substituted C8-C moiety. 18 Fatty monocarboxylic acid moiety. In some embodiments, A is unsubstituted or substituted C. 10 -C 16 Fatty monocarboxylic acid moiety. In some embodiments, A is unsubstituted or substituted C. 10 Fatty monocarboxylic acid moiety. In some embodiments, A is unsubstituted or substituted C. 12 Fatty monocarboxylic acid moiety. In some embodiments, A is unsubstituted or substituted C. 14 Or C 16 Fatty monocarboxylic acid moiety. In some embodiments, A is -C(O)A. a A a Is it unsubstituted or substituted C? 3- C 23 Alkyl group. In some embodiments, A a It is C7 alkyl, C8 alkyl, C9 alkyl, C 10 Alkyl, C 11 Alkyl, C 12 Alkyl, C 13Alkyl, C 14 Alkyl, C 15 Alkyl, C 16 Alkyl or C 17 Alkyl groups, each of which is either unsubstituted or substituted.

[0020] In some implementations, L Z Is it a key or a binary connector: –(X) m - where m is an integer from 1 to 20, and each X is independently selected from amino acid residues and -N(R N (C2 alkylene X) a ) x1 X b The group consisting of C(O), where R N Is it H or C? 1-6 Alkyl, wherein X a It is -O-, -S-, -NH- or -N(C 1-6 Alkyl)-, where x1 is an integer from 1 to 10, and where X b It is C 1-3 Alkylene.

[0021] In some implementations, L Z It is a divalent linker containing one or more amino acid residues. In some embodiments, the amino acid residues are neutral. In some embodiments, L Z Contains one or more amino acid residues, each independently selected from the group consisting of: alanine (Ala, A), asparagine (Asn, N), glutamine (Gln, Q), glycine (Gly, G), isoleucine (Ile, I), leucine (Leu, L), methionine (Met, M), phenylalanine (Phe, F), proline (Pro, P), serine (Ser, S), threonine (Thr, T), tryptophan (Trp, W), tyrosine (Tyr, Y), valine (Val, V), pyrrolidone (Pyl, O), pyrrolidone-carboxy-lysine (PCL), NR 5C5 alkylene C(O) (Ahx), leucine (Nle), valine (Nva), 2-aminooctanoic acid (Aoc), 2-naphthylalanine (2-Nal), 3-(trifluoromethyl)phenylalanine (TFP), homophenylalanine (hPhe), cyclohexylalanine (Cha), 1-naphthylalanine (1-Nal), 4-benzoyl-L-phenylalanine (Bpa), 2-methoxy-4-vinylphenylalanine (MvF), 4-fluorophenylalanine (Bpa), 4-phenyl-2,3- -Dihydroxy-6-nitrophenylalanine (pNIPA), 2-(2-naphthyl)alanine (2-Nal-ala), 4-(4-propoxyphenyl)alanine (Ppa), 4-carboxyphenylalanine (4-CPA), 4-butylphenylalanine (Bua), 2-nitrophenylalanine (2-Npa), 4-azidophenylalanine (4-AzF), 2-(4-nitrophenyl)ethylalanine (2-Npe), 3-iodo-L-tyrosine (Ity), and 5,5,5-trifluoroleucine (TFL). In some embodiments, L Z It comprises one or more neutral amino acid residues, wherein each neutral amino acid residue is independently Gly, D-Pro, Pro, D-Ser, and Ser. In some embodiments, L Z It contains one or more Gly.

[0022] In some implementations, L Z Includes -N(R) N (C2 alkylene X) a ) x1 X b C(O), where R N Let H be an integer from 1 to 10, and let X be a variable. b It is C 1- C3 alkylene. In some embodiments, R N It is H. In some implementations, L ZIt comprises one or more portions, each independently selected from -NH(C2alkyleneO)2C1alkyleneC(O) (OEG), -NH(C2alkyleneO)C2alkyleneC(O) (PEG1), -NH(C2alkyleneO)3C2alkyleneC(O) (PEG3), or -NH(C2alkyleneO)6C2alkyleneC(O) (PEG6). In some embodiments, each X is independently selected from the group consisting of: Ahx, Gly, D-Ala, Ala, D-Val, Val, D-Leu, Leu, D-Phe, Phe, D-Pro, Pro, D-Met, Met, D-Trp, Trp, D-Thr, Thr, D-Tyr, Tyr, D-Nle, Nle, D-Ser, Ser, OEG, and PEG1. In some embodiments, each X is independently selected from the group consisting of: Gly, Pro, Ser, and OEG. In some embodiments, m is an integer from 1 to 15. In some implementations, m is an integer from 1 to 10. In some implementations, m is an integer from 1 to 6.

[0023] In some implementations, L Z It is a bivalent connector containing 1 to 6 OEGs. In some implementations, L Z It is a bivalent connector containing 1 to 6 Gly. In some implementations, L Z Yes – (Gly) 2-5 –. In some implementations, L Z It contains 2 to 5 Gly, and these 2 to 5 Gly are not consecutive. In some implementations, L Z Yes key, -OEG-OEG-, -OEG-, -Gly-Gly-Gly-, -Gly-Ser-Gly-Ser-Gly-Ser-, - Pro-Gly-Pro-Gly-Pro-Gly-, -γGlu-γGlu -OEG-OEG-, - Asp-Asp-Gly-Gly-Gly-, -Gly-Gly-Gly-Gly-Gly-Gly-, -Gly-Tyr-Gly-, -Gly-Ser-Gly-, -Gly- or -Gly-Gly-. In some embodiments, L Z It is -Gly-Gly-Gly-.

[0024] In some embodiments, E comprises a chemotherapeutic agent, a toxin, an immunomodulator, a diagnostic agent, a radionuclide, or a chelating group. In some embodiments, E comprises a radionuclide selected from the group consisting of: 14 C 15 N、 18 F, 75 Br、 76 Br、77 Br, 123 I, 124 I, 125 I, 131 I, 35 S, 18 F, 211 At, 32 P, 33 P and 125I. In some embodiments, E comprises a chelating group derived from a chelating agent. In some embodiments, the chelating agent is selected from the group consisting of: 1,4,7-triazacyclononane (TACN), 1,4,7-triazacyclononane-triacetic acid (NOTA), 1,4,7-triazacyclononane-N-succinic acid-N',N''-diacetic acid (NOTASA), 1,4,7-triazacyclononane-N-glutamic acid-N',N''-diacetic acid (NODAGA), 1,4,7-triazacyclononane-N,N',N''-tris(methylenephosphonic acid) acid (NOTP), 1,4,7,10-tetraazacyclododecane (

[12] aneN4)(c yclen), 1,4,7,10-tetraazacyclotridecane (

[13] aneN4), 1,4,7,11-tetraazacyclotetradecane (iso-cyclam), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 2-(1,4,7,10-tetraazacyclododecane-1-yl)acetate (DO1A), 2,2'-(1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid (DO2A), 2,2',2''-(1,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)triacetic acid (DO3A), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylphosphonic acid) (DOTP), 1,4,7,10-tetraazacyclododecane-1,7-bis(methylphosphonic acid) (DO2P), 1 ,4,7,10-Tetraazacyclododecane-1,4,7-tris(methylphosphonic acid) (DO3P), 1,4,7,10-tetraazacyclododecane-1-glutamic acid-4,7,10-triacetic acid (DOTAGA), 1,4,7,10-tetraazacyclododecane-1-succinic acid-4,7,10-triacetic acid (DOTASA), 1,4,8,11-tetraazacyclotetradecane (

[14] aneN4) (cyclam), 1,4,8,12-tetraazacyclopentadecane (

[15] aneN4), 1,5,9,13-tetraazacyclododecane (

[16] aneN4), 1,4 -Ethylene-1,4,8,11-tetraazacyclotetradecane (et-cyclam), 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA), 2-(1,4,8,11-tetraazacyclotetradecane-1-yl)acetic acid (TE1A), 2,2'-(1,4,8,11-tetraazacyclotetradecane-1,8-diyl)diacetic acid (TE2A), 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CB-TE2A), 3,6,10,13,16,19-hexaazabicyclo[6.6.2].6] Eicosane (Sar), 1,4,7,10-tetra-(2-carbamoyl-methyl)-cyclododecane (TCMC), N,N'-bis[(6-carboxy-2-pyridine)methyl]-4,13-diaza-18-crown ether-6 (macropa), phthalocyanine, porphyrin, PCTA (3,6,9,15-tetraazabicyclo[9.3.1]pentadecano-1(15),11,13-trien-3,6,9-triacetic acid), DEPA (7-[2-(biscarboxymethylamino)ethyl]-4,10-biscarboxymethyl-1,4,7,10-tetraazacyclododecane-1-yl-acetic acid), DTPA (1,1,4,7,7-diethylenetriaminepentaacetic acid), CHX-DTPA (cyclohexane-1,2 1,2-diamine N,N,N',N'-tetraacetic acid, BATPA (1,2-bis[2-aminophenoxy]ethane-N,N,N',N'-tetraacetic acid), TTHA (triethylenetetramine N,N,N',N'',N''',N'''-hexaacetic acid), HBED (N,N'-bis[2-hydroxybenzyl]ethylenediamine-N,N'-diaacetic acid), EGTA (ethylene glycol bis[2-aminoethyl ether]-N,N,N',N'-tetraacetic acid), EDTMP (ethylenediamine tetra- [Methylenephosphonic acid]), TRAP (triazacyclononanoic acid), SHBED (N,N'-bis[2-hydroxy-5-sulfobenyl]ethylenediaminediacetic acid), H6Sbbpen (N,N'-bis-[2-hydroxy-5-sulfobenyl]-N,N'-bis[2-methylpyridine]ethylenediamine), THP (tris(3,4-hydroxypyridinone)), DFO (deferroamine), FSC (fusarium oxychloride), 6SS (N,N'-bis[2,2-dimethyl-2- ... [-mercaptoethyl]ethylenediamine-N,N'-diacetic acid), ECC (ethylene cysteine), ECD (cysteine ​​ethyl ester dimer), NETA ([2-{4,7-biscarboxymethyl(1,4,7)triazacyclononane-1-yl-ethyl}carbonylmethylamino]acetic acid), THPN (tetra(3-hydroxy-4-pyridinone)), H2dedpa (1,2-[{6-(carboxylic acid-)pyridin-2-yl}methylamino]ethane), H4octapa (N,N'-bis[6-carboxy-2-pyridinylmethyl]ethylenediamine-N,N'-diacetic acid), H2bispa2 (6,6'-[{9-hydroxy-1,5-bis-(methoxycarbonyl)-2,4-bis(pyridin-2-yl)-3,7-diazabicyclo[3.3]).[1]nonane-3,7-diyl}bis(methylene)]pyridinedicarboxylic acid), DOTMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl-tetra(methylphosphonic acid)), PEPA (1,4,7,10,13-pentazocyclopentadecanoacetic acid), HEHA (1,4,7,10,13,16-hexazocyclooctadecanehexaacetic acid), H2hox, H2CHXhox, H2octox, H2pyhox, H4neunopa, TETPA, H4pypa, H4py4pa, DTPAM, EGTAM, ampam, Me-3,2-HOPO, 3,4,3-(LI-1,2-HOPO), and macrocyclic tetraphthalimides. In some embodiments, the chelating group is derived from DOTA or DOTAGA.

[0025] In some embodiments, the radionuclides are each independently a radioisotope of As, Se, K, Sc, Ti, Cr, Mn, Fe, Co, Ni, Cu, Ga, Ge, Rb, Sr, Y, Zr, Nb, Tc, Rh, Pd, In, Sn, Sb, Zn, Ta, W, Re, Os, Ir, Pt, Au, Hg, Tl, Pb, Bi, Po, Fr, Pm, lanthanides, actinides, Mg, Al, Ca, Cd, or Ba. In some embodiments, the lanthanides are Lu, Sm, Ho, or Tb. In some embodiments, the actinides are Ac, Th, or U. In some embodiments, one or more radionuclides are each independently selected from the group consisting of: 99 Tc, 99m Tc, 188 Re、 186 Re、 153 Sm、 66 Ga、 67 Ga、 68 Ga、 111 In、 123 In、 59 Fe、 63 Zn, 52 Fe、 52 Mn, 45 Ti、 60 Cu、 61 Cu、 67 Cu、 64 Cu、 62 Cu、 82 Rb、 195m Pt, 191m Pt, 193m Pt, 117m Sn、 89 Zr、 177 Lu、 18 F,188 Re、 186 Re、 153 Sm、 66 Ho、 86 Y、 87 Y、 90 Y、 89 Sr、 153 Gd, 159 Gd, 225 Ac、 212 Bi、 213 Bi、 198 Au、 199 Au、 193m Pt, 197 Pt, 103 Pd, 109 Pd, 105 Rh、 101m Rh、 103m Rh、 223 Ra、 224 Ra、 97 Ru、 227 Th、 229 Th、 161 Tb, 149 Tb, 203 Pb, 212 Pb, 201 TI, 119 Sb, 58m Co、 55 Co、 57 Co、 47 Sc、 149 Pm, 142 Pr、 161 Ho、 166 Ho、 175 Yb and 51 Cr. In some implementations, E is 177 Lu-DOTA-、 177 Lu-DOTAGA-、 225 Ac-DOTA- or 225 Ac-DOTAGA-.

[0026] In some implementation schemes, Z is:

[0027] (II),

[0028] in:

[0029] u is 0 or 1;

[0030] R 0 It was by a C6-C 10aryl-substituted C1-C6 alkyl groups, wherein the C6-C 10 The aryl group may optionally be substituted by one or more substituents, each substituent being independently a halogen or NO2;

[0031] R 1 It was by a C6-C 10 aryl-substituted C1-C6 alkyl groups, wherein the C6-C 10 The aryl group may be optionally substituted by one or more substituents, each substituent being independently -OH, -O (C1-C6 alkyl), or -N (R). a )C(O)R 1a And R 1a It is a 3- to 8-membered heterocycle optionally substituted with one or more oxygens;

[0032] R 2 It was by a C6-C 10 aryl or 5 to 12 heteroaryl substituted C1-C6 alkyl groups, wherein the C6-C 10 The aryl or 5- to 12-membered heteroaryl group is optionally substituted by one or more substituents, each substituent being independently -OH, -O (C1-C6 alkyl) or -N (R a )C(O)NH(R a );

[0033] x is 0 or 1;

[0034] R x It is -N(R) a )C(O)-(C6-C 10 (Aromatic);

[0035] R 3 It is caused by one or more -NH((R) a ) substituted C1-C6 alkyl groups;

[0036] R 4 It is a C1-C6 alkyl group substituted with one or more -OH groups;

[0037] y is 0 or 1;

[0038] R 4 It was by a C6-C 10 Aryl-substituted C1-C6 alkyl groups;

[0039] R z Is -OH or , where R z1 It is a C1-C6 alkyl group substituted with one or more substituents, each substituent being independently selected from -OH and optionally substituted with one or more -OH groups. 10 Group composed of aryl groups; R z2It is -COOH, -C(O)NH2, or a C1-C6 alkyl group substituted with one or more -OH groups; and

[0040] R a Each time it appears, it is independently H or C1-C3 alkyl.

[0041] In some implementations, u is 1, and R 0 It is a C1-C6 alkyl group substituted with a phenyl group, wherein the phenyl group is either unsubstituted or substituted with one or more halogens.

[0042] In some implementation schemes, R 1 It was by a C6-C 10 aryl-substituted methyl groups, wherein C6-C 10 The aryl group may be optionally substituted by one or more substituents, each substituent being independently -OH or -NHC(O)R. 1a , where R 1a It is a 3- to 8-membered heterocycle that is optionally substituted with one or more oxygens.

[0043] In some implementation schemes, R 2 It was by a C6-C 10 Aryl or 5 to 12 heteroaryl-substituted C1-C6 alkyl groups, wherein C6-C 10 The aryl group may optionally be substituted by one or more substituents, each substituent being independently -OH or -NHC(O)NH2.

[0044] In some implementation schemes, R 3 It is a C1-C6 alkyl group substituted with one or more NH2.

[0045] In some implementation schemes, R 4 It is a C1-C3 alkyl group substituted with one or more -OH groups.

[0046] In some implementation schemes, Z is:

[0047] (TOC)

[0048] (NOC)

[0049] (TATE)

[0050] (octreotide)

[0051] (JR11) or

[0052] (BASS).

[0053] In some implementation schemes, Z is:

[0054] (II-A),

[0055] Where R 3a It is CH2OH, CO2H, or CONH2.

[0056] In some embodiments, the compound comprises a structure selected from any of those in Table 1.

[0057] In some implementations, the compounds provided herein are used for imaging or diagnosis, or for treatment.

[0058] In one aspect, this article provides pharmaceutical compositions comprising the compounds provided herein or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients.

[0059] In one aspect, this document provides a kit comprising a compound provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, along with instructions for using the kit to diagnose a disease or condition in a subject with such need.

[0060] In one aspect, this document provides a kit containing a compound provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, along with instructions for using the kit to treat a disease or condition in a subject who requires such treatment.

[0061] In one aspect, this document provides methods for treating diseases and conditions in subjects with such needs, methods comprising administering to the subject a pharmaceutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein. In some embodiments, the disease or condition is cancer. In some embodiments, the cancer is cancer with high expression of SSTR2. In some embodiments, the cancer is medullary thyroid carcinoma (MTC), small cell lung cancer (SCLC), or a neuroendocrine tumor.

[0062] In one aspect, this article provides a method for inhibiting cell proliferation activity, which includes administering an effective amount of one or more compounds provided herein or salts thereof.

[0063] In one aspect, this article provides a method for imaging the tissues of a subject by administering to the subject in need an imaging-effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof, and applying imaging techniques to detect emitted gamma rays.

[0064] In one aspect, this article provides a method for diagnosing cancer in a subject by administering a diagnostically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, and by applying imaging techniques to detect emitted gamma rays. Attached Figure Description

[0065] The accompanying drawings illustrate some embodiments of the features and advantages of this disclosure. These embodiments are not intended to limit the scope of the appended claims in any way.

[0066] Figure 1 Exemplary examples of the application of this application are shown. 177 Biodistribution of Lu-labeled compounds in different organs / tissues of H524 tumor-bearing mice 24 h later.

[0067] Figure 2A and Figure 2B It shows the application of radioactive isotopes 177 Lu-labeled compound 027 and 177 Biodistribution of Lu-labeled DOTATATE at different time points in the NET AR42J xenograft mouse model.

[0068] Figure 3A and Figure 3B It shows the application of radioactive isotopes 177 Lu-labeled compound 027 and 177 Biodistribution of Lu-labeled DOTATATE at different time points in the SCLC H524 xenograft mouse model.

[0069] Figure 4A and Figure 4B An exemplary application of this application is shown. 177 Mouse SPECT / CT imaging results in AR42J tumor-bearing mice, 4 h after administration of Lu-labeled compounds, with or without 1000-fold additional amounts of unlabeled DOTATATE.

[0070] Figure 5A and Figure 5B It shows 177 In vivo efficacy study of Lu-labeled compound 027 in AR42J xenograft mouse model.

[0071] Figures 6A-6C It shows 177 Lu-labeled compound 027 in 177 Preliminary in vivo efficacy of Lu-labeled reference compounds after treatment.

[0072] Figure 7A and Figure 7B It shows 177In vivo efficacy study of Lu-labeled compound 027 in H524 xenograft mouse model.

[0073] Figure 8A and Figure 8B It shows 177 In vivo efficacy study of Lu-labeled compound 027 in H69 xenograft mouse model.

[0074] Figure 9 It shows the application of radioactive isotopes 225 Biological distribution of Ac-labeled compound 027 at different time points in the NET AR42J xenograft model.

[0075] Figure 10A and Figure 10B It shows 225 In vivo efficacy study of Ac-labeled compound 027 in AR42J rat pancreatic cancer cell xenograft model.

[0076] Figure 11 It shows 68 PET / CT imaging study of Ga-labeled compound 027. Invention Details

[0078] This application provides compounds comprising three functional units linked via a trivalent moiety: a somatostatin type 2 receptor (SSTR2) binding moiety, an effector moiety, and a fatty acid moiety. Methods of using such compounds are also provided. The compounds described herein exhibit promising therapeutic potential. This invention is based, at least in part, on the surprising discovery that, compared to conventional molecules containing an SSTR2 binding moiety such as DOTATATE, the compounds provided herein i) exhibit higher in vitro and in vivo binding affinity for SSTR2; and ii) provide higher uptake in SSTR2-expressing tumors while maintaining rapid systemic clearance, thus enabling more efficient tumor-targeting drug delivery and potentially a larger therapeutic window. These advantageous features make the compounds provided herein particularly suitable for the diagnosis or treatment of a wide range of diseases characterized by high SSTR2 expression.

[0079] I. Definition

[0080] As used herein, the following words and phrases are generally intended to have the meanings described below, unless the context in which they are used indicates otherwise.

[0081] As used in this article, the “about” parameter or value includes and describes the parameter or value itself. For example, “about X” includes and describes X itself.

[0082] "A" and "the" include plural indicators unless the context clearly indicates otherwise. Thus, for example, reference to "compound" includes multiple such compounds, and reference to "determination" includes reference to one or more compounds and their equivalents known to those skilled in the art.

[0083] "Alkyl" refers to a saturated hydrocarbon chain that is unbranched or branched. As used herein, alkyl groups can have 1 to 20 carbon atoms (i.e., C64-C ... 1-20 Alkyl groups, 8 to 20 carbon atoms (i.e., C464-C ... 8-20 Alkyl groups), 10 to 18 carbon atoms (i.e., C464) 10-18 Alkyl groups), 10 to 16 carbon atoms (i.e., C464) 10-16 Alkyl groups or 12 to 16 carbon atoms (i.e., C46) 12-16 alkyl).

[0084] As used herein, the term "cycloalkyl" refers to a non-aromatic (e.g., saturated or partially unsaturated) carbocyclic moiety. The term "cycloalkyl" encompasses both monocyclic and polycyclic moieties, wherein the polycyclic moiety may be fused, bridged, or spirocyclic. A cycloalkyl group includes any polycyclic carbocyclic moiety comprising at least one non-aromatic ring, regardless of its connection point to the remainder of the molecule. As used herein, a cycloalkyl group includes, for example, having 3 to 20 cyclic carbon atoms (i.e., C64 ... 3-20 cycloalkyl groups), 3 to 16 cyclic carbon atoms (i.e., C164 ... 3-16 cycloalkyl groups), 3 to 14 cyclic carbon atoms (i.e., C14) 3-14 cycloalkyl groups), 3 to 12 cyclic carbon atoms (i.e., C12C ... 3-12 cycloalkyl groups), 3 to 10 cyclic carbon atoms (i.e., C10, C20, C30, C40, C50, C60, C7 ... 3-10 cycloalkyl groups), 3 to 8 cyclic carbon atoms (i.e., C1646-C264 ... 3-8 cycloalkyl groups), 3 to 6 cyclic carbon atoms (i.e., C164-C ... 3-6 cycloalkyl groups or 3 to 5 cyclic carbon atoms (i.e., C164, C264, C364, C464, C5 ... 3-5 Cycloalkyl rings.

[0085] As used herein, the term "aryl" refers to an aromatic (e.g., fully unsaturated) carbocyclic moiety. The term "aryl" encompasses both monocyclic and polycyclic fused-ring moieties. As used herein, aryl encompasses a ring having, for example, 6 to 20 cyclic carbon atoms (i.e., C24-C24-C24). 6-20 aryl), 6 to 16 cyclic carbon atoms (i.e., C 6-16 aryl), 6 to 14 cyclic carbon atoms (i.e., C 6-14 aryl), 6 to 12 cyclic carbon atoms (i.e., C 6-12 aryl group or 6 to 10 cyclic carbon atoms (i.e., C46, ​​C56, C6 ... 6-10 The ring moiety of an aryl group. Examples of aryl moiety include, but are not limited to, phenyl, naphthyl, and anthracene.

[0086] As used herein, the term "heteroaryl" refers to an aromatic (e.g., fully unsaturated) ring moiety having one or more (e.g., 1, 2, 3, 4, or 5) cyclic heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The term "heteroaryl" includes both monocyclic and polycyclic fused ring moieties. As used herein, a heteroaryl group may have, for example, 5 to 20 cyclic atoms (i.e., 5 to 20-membered heteroaryl), 5 to 16 cyclic atoms (i.e., 5 to 16-membered heteroaryl), 5 to 14 cyclic atoms (i.e., 5 to 14-membered heteroaryl), 5 to 12 cyclic atoms (i.e., 5 to 12-membered heteroaryl), 5 to 10 cyclic atoms (i.e., 5 to 10-membered heteroaryl), 5 to 8 cyclic atoms (i.e., 5 to 8-membered heteroaryl), or 5 to 6 cyclic atoms (i.e., 5 to 6-membered heteroaryl), each independently having 1 to 5 cyclic heteroatoms, 1 to 4 cyclic heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatomum independently selected from nitrogen, oxygen, and sulfur. Any monocyclic or polycyclic aromatic ring moiety containing one or more cyclic heteroatoms is considered a heteroaryl, regardless of its connection points to the rest of the molecule (i.e., the heteroaryl moiety can be connected to the rest of the molecule via any cyclic carbon or any cyclic heteroatom of the heteroaryl moiety). Any aromatic ring having one or more fused rings and containing at least one heteroatom is considered a heteroaryl, regardless of its connection to the rest of the molecule (i.e., via any fused ring). Heteroaryl does not encompass or overlap with aryl groups as defined above.

[0087] As used herein, the term "heterocyclic group" refers to a non-aromatic (e.g., saturated or partially unsaturated) cyclic moiety having one or more (e.g., 1, 2, 3, 4, or 5) cyclic heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The term "cycloalkyl" includes monocyclic and polycyclic moieties, wherein the polycyclic moieties may be fused, bridged, or spirocyclic. Any non-aromatic monocyclic or polycyclic moieties containing at least one cyclic heteroatom are considered heterocyclic groups, regardless of their connection points to the rest of the molecule (i.e., the heterocyclic moieties may be connected to the rest of the molecule via any cyclic carbon or any cyclic heteroatom of the heterocyclic moieties). Furthermore, the term heterocyclic group is intended to cover any polycyclic moieties containing at least one cyclic heteroatom, wherein the polycyclic moieties contain at least one non-aromatic ring, regardless of their connection points to the rest of the molecule. As used herein, heterocyclic groups may have, for example, 3 to 20 cyclic atoms (i.e., 3 to 20-membered heterocyclic groups), 3 to 16 cyclic atoms (i.e., 3 to 16-membered heterocyclic groups), 3 to 14 cyclic atoms (i.e., 3 to 14-membered heterocyclic groups), 3 to 12 cyclic atoms (i.e., 3 to 12-membered heterocyclic groups), 3 to 10 cyclic atoms (i.e., 3 to 10-membered heterocyclic groups), or 3 to 8 cyclic atoms (i.e., 3 to 8-membered heterocyclic groups). ), 3 to 6 cyclic atoms (i.e., 3 to 6-membered heterocyclic groups), 3 to 5 cyclic atoms (i.e., 3 to 5-membered heterocyclic groups), 5 to 8 cyclic atoms (i.e., 5 to 8-membered heterocyclic groups), or 5 to 6 cyclic atoms (i.e., 5 to 6-membered heterocyclic groups), each independently having 1 to 5 cyclic heteroatoms, 1 to 4 cyclic heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatomum independently selected from nitrogen, oxygen, and sulfur.

[0088] "Halogen" or "halogenated" includes fluorinated, chlorinated, bromine-substituted, and iodinated.

[0089] "Oxytochemical" refers to the partial = O.

[0090] The terms “optional” or “optionally” mean that the events or conditions described below may or may not occur. The term “optionally substituted” means that any one or more hydrogen atoms on a specified atom or group may or may not be substituted with portions other than hydrogen. Unless otherwise stated, “optionally substituted” means that a group may be unsubstituted or substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents listed for that group, wherein the substituents may be the same or different. In one embodiment, the optionally substituted group has one substituent. In another embodiment, the optionally substituted group has two substituents. In another embodiment, the optionally substituted group has three substituents. In some embodiments, the optionally substituted group has more than one substituent, wherein each substituent is independently selected. In another embodiment, the optionally substituted group has four substituents. In some embodiments, the optionally substituted group has 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, or 2 to 5 substituents. In one embodiment, the optionally substituted group is unsubstituted. Substituents can be the same or different. When multiple substituents are present in a part or compound, it should be understood that each substituent can independently select each other substituent.

[0091] As used herein, optional substituents may be selected from the following group: C6-C 24 Aryl, C5-C 24 heteroaryl, hydroxyl, C1-C 20 Alkoxy, C6-C 24 Aryloxy, cyano, halogen, nitro, C1-C 20 Fluoroalkoxy and amino groups, encompassing –NH2 and mono-, di-, and tri-substituted amino groups and their protected derivatives, or selected from the group consisting of -X, -OR', -SR', -NH2, -N(R')(R op ), -N(R op )3, =NR', -CX3, -CN, -NO2, -NR'C(=O)H, -NR'C(=O)R op -NR'C(=O)R op , -C(=O)R', -C(=O)NH2, -C(=O)N(R')R op -S(=O)2R op -S(=O)2NH2, -S(=O)2N(R')R op -S(=O)2NH2, -S(=O)2N(R')R op -S(=O)2OR', -S(=O)R op -OP(=O)(OR')(OR)op -OP(OH)3, -P(=O)(OR')(OR) op ), -PO3H2, -C(=O)R', -C(=S)R op -CO2R', -C(=S)OR op , -C(=O)SR', -C(=S)SR', -C(=S)NH2, -C(=S)N(R')(R op )2, -C(=NR')NH2, -C(=NR')N(R')R op And its salts, wherein each X is independently chosen from the group consisting of -F, -Cl, -Br and -I; and wherein each R op Independently selected from the following groups: C1-C 20 Alkyl, C2-C 20 alkenyl, C2-C 20 alkynyl group, C6-C 24 Aryl, C3-C 24 Heterocyclic group, C5-C 24 heteroaryl, protecting group and prodrug moiety or two R op C3-C is defined together with the heteroatoms they are attached to. 24 Heterocyclic group; and R' is hydrogen or R op , where R op Selected from the following group: 1-C 20 Alkyl, C6-C 24 Aryl, C3-C 24 Heterocyclic group, C5-C 24 Heteroaryl groups and protecting groups.

[0092] In some implementations, the optional substituents are each independently selected from the group consisting of: -X, -OH, -OR. op -SH, -SR op -NH2, -NH(R) op ), -NR'(R op )2、-N(R op 3, =NH, =NR op , -CX3, -CN, -NO2, -NR'C(=O)H, NR'C(=O)R op , –CO2H, -C(=O)H, -C(=O)R op -C(=O)NH2, -C(=O)NR'R op -S(=O)2R op -S(=O)2NH2, -S(=O)2N(R')R op , -S(=O)2NH2, -S(=O)2N(R')(R op-S(=O)2OR', -S(=O)R op -C(=S)R op -C(=S)NH2, -C(=S)N(R')R op -C(=NR')N(R) op )2 and its salts, wherein each X is independently chosen from the group consisting of -F and -Cl, R op In some implementation schemes, the following group is selected: C1-C6 alkyl, C6-C 10 Aryl, C3-C 10 Heterocyclic group, C5-C 10 Heteroaryl and protecting group; and R' is independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C6-C 10 Aryl, C3-C 10 Heterocyclic group, C5-C 10 The heteroaryl group and protecting group are independently selected from R op .

[0093] In some implementations, the optional substituents are each independently selected from the group consisting of: -X, -R op -OH, -OR op -NH2, -NH(R) op ), -N(R op )2、-N(R op )3, -CX3, -NO2, -NHC(=O)H, -NHC(=O)R op -C(=O)NH2, -C(=O)NHR op -C(=O)N(R) op )2、-CO2H、-CO2R op -C(=O)H, -C(=O)R op -C(=O)NH2, -C(=O)NH(R) op -C(=O)N(R) op )2, -C(=NR')NH2, -C(=NR')NH(R op -C(=NR')N(R) op 2. Protecting groups and their salts, wherein each X is -F; R op Independently selected from the group consisting of: C1-C6 alkyl, C6-C 10 Aryl, C5-C 10 Heteroaryl and protecting group; and R' is selected from the group consisting of hydrogen, C1-C6 alkyl and protecting group, independently selected from R op .

[0094] As used herein, the term "radionucleus" refers to any atom or ion capable of undergoing radioactive decay. The term radionucleus is used herein synonymously with radioactive nuclide, radioisotope, and radioactive isotope.

[0095] As used herein, the term "chelating group" is a chelating agent capable of complexing with a radionuclide.

[0096] As used herein, "fatty acid moiety" refers to a fatty acid that is covalently linked to the remainder of a compound. In some embodiments, the fatty acid moiety is a fatty acid that is covalently linked to the remainder of a compound by a carboxyl group of the fatty acid, for example, an amide bond. In some embodiments, "fatty monocarboxylic acid" may refer to a fatty acid having only a single carboxyl group. In some embodiments, the fatty monocarboxylic acid moiety is covalently linked to the remainder of a compound by a single carboxyl group of the fatty monocarboxylic acid, for example, an amide bond. In some embodiments, the fatty monocarboxylic acid moiety has the formula -C(O)A. a A a It is an unsubstituted or substituted alkyl group that is no longer substituted by -COOH.

[0097] As used herein, “treatment” or “treating” is a method for achieving a beneficial or desired outcome (e.g., clinical outcome). For the purposes of this disclosure, a beneficial or desired outcome includes, but is not limited to, relief of symptoms and / or reduction of the severity of symptoms and / or prevention of exacerbation of symptoms associated with the disease or condition. In one variation, a beneficial or desired clinical outcome includes, but is not limited to, relief of symptoms and / or reduction of the severity of symptoms and / or prevention of exacerbation of symptoms associated with the disease.

[0098] As used herein, the term "effective amount" refers to an amount of at least one agent sufficient to achieve a desired outcome, such as imaging at least one cell or tissue, diagnosing a disease or condition, or treating a disease or condition. In some cases, the method is in vitro, and the desired outcome may include certain desired alterations in cellular or biological processes. In some cases, the method is in vivo, and the outcome may include a reduction and / or relief of signs, symptoms, or causes of a disease. In some cases, the outcome is the death or reduction of the growth of at least one abnormally proliferating cell (e.g., cancer cells).

[0099] In some cases, "effective amount" is considered in the context of therapeutic use and may optionally be referred to as "therapeutic effective amount". "Therapeutic effective amount" means the amount of a compound or composition comprising the compound or a salt thereof as described herein, which is sufficient to produce the desired therapeutic outcome and / or provide a clinically significant reduction in disease.

[0100] As used herein, “individual” or “subject” means mammal, including but not limited to primates, humans, cattle, horses, cats, dogs, or rodents. In one variant, the individual or subject is a human.

[0101] As used herein, "pharmaceuticalally acceptable" or "pharmacologically acceptable" means a material that is not desirable in a non-biological or other respectable way, for example, a material that can be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a harmful manner with any other component of the composition containing the material. Pharmaceutically acceptable carriers or excipients preferably meet the required standards for toxicological and preparative testing and / or are included in the inactive ingredient guidelines established by the U.S. Food and Drug Administration.

[0102] “Pharmaceutically acceptable salts” are those that retain at least some of the biological activity of the free (non-salt) compound and can be administered to an individual as a drug or medicine. Examples of such salts include: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or acid addition salts formed with organic acids such as acetic acid, trifluoroacetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid, etc.; (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion); or salts formed when coordinated with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, etc. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, etc. Other examples of pharmaceutically acceptable salts include those listed in Berge et al., PharmaceuticalSalts, J. Pharm. Sci. 1977 Jan; 66(1):1-19. Pharmaceutically acceptable salts can be prepared in situ during the preparation process, or by reacting the purified compound of this disclosure, in its free acid or base form, with a suitable organic or inorganic base or acid, and then separating the resulting salt during a subsequent purification process.

[0103] As used herein, the term "excipient" refers to an inert or inactive substance that can be used in the preparation of a medicine or pharmaceutical product, such as a tablet containing a compound of this disclosure as an active ingredient. The term "excipient" can cover a wide range of substances, including but not limited to any substance used as a binder, disintegrant, coating, compression / encapsulation aid, emulsion or lotion, lubricant, parenteral solution, material for chewable tablets, sweetener or flavoring agent, suspending / gelling agent, or wet granulation agent.

[0104] In some embodiments, unless otherwise stated, the term "amino acid" as used herein encompasses naturally occurring amino acids, non-naturally occurring amino acids, chemically modified naturally occurring or non-naturally occurring amino acids, D-enantiomers of naturally occurring or non-naturally occurring amino acid residues or modified amino acid residues, and amino acid residues derived from naturally occurring or non-natural β- or γ-amino acids. In some embodiments, as used herein, "non-natural amino acid" refers to an amino acid that is not naturally occurring and is obtained through synthesis or by modifying a natural amino acid. In some embodiments, as used herein, "naturally occurring amino acid" refers to amino acids that are naturally occurring and encoded by the genetic code, as well as those encoded amino acids that are subsequently modified in vivo. It should be understood that in some embodiments, any amino acid or amino acid residue described herein may be covalently linked to one or more amino acids or amino acid residues described herein via a peptide bond.

[0105] "Stereoisomers" are compounds composed of identical atoms bonded by the same bonds but with different three-dimensional structures, and are not interchangeable. This disclosure considers various stereoisomers and mixtures thereof, and includes "enantiomers" and "diastereomers." "Enantiomers" are two stereoisomers whose molecules are mirror images of each other and are not superimposed on each other. "Diastereomers" are stereoisomers having at least two asymmetric atoms but not being mirror images of each other.

[0106] It should be understood that aspects and implementation schemes described herein as “comprising” include implementation schemes that are “composed of” and “substantially composed of”.

[0107] II. Compounds

[0108] In one aspect, this document provides compounds comprising an SSTR2-binding moiety, an effector moiety (e.g., a radioactive effector moiety), and a fatty acid moiety linked via a trivalent portion. In some embodiments, the SSTR2-binding moiety of the compounds provided herein can direct the compound to bind to SSTR2 expressed in certain cells, and the effector moiety can be used to kill cells or enable cell imaging. In some embodiments, the cells are tumor cells expressing SSTR2.

[0109] In some embodiments, the fatty acid moiety and / or one or more linker moieties in the compounds provided herein can increase the potency of the compound compared to compounds without a fatty acid moiety and / or a linker moiety (e.g., compound DOTATATE). This increased potency includes, but is not limited to, higher binding affinity for human SSTR2, increased tumor uptake combined with rapid systemic clearance, and combinations thereof. In some embodiments, the fatty acid moiety in the compounds provided herein can increase the potency of the compound compared to compounds without a fatty acid moiety. In some embodiments, the fatty acid moiety in the compounds provided herein, including L... A L Z and L E One or more connectors can increase the potency of the compound.

[0110] DOTATATE (also known as DOTA-TATE, DOTA-octreotate, oxodotreotide, DOTA-(Tyr3)-octreotate, and DOTA-O-Tyr3-octreotate) is an 8-amino acid-long peptide that is a covalently bonded DOTA bifunctional chelator. The chemical structure of DOTATATE is as follows:

[0111] (DOTATATE).

[0112] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts exhibit increased potency compared to DOTATATE or its radionuclide complexes, such as higher binding affinity for human SSTR2, increased tumor uptake coupled with rapid systemic clearance, and any combination thereof.

[0113] In some embodiments, the compound described herein or its pharmaceutically acceptable salt has a higher binding affinity for human SSTR2 compared to DOTATATE or its radionuclide complex. In some embodiments, the compound or its pharmaceutically acceptable salt has at least twice the binding affinity for human SSTR2 compared to DOTATATE or its radionuclide complex. In some embodiments, the compound described herein or its pharmaceutically acceptable salt has at least four times the binding affinity for human SSTR2 compared to DOTATATE or its radionuclide complex. In some embodiments, the compound described herein or its pharmaceutically acceptable salt has at least eight times the binding affinity for human SSTR2 compared to DOTATATE or its radionuclide complex.

[0114] In some embodiments, the compounds provided herein are compounds of formula (I):

[0115] (I)

[0116] in:

[0117] T is the trivalent component.

[0118] Z is the somatostatin receptor 2 (SSTR2) binding site, where Z is located via the linker L Z Combined with T,

[0119] E is the effector part, where E is connected via the connector L. E Combined with T,

[0120] A is the unsubstituted or substituted fatty acid moiety, wherein A is via the linker L A With T, and

[0121] L Z L E and L A Each is an independent key or a binary connector.

[0122] In some embodiments, A is a fatty monocarboxylic acid moiety; in other embodiments, A is an unsubstituted or substituted C8-C moiety. 18 The fatty monocarboxylic acid moiety may optionally be unsubstituted or substituted C8, C9, C16, C26, C36, C46, ​​C56, C66, C66, C76, C86, C9 ... 10 C 11 C 12 C 13 C 14 C 15 C 16 C 17 Or C 18 Fatty monocarboxylic acid moiety. In some implementations, L A Contains one or more amino acid residues, N(R) N (C2-alkyleneO)2C1-alkyleneC(O), -N(R) N (C2-alkyleneO)C2-alkyleneC(O), -N(R) N (C2-alkyleneO)3C2-alkyleneC(O) or -N(R) N (C2-alkyleneO)6C2-alkyleneC(O), where R N Is it H or C? 1- C6 alkyl. In some embodiments, R N It is H. In some implementations, R N It is methyl, ethyl, or propyl. In some embodiments, L A It is a bivalent connector containing 1 to 5 Asp. In some implementations, L ZIt is a divalent linker containing one or more amino acid residues, such as OEG, PEG1, PEG3, or PEG6. In some embodiments, L Z It is a bivalent connector containing 1 to 6 Gly. Therefore, in some embodiments, A is unsubstituted or substituted C8, C 9、 C 10 C 11 C 12 C 13 C 14 C 15 C 16 C 17 Or C 18 The fatty monocarboxylic acid portion, L A It is a bivalent connector containing 1 to 5 Asp, and L Z It is a bivalent connector containing 1 to 6 Gly.

[0123] In some embodiments, the compounds described herein have a negative net charge after recombination with radionuclides, including but not limited to radionuclides. 177 Lu、 225 Ac and 111 In this embodiment, when counting net charge under physiological pH conditions, the charge of the radionuclide-chelating agent unit is zero for the trivalent radionuclide-DOTA complex and -1 for the trivalent radionuclide-DOTAGA complex. In some embodiments, when the net charge is calculated as described above, the compound described herein has a net charge of -1 to -8 after recombination with a radionuclide, for example, any one of -1, -2, -3, -4, -5, -6, -7, or -8. In some embodiments, the compound described herein comprises at least one radionuclide, for example... 177 Lu has a net charge of -1 to -5, for example, any one of about -1, -2, -3, -4 or -5.

[0124] Each component of the compounds presented herein is further described below.

[0125] Trivalent connector T

[0126] In some embodiments, T can be any portion capable of attaching to at least three groups. In some embodiments, T can be any portion containing at least three terminal functional groups, with each terminal functional group attached to one of the attachment portions. The at least three terminal functional groups can be the same or different.

[0127] In some embodiments, T comprises one or more amino acid residues. In some embodiments, T may be associated with L via the N-terminus, C-terminus, and side chain of the amino acid. Z L Eand L A The N-terminus, C-terminus, and side chain may or may not belong to the same amino acid. In some embodiments, T comprises 1, 2, 3, 4, or 5 amino acids. In some embodiments, T comprises one or more amino acid residues, each independently selected from the group consisting of: Lys, D-Lys, ornithine (Orn), homolysine, 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab), cysteine, homocysteine, glutamine, glutamic acid, asparagine, aspartic acid, 3,5-bis(aminomethyl)benzoic acid (Bab), 4-aminomethylphenylalanine (Amp), 4R-4-aminoproline (Apr), 4-(2-aminoethoxy)phenylalanine, 4-aminopiperidine-4-carboxylic acid (Apc), and 2-((1,3-diaminoprop-2-yl)oxy)acetic acid (Dpa). In some embodiments, T comprises Lys, D-Lys, Amp, Apr, or Bab. In some embodiments, T comprises Lys or D-Lys. In some embodiments, T is Lys or D-Lys. In some embodiments, T is a single amino acid.

[0128] In some embodiments, when T contains any of the amino acid residues selected from the group consisting of Lys, D-Lys, Orn, homolysine, 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab), cysteine, homocysteine, glutamine, glutamic acid, asparagine, aspartic acid, 4R-4-aminoproline (Apr), and 4-(2-aminoethoxy)phenylalanine, then A is amino-conjugated with T. In some embodiments, when T contains Lys or D-Lys, then A is amino-conjugated with Lys or D-Lys.

[0129] In some embodiments, T is Lys and the compound of formula (I) is a compound of formula (IA) or (IB):

[0130] (IA) (IB).

[0131] In some embodiments, T is D-Lys and the compound of formula (I) is a compound of formula (IAa) or (IBa):

[0132] (IAa) (IBa).

[0133] In some embodiments, T is L-Lys and the compound of formula (I) is a compound of formula (IAb) or (IBb):

[0134] (IAb) (IBb).

[0135] In some embodiments, T is Amp and the compound of formula (I) is a compound of formula (IC) or (ID):

[0136] (IC) (ID).

[0137] In some embodiments, T is Bab and the compound of formula (I) is a compound of formula (IE):

[0138] (IE).

[0139] In some embodiments, T is Apr and the compound of formula (I) is a compound of formula (IF) or formula (IG):

[0140] (IF), (IG).

[0141] In some embodiments, T is Dab and the compound of formula (I) is a compound of formula (IH) or (II):

[0142] (IH), (II).

[0143] Connector L A

[0144] In some implementations, L A It is the key or any binary connector between T and A. In some implementations, L A Is it a key or a binary connector: –(Y) n –,

[0145] in:

[0146] n is an integer from 1 to 20, and

[0147] Each Y is independently selected from amino acid residues and -N(R) N (C2 alkylene Y) a ) y1 Y b The group consisting of C(O), where R N Is it H or C? 1- C6 alkyl, wherein Y a It is -O-, -S-, -NH- or -N(C 1-C6 alkyl)-, where y1 is an integer from 1 to 10, and where Y b It is C 1- C3 alkylene

[0148] In some implementations, L A It contains one or more amino acid residues. In some embodiments, L A Contains one or more amino acid residues and L A It can be connected to A and T via the main chain or side chain. In some implementations, L A Contains one or more (e.g., an integer number between 1 and 20, 1 and 15, or 1 and 10, or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid residues, each independently selected from the group consisting of: alanine (Ala, A), asparagine (Asn, N), aspartic acid (Asp, D), glutamine (Gln, Q), glutamic acid (Glu, E), γGlu, glutamine (Gln), glycine (Gly, G), isoleucine (Ile, I), leucine (Leu, L), εLys, methionine (Met, M), phenylalanine (Phe, F), proline (Pro, P), serine (Ser, S), threonine (Thr, T), tryptophan (Trp, W), tyrosine (Tyr, Y), valine (Val, V), pyrrolidone (Pyl, O), pyrrolidone-carboxy-lysine (PCL), γ-carboxyglutamic acid (Gla), NR 5 C5 alkylene C(O)(Ahx), cysteine ​​(Cya), leucine (Nle), valine (Nva), 2-aminooctanoic acid (Aoc), 2-naphthylalanine (2-Nal), 3-(trifluoromethyl)phenylalanine (TFP), homophenylalanine (hPhe), cyclohexylalanine (Cha), 1-naphthylalanine (1-Nal), 4-benzoyl-L-phenylalanine (Bpa), 2-methoxy-4-vinylphenylalanine (MvF), 4-fluorophenylalanine (Bpa), 4-phenyl-2, 3-Dihydroxy-6-nitrophenylalanine (pNIPA), 2-(2-naphthyl)alanine (2-Nal-ala), 4-(4-propoxyphenyl)alanine (Ppa), 4-carboxyphenylalanine (4-CPA), 4-butylphenylalanine (Bua), 2-nitrophenylalanine (2-Npa), 4-azidophenylalanine (4-AzF), 2-(4-nitrophenyl)ethylalanine (2-Npe), 3-iodo-L-tyrosine (Ity), and 5,5,5-trifluoroleucine (TFL) or their D enantiomers.

[0149] In some implementations, L AIt comprises one or more (e.g., an integer number between 1 and 20, 1 and 15, or 1 and 10, or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) negatively charged amino acid residues, wherein each amino acid residue is independently and optionally selected from the group consisting of D-Asp, Asp, D-Glu, Glu, D-γGlu, γGlu, and Cya.

[0150] In some implementations, L A It contains one or more (e.g., an integer number between 1 and 20, 1 and 15, or 1 and 10, or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) D-Asp, Asp, or any combination thereof.

[0151] In some implementations, L A It contains one or more (e.g., an integer number between 1 and 20, 1 and 15, or 1 and 10, or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) neutral amino acid residues, wherein each amino acid residue is independently and optionally selected from the group consisting of Gly, D-Pro, Pro D-Ser, and Ser.

[0152] In some implementations, L A It does not contain Glu, D-Glu, D-γGlu, or γGlu.

[0153] In some implementations, L A Includes -N(R) N (C2-alkyleneO) y1 Y b C(O), where R N Is it H or C? 1- C6 alkyl, y1 is an integer from 1 to 10, and Y b It is C 1- C3 alkylene. In some embodiments, -N(R N (C2 alkylene Y) a ) y1 Y b C(O)- is N(R) N (C2-alkyleneO)2C1-alkyleneC(O), -N(R) N (C2-alkyleneO)C2-alkyleneC(O), -N(R) N (C2-alkyleneO)3C2-alkyleneC(O) or -N(R) N (C2-alkyleneO)6C2-alkyleneC(O), where R N Is it H or C? 1- C6 alkyl. In some embodiments, R N It is H. In some implementations, R NIt is methyl, ethyl, or propyl. In some embodiments, -N(R) N (C2 alkylene Y) a ) y1 Y b C(O)- is -NH(C2alkyleneO)2C1alkyleneC(O) (OEG), -NH(C2alkyleneO)C2alkyleneC(O) (PEG1), -NH(C2alkyleneO)3C2alkyleneC(O) (PEG3) or -NH(C2alkyleneO)6C2alkyleneC(O) (PEG6). In some embodiments, L A Includes OEG. In some implementations, L A Contains PEG1. In some implementations, L A Contains PEG3. In some implementations, L A Contains PEG6. It should be noted that a specific directionality is not expected unless the directionality of the groups is specified. For example, -N(R) provided in this document... N (C2 alkylene Y) a ) y1 Y b C(O) encompasses -N(R) N (C2 alkylene Y) a ) y1 Y b C(O) and C(O)Y b (C2 alkylene Y) a ) y1 N(R N Both.

[0154] In some implementations, n is an integer from 1 to 15. In some implementations, n is an integer from 1 to 10. In some implementations, n is an integer from 1 to 5. In some implementations, n is any one of 1, 2, or 3.

[0155] In some embodiments, each Y is independently selected from the group consisting of: Ahx, Cya, Gla, Gly, D-Ala, Ala, D-Val, Val, D-Leu, Leu, D-Phe, Phe, D-Pro, Pro, D-Met, Met, D-Trp, Trp, D-Thr, Thr, D-Tyr, Tyr, D-Nle, Nle, D-Ser, Ser, D-Asp, Asp, D-Glu, Glu, D-γGlu, γGlu, Cya, OEG, and PEG1. In some embodiments, each Y is independently selected from the group consisting of: Gly, D-Asp, Asp, D-Glu, Glu, D-γGlu, γGlu, Cya, and OEG.

[0156] In some implementations, LA It is a bivalent connector containing 1 to 5 Asp. In some implementations, L A It includes –(Asp) 2-5 – a bivalent connector. In some implementations, L A It contains –(D-Asp) 2-5 – a bivalent connector. In some implementations, L A It contains 2 to 5 Asp, and 2 to 5 of these Asp are in L A The two Asp are discontinuous. In some implementations, at least two Asp are in L. A It is discontinuous. For example, L A There can be another amino acid or OEG between the two Asp.

[0157] In some implementations, L A Yes bond, -γGlu-γGlu-, -Glu-γGlu-, -Asp-, -Asp-Asp-, -γGlu-, -Gly-Ser-Gly-, -Asp-Asp-Asp-, -γGlu-γGlu-OEG-OEG-, -Asp-Asp-Gly-Gly-Gly-, -Asp- , -Glu-Glu-, -D-Asp-D-Asp-, -Gly-Gly-, -Asp-Asp-Asp-Asp-, -Cya-, -Cya-Cya-, -Gla-, -eLys-eLys-, -Ahx-Ahx-, -Gly-Ser-Gly-, or -Asp-Asp-OEG-.

[0158] In some implementations, L A It is a key. In some implementations, L A Is -Asp-, -Asp-Asp-, -Asp-Asp-Asp-, -D-Asp-D-Asp-, -Cya-, -Cya-Cya-, or -Asp-Asp-Asp-Asp-.

[0159] Fatty acid portion A

[0160] In some embodiments, A is a fatty acid moiety. It should be understood that in some embodiments, the fatty acid moiety described herein may be covalently linked to the remainder of the compound via a covalent bond (e.g., an amide bond) formed by the carboxyl group of the fatty acid. In some embodiments, A is a fatty monocarboxylic acid moiety, wherein the fatty monocarboxylic acid moiety is covalently linked to the remainder of the compound via a covalent bond (e.g., an amide bond) formed by a single carboxyl group of the fatty monocarboxylic acid. In some embodiments, the fatty acid moiety has the formula -C(O)A. 1 A 1It is unsubstituted C3-C 23 Alkyl groups, or C3-C groups substituted with one or more -COOH groups and optionally further substituted with other substituents. 23 Alkyl group. In some embodiments, the fatty acid moiety is a fatty monocarboxylic acid moiety having the formula -C(O)A. a A a It is unsubstituted C3-C 23 Alkyl groups or substituted C3-C groups no longer replaced by -COOH 23 Alkyl group. In some embodiments, A a It is unsubstituted C3-C 23 Alkyl group. In some embodiments, the fatty acid moiety may be saturated or unsaturated, and when unsaturated, it may contain any one of 1, 2, 3, 4, or 5 double or triple bonds. In some embodiments, A is the saturated fatty acid moiety.

[0161] In some implementations, A is unsubstituted or substituted C4-C 24 (For example, C6-C) 24 C4-C 20 C6-C 20 C8-C 20 C8-C 28 Or C 10 -C 18 (A) fatty monocarboxylic acid moiety. In some embodiments, A is unsubstituted or substituted C8-C. 18 Fatty monocarboxylic acid moiety. In some embodiments, A is unsubstituted or substituted C. 10 -C 16 Fatty monocarboxylic acid moiety. In some embodiments, A is unsubstituted or substituted C. 12 -C 16 The fatty monocarboxylic acid moiety. In some embodiments, A is an unsubstituted or substituted C8 fatty monocarboxylic acid moiety. In some embodiments, A is an unsubstituted or substituted C9 fatty monocarboxylic acid moiety. In some embodiments, A is an unsubstituted or substituted C9 fatty monocarboxylic acid moiety. 10 Fatty monocarboxylic acid moiety. In some embodiments, A is unsubstituted or substituted C. 11 Fatty monocarboxylic acid moiety. In some embodiments, A is unsubstituted or substituted C. 12 Fatty monocarboxylic acid moiety. In some embodiments, A is unsubstituted or substituted C. 13 Fatty monocarboxylic acid moiety. In some embodiments, A is unsubstituted or substituted C. 14 Fatty monocarboxylic acid moiety. In some embodiments, A is unsubstituted or substituted C. 15 Fatty monocarboxylic acid moiety. In some embodiments, A is unsubstituted or substituted C. 16Fatty monocarboxylic acid moiety. In some embodiments, A is unsubstituted or substituted C. 17 Fatty monocarboxylic acid moiety. In some embodiments, A is unsubstituted or substituted C. 18 Fatty monocarboxylic acid portion.

[0162] In some implementations, A is -C(O)A a A a Is it unsubstituted or substituted C3-C? 23 Alkyl group. In some embodiments, A a It is C7 alkyl, C8 alkyl, C9 alkyl, C 10 Alkyl, C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl, C 16 Alkyl or C 17 Alkyl groups, each of which may be unsubstituted or substituted. In some embodiments, A a It is C7 alkyl, C8 alkyl, C9 alkyl, C 10 Alkyl, C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl, C 16 Alkyl or C 17 Alkyl groups, each of which is unsubstituted. In some embodiments, A a It is C7 alkyl, C8 alkyl, C9 alkyl, C 10 Alkyl, C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl, C 16 Alkyl or C 17 Alkyl groups, each of which is not replaced by -COOH.

[0163] Connector L Z

[0164] In some implementations, L Z It is the key between T and Z or any divalent connector. In some implementations, L Z Is it a key or a binary connector: –(X) m –,

[0165] in:

[0166] m is an integer from 1 to 20, and

[0167] Each X is independently selected from amino acid residues and -N(R) N (C2 alkylene X) a ) x1 Y b The group consisting of C(O), where R N Is it H or C? 1-6 Alkyl, wherein X a It is -O-, -S-, -NH- or -N(C 1-6 Alkyl)-, where x1 is an integer from 1 to 10, and where X b It is C 1-3 Alkylene.

[0168] In some implementations, L Z It contains one or more amino acid residues. In some embodiments, L Z Contains one or more amino acid residues and L Z It can be connected to Z and T via the main chain or side chain. In some implementations, L Z It is a divalent linker containing one or more (e.g., an integer number between 1 and 20, 1 and 15, or 1 and 10, or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid residues, each independently selected from the group consisting of: alanine (Ala, A), asparagine (Asn, N), glutamine (Gln, Q), glycine (Gly, G), isoleucine (Ile, I), leucine (Leu, L), methionine (Met, M), phenylalanine (Phe, F), proline (Pro, P), serine (Ser, S), threonine (Thr, T), tryptophan (Trp, W), tyrosine (Tyr, Y), valine (Val, V), pyrrolidone (Pyl, O), pyrrolidone-carboxy-lysine (PCL), NR 5C5 alkylene C(O) (Ahx), leucine (Nle), valine (Nva), 2-aminooctanoic acid (Aoc), 2-naphthylalanine (2-Nal), 3-(trifluoromethyl)phenylalanine (TFP), homophenylalanine (hPhe), cyclohexylalanine (Cha), 1-naphthylalanine (1-Nal), 4-benzoyl-L-phenylalanine (Bpa), 2-methoxy-4-vinylphenylalanine (MvF), 4-fluorophenylalanine (Bpa), 4-phenyl-2,3- -Dihydroxy-6-nitrophenylalanine (pNIPA), 2-(2-naphthyl)alanine (2-Nal-ala), 4-(4-propoxyphenyl)alanine (Ppa), 4-carboxyphenylalanine (4-CPA), 4-butylphenylalanine (Bua), 2-nitrophenylalanine (2-Npa), 4-azidophenylalanine (4-AzF), 2-(4-nitrophenyl)ethylalanine (2-Npe), 3-iodo-L-tyrosine (Ity), and 5,5,5-trifluoroleucine (TFL).

[0169] In some implementations, L Z It contains one or more neutral amino acid residues. In some embodiments, L Z It does not contain negatively charged amino acid residues. In some embodiments, L Z It contains one or more (e.g., an integer number between 1 and 20, 1 and 15, or 1 and 10, or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) neutral amino acid residues, wherein each neutral amino acid residue is independently Gly, D-Pro, Pro, D-Ser, and Ser.

[0170] In some implementations, L Z Contains one or more (e.g., an integer number between 1 and 20, 1 and 15, or 1 and 10, or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) Gly.

[0171] In some implementations, L Z Includes -N(R) N (C2-alkyleneO) x1 X b C(O), where R N Is it H or C? 1- C6 alkyl, x1 is an integer from 1 to 10, and X b It is C 1- C3 alkylene. In some embodiments, -N(R N (C2 alkylene X) a ) x1 X b C(O)- is -N(R) N(C2-alkyleneO)2C1-alkyleneC(O), -N(R) N (C2-alkyleneO)C2-alkyleneC(O), -N(R) N (C2-alkyleneO)3C2-alkylene(O) or -N(R) N (C2-alkyleneO)6C2-alkyleneC(O), where R N Is it H or C? 1- C6 alkyl. In some embodiments, R N It is H. In some implementations, R N It is methyl, ethyl, or propyl. In some embodiments, L Z It comprises one or more portions, each independently selected from the group consisting of: -NH(C2alkyleneO)2C1alkyleneC(O) (OEG), -NH(C2alkyleneO)C2alkyleneC(O) (PEG1), -NH(C2alkyleneO)3C2alkyleneC(O) (PEG3) or -NH(C2alkyleneO)6C2alkyleneC(O) (PEG6). In some embodiments, L Z Includes OEG. In some implementations, L A Contains PEG1. In some implementations, L A Contains PEG3. In some implementations, L A Contains PEG6.

[0172] In some implementations, m is an integer from 1 to 15. In some implementations, m is an integer from 1 to 10. In some implementations, m is an integer from 1 to 6. In some implementations, m is any one of 1, 2, or 3.

[0173] In some embodiments, each X is independently selected from the group consisting of: Ahx, Gly, D-Ala, Ala, D-Val, Val, D-Leu, Leu, D-Phe, Phe, D-Pro, Pro, D-Met, Met, D-Trp, Trp, D-Thr, Thr, D-Tyr, Tyr, D-Nle, Nle, D-Ser, Ser, OEG, and PEG1. In some embodiments, each X is independently selected from the group consisting of: Gly, Pro, Ser, and OEG.

[0174] In some implementations, L Z It is a bivalent connector containing 1 to 6 Gly. In some implementations, L Z Yes – (Gly) 2-5 –. In some implementations, L Z It contains 2 to 5 Gly, and these 2 to 5 Gly are not consecutive. In some implementations, at least two Gly are in L. ZIt is discontinuous. For example, L Z There can be another amino acid or OEG between the two Asp.

[0175] In some implementations, L Z It does not contain -C2 alkylene O-. In some embodiments, L Z It does not contain OEG. In some implementations, L Z It does not contain PEG3. In some implementations, L Z It does not contain PEG6.

[0176] In some implementations, L Z Yes key, -OEG-OEG-, -OEG-, -Gly-Gly-Gly-, -Gly-Ser-Gly-Ser-Gly-Ser-, - Pro-Gly-Pro-Gly-Pro-Gly-, -γGlu-γGlu -OEG-OEG-, - Asp-Asp-Gly-Gly-Gly-, -Gly-Gly-Gly-Gly-Gly-Gly-, -Gly-Tyr-Gly-, -Gly-Ser-Gly-, -Gly- or -Gly-Gly-.

[0177] In some implementations, L Z It is a key. In some implementations, L Z It is -Gly-Gly-Gly-.

[0178] Effector E

[0179] In some implementations, E comprises a chemotherapeutic agent, a toxin, an immunomodulator, a diagnostic agent, a radionuclide, a chelating group, or any combination thereof.

[0180] In some embodiments, E comprises one or more radionuclides, each of which is independently a radioisotope of C, N, O, F, P, S, Cl, Br, I, Se, or At. In some embodiments, one or more radionuclides are independently selected from the group consisting of: 14 C 15 N、 18 F, 75 Br、 76 Br、 77 Br、 123 I, 124 I, 125 I, 131 I, 35 S, 18 F, 211 At、 32 P, 33 P and 125I. In some embodiments, E comprises one or more radionuclides and the compound can be used for imaging, and the one or more radionuclides used for imaging are selected from... 18 F or 123 I. In some embodiments, E comprises one or more radionuclides, and the compound can be used to kill cells or treat diseases, and the one or more radionuclides are selected from... 211 At、 32 P, 33 P or 125 I.

[0181] In some implementations, E is connected to L via any of the available functional groups. E In some embodiments, E comprises a chelating group containing two or more carboxyl groups, and E is linked to L via a carboxyl functional group. E .

[0182] In some embodiments, E comprises a chelating group derived from a chelating agent, and the chelating agent is a cyclic bifunctional chelating group or an acyclic bifunctional chelating group capable of compounding one or more radionuclides.

[0183] Those skilled in the art will understand that, as used herein, "chelating group derived from chelating agent" refers to a chelating agent derived from L... E A chelating agent derivative formed by linking to a trivalent group of a compound of formula (I). For example, "chelating group derived from the chelating agent" can be a "-OH" (or an ester thereof) without a usable carboxyl group (or ester thereof) on the chelating agent, an "H" portion without a usable amino group on the chelating agent, an "NCS" portion without a usable isothiocyanate group on the chelating agent, a chelating agent with an "H" portion without a usable maleimide group on the chelating agent, or an acetylene group available on the chelating agent reacting via L E The chelating agent, after being linked to the trivalent group of the compound of formula I, or the tetrazolium group available on the chelating agent, reacts with the L... E A chelating agent attached to a trivalent group of a compound of formula (I). For example, those skilled in the art will understand that when E is a chelating group derived from DOTA, one "-OH" from one of the four available carboxyl groups on DOTA is removed to form a chelating agent with L in the compound of formula (I). E Connection (or when L) E When it is a direct bond, a T is formed.

[0184] In some embodiments, the chelating group is derived from a chelating agent selected from the group consisting of: 1,4,7-triazacyclononane (TACN), 1,4,7-triazacyclononane-triacetic acid (NOTA), 1,4,7-triazacyclononane-N-succinic acid-N',N''-diacetic acid (NOTASA), 1,4,7-triazacyclononane-N-glutamic acid-N',N''-diacetic acid (NODAGA), 1,4,7-triazacyclononane-N,N',N''-tris(methylenephosphonic acid) acid (NOTP), 1,4,7,10-tetraazacyclododecane (

[12] aneN) 4)(cyclen), 1,4,7,10-tetraazacyclotridecane (

[13] aneN4), 1,4,7,11-tetraazacyclotetradecane (iso-cyclam), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 2-(1,4,7,10-tetraazacyclododecane-1-yl)acetate (DO1A), 2,2'-(1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid (DO2A), 2,2',2''-(1,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)triacetic acid (DO3A), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylphosphonic acid) (DOTP), 1,4,7,10-tetraazacyclododecane-1,7-bis(methylphosphonic acid) (DO2P), 1 ,4,7,10-Tetraazacyclododecane-1,4,7-tris(methylphosphonic acid) (DO3P), 1,4,7,10-tetraazacyclododecane-1-glutamic acid-4,7,10-triacetic acid (DOTAGA), 1,4,7,10-tetraazacyclododecane-1-succinic acid-4,7,10-triacetic acid (DOTASA), 1,4,8,11-tetraazacyclotetradecane (

[14] aneN4) (cyclam), 1,4,8,12-tetraazacyclopentadecane (

[15] aneN4), 1,5,9,13-tetraazacyclohexadecane (

[16] aneN4), 1,4- Ethylene-1,4,8,11-tetraazacyclotetradecane (et-cyclam), 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA), 2-(1,4,8,11-tetraazacyclotetradecane-1-yl)acetic acid (TE1A), 2,2'-(1,4,8,11-tetraazacyclotetradecane-1,8-diyl)diacetic acid (TE2A), 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CB-TE2A), 3,6,10,13,16,19-hexaazabicyclo[6.6.2].6] Eicosane (Sar), 1,4,7,10-tetra-(2-carbamoyl-methyl)-cyclododecane (TCMC), N,N'-bis[(6-carboxy-2-pyridine)methyl]-4,13-diaza-18-crown ether-6 (macropa), phthalocyanine, porphyrin, PCTA (3,6,9,15-tetraazabicyclo[9.3.1]pentadecano-1(15),11,13-trien-3,6,9-triacetic acid), DEPA (7-[2-(biscarboxymethylamino)ethyl]-4,10-biscarboxymethyl-1,4,7,10-tetraazacyclododecane-1-yl-acetic acid), DTPA (1,1,4,7,7-diethylenetriaminepentaacetic acid), CHX-DTPA (cyclohexane-1,2 1,2-diamine N,N,N',N'-tetraacetic acid, BATPA (1,2-bis[2-aminophenoxy]ethane-N,N,N',N'-tetraacetic acid), TTHA (triethylenetetramine N,N,N',N'',N''',N'''-hexaacetic acid), HBED (N,N'-bis[2-hydroxybenzyl]ethylenediamine-N,N'-diaacetic acid), EGTA (ethylene glycol bis[2-aminoethyl ether]-N,N,N',N'-tetraacetic acid), EDTMP (ethylenediamine tetra- [Methylenephosphonic acid]), TRAP (triazacyclononanoic acid), SHBED (N,N'-bis[2-hydroxy-5-sulfobenyl]ethylenediaminediacetic acid), H6Sbbpen (N,N'-bis-[2-hydroxy-5-sulfobenyl]-N,N'-bis[2-methylpyridine]ethylenediamine), THP (tris(3,4-hydroxypyridinone)), DFO (deferroamine), FSC (fusarium oxychloride), 6SS (N,N'-bis[2,2-dimethyl-2- ... [-mercaptoethyl]ethylenediamine-N,N'-diacetic acid), ECC (ethylene cysteine), ECD (cysteine ​​ethyl ester dimer), NETA ([2-{4,7-biscarboxymethyl(1,4,7)triazacyclononane-1-yl-ethyl}carbonylmethylamino]acetic acid), THPN (tetra(3-hydroxy-4-pyridinone)), H2dedpa (1,2-[{6-(carboxylic acid-)pyridin-2-yl}methylamino]ethane), H4octapa (N,N'-bis[6-carboxy-2-pyridinylmethyl]ethylenediamine-N,N'-diacetic acid), H2bispa2 (6,6'-[{9-hydroxy-1,5-bis-(methoxycarbonyl)-2,4-bis(pyridin-2-yl)-3,7-diazabicyclo[3.3]).[1] Nonane-3,7-diyl}bis(methylene)]pyridine dicarboxylic acid), DOTMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl-tetra(methylphosphonic acid)), PEPA (1,4,7,10,13-pentazocyclopentadecanoacetic acid), HEHA (1,4,7,10,13,16-hexazocyclooctadecanehexaacetic acid), H2hox, H2CHXhox, H2octox, H2pyhox, H4neunopa, TETPA, H4pypa, H4py4pa, DTPAM, EGTAM, ampam, Me-3,2-HOPO, 3,4,3-(LI-1,2-HOPO), and macrocyclic tetraphthalimide. In some embodiments, E comprises a chelating group derived from DOTA or DOTAGA and is associated with L via any available carboxyl functional group. 1 connect.

[0185] In some embodiments, E comprises a chelating group further complexed with one or more radionuclides. In some embodiments, the radionuclides complexed with the chelating group are each independently a radioisotope of As, K, Sc, Ti, Cr, Mn, Fe, Co, Ni, Cu, Ga, Ge, Rb, Sr, Y, Zr, Nb, Tc, Rh, Pd, In, Sn, Sb, Zn, Ta, W, Re, Os, Ir, Pt, Au, Hg, Tl, Pb, Bi, Po, Fr, Pm, lanthanides (such as La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu), actinides (such as Ac, Th, U), Mg, Al, Ca, Cd, or Ba. In some embodiments, the lanthanides are Lu, Sm, Ho, or Tb. In some embodiments, the actinides are Ac, Th, or U.

[0186] In some implementations, one or more radionuclides combined with the chelating agent are each independently selected from the group consisting of: 199 Tc, 99m Tc, 188 Re、 186 Re、 153 Sm、 66 Ga、 67 Ga、 68 Ga、 111 In、 123 In、 59 Fe、 63 Zn, 52 Fe、 52 Mn, 45 Ti、 60 Cu、 61 Cu、67 Cu、 64 Cu、 62 Cu、 82 Rb、 195m Pt, 191m Pt, 193m Pt, 117m Sn、 89 Zr、 177 Lu、 18 F, 188 Re、 186 Re、 153 Sm、 66 Ho、 86 Y、 87 Y、 90 Y、 89 Sr、 153 Gd, 159 Gd, 225 Ac、 212 Bi、 213 Bi、 198 Au、 199 Au、 193m Pt, 197 Pt, 103 Pd, 109 Pd, 105 Rh、 101m Rh、 103m Rh、 223 Ra、 224 Ra、 97 Ru、 227 Th、 229 Th、 161 Tb, 149 Tb, 203 Pb, 212 Pb, 201 TI, 119 Sb, 58m Co、 55 Co、 57 Co、 47 Sc、 149 Pm, 142 Pr、 161 Ho、 166 Ho、 175 Yb and 51 Cr.

[0187] In some embodiments, the compounds provided herein can be used for imaging, and one or more radionuclides complexed with the chelating group for imaging are selected from the group consisting of: 99m Tc, 188 Re、 186 Re、 153 Sm、66 Ga、 67 Ga、 68 Ga、 111 In、 59 Fe、 63 Zn, 52 Fe、 52 Mn, 45 Ti、 60 Cu、 61 Cu、 67 Cu、 64 Cu、 62 Cu、 82 Rb、 198 Au、 199 Au、 195m Pt, 191m Pt, 193m Pt, 117m Sn、 89 Zr、 177 Lu、 18 F, 203 Pb, 44 Sc、 51 Cr 101m Rh and 166 Ho.

[0188] In some embodiments, the compounds provided herein can be used to kill cells or treat diseases, and one or more radionuclides used to kill cells or treat diseases are selected from the group consisting of: 188 Re、 186 Re、 153 Sm、 66 Ho、 90 Y、 89 Sr、 111 In、 153 Gd, 225 Ac、 212 Bi、 213 Bi、 60 Cu、 61 Cu、 67 Cu、 64 Cu、 62 Cu、 198 Au、 99 Au、 195m Pt, 193m Pt, 197 Pt, 117m Sn、 103 Pd, 105 Rh、 103m Rh、 177 Lu、 223 Ra、 224 Ra、227 Th、 229 Th、 149 Tb, 161 Tb, 203 Pb, 212 Pb, 201 TI, 119 Sb, 58m Co、 47 Sc、 149 Pm, 161 Ho、 159 Gd, 142 Pr、 166 Ho and 175 Yb. In some embodiments, one or more radionuclides used for treatment are selected from the group consisting of: 177 Lu、 212 Pb and 225 Ac. In some implementations, the radionuclide used to kill cells or treat disease is 177 Lu or 225 Ac. In some implementations, one or more radionuclides used to kill cells or treat disease are 177 Lu. In some implementations, one or more radionuclides are used to kill cells or treat diseases. 225 Ac.

[0189] In some implementations, E is 177 Lu-DOTA-、 177 Lu-DOTAGA-、 225 Ac-DOTA- or 225 Ac-DOTAGA-.

[0190] Connector L E

[0191] In some implementations, L E It is the key or any divalent connector between T and E. In some implementations, L E Is it a key or divalent connector: -(U) k –,

[0192] in:

[0193] k is an integer between 1 and 20, and

[0194] Each U is independently selected from amino acid residues and -N(R) N (C2 alkylene U) a ) k1 U b The group consisting of C(O), where R N Is it H or C? 1-6 Alkyl, wherein Ua It is -O-, -S-, -NH- or -N(C 1-6 Alkyl)-, where k1 is an integer from 1 to 10, and where U b It is C 1-3 Alkylene.

[0195] In some implementations, L E It contains one or more amino acid residues. In some embodiments, L E Contains one or more amino acid residues and L E It can be connected to E and T via the main chain or side chain. In some implementations, L E It is a divalent linker containing one or more amino acids (e.g., an integer number between 1 and 20, 1 and 15, or 1 and 10, or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10).

[0196] In some implementations, L E Includes -N(R) N (C2 alkylene U) a ) k1 U b C(O), where R N Is it H or C? 1- C6 alkyl, wherein U a It is -O-, -S-, -NH- or -N(C 1- C6 alkyl)-, where k1 is an integer from 1 to 10, and where U b It is C 1- C3 alkylene. In some embodiments, -N(R N (C2 alkylene U) a ) k1 U b C(O) is -N(R) N (C2-alkyleneO)2C1-alkyleneC(O), -N(R) N (C2-alkyleneO)C2-alkyleneC(O), -N(R) N (C2-alkyleneO)3C2-alkylene(O) or -N(R) N (C2-alkyleneO)6C2-alkyleneC(O), where R N Is it H or C? 1- C6 alkyl. In some embodiments, R N It is H. In some implementations, R N It is methyl, ethyl, or propyl. In some embodiments, L EIt comprises one or more portions, each independently selected from the group consisting of: NH(C2alkyleneO)2C1alkyleneC(O) (OEG), -NH(C2alkyleneO)C2alkyleneC(O) (PEG1), -NH(C2alkyleneO)3C2alkyleneC(O) (PEG3) or -NH(C2alkyleneO)6C2alkyleneC(O) (PEG6). In some embodiments, L E Includes OEG. In some implementations, L E Contains PEG1. In some implementations, L E Contains PEG3. In some implementations, L E Contains PEG6.

[0197] In some implementations, k is an integer from 1 to 15. In some implementations, k is an integer from 1 to 10. In some implementations, k is an integer from 1 to 6. In some implementations, k is any one of 1, 2, or 3.

[0198] In some implementations, L E It is a key.

[0199] SSTR2 joint part

[0200] In some embodiments, Z is a target moiety capable of specifically binding to human SSTR2. In some embodiments, Z is linked to L via any of its available functional groups. Z In some embodiments, Z comprises an amino functional group, and Z is linked to L via the amino functional group. Z In some implementations, Z is:

[0201] (II),

[0202] in:

[0203] u is 0 or 1;

[0204] R 0 It was by a C6-C 10 Aryl-substituted C1-C6 alkyl groups, and C6-C groups optionally substituted with one or more substituents. 10 Aryl group, each substituent is independently a halogen or NO2;

[0205] R 1 It was by a C6-C 10 aryl-substituted C1-C6 alkyl groups, wherein the C6-C 10 The aryl group may be optionally substituted by one or more substituents, each substituent being independently -OH, -O (C1-C6 alkyl), or -N (R). a )C(O)R 1aAnd R 1a It is a 3- to 8-membered heterocycle optionally substituted with one or more oxygens;

[0206] R 2 It was by a C6-C 10 aryl or 5 to 12 heteroaryl substituted C1-C6 alkyl groups, wherein the C6-C 10 The aryl or 5- to 12-membered heteroaryl group is optionally substituted by one or more substituents, each substituent being independently -OH, -O (C1-C6 alkyl) or -N (R a )C(O)NH(R a );

[0207] x is 0 or 1;

[0208] R x It is -N(R) a )C(O)-(C6-C 10 (Aromatic);

[0209] R 3 It is caused by one or more -NH((R) a ) substituted C1-C6 alkyl groups;

[0210] R 4 It is a C1-C6 alkyl group substituted with one or more -OH groups;

[0211] y is 0 or 1;

[0212] R y It was by a C6-C 10 Aryl-substituted C1-C6 alkyl groups;

[0213] R z Is -OH or , where R z1 It is a C1-C6 alkyl group substituted with one or more substituents, each substituent being independently selected from -OH and optionally substituted with one or more -OH groups. 10 Group composed of aryl groups; R z2 It is -COOH, -C(O)NH2, or a C1-C6 alkyl group substituted with one or more -OH groups; and

[0214] R a Each time it appears, it is independently H or C1-C3 alkyl.

[0215] In some implementations, u is 1, and R 0 It is a C1-C6 alkyl group substituted with a phenyl group (e.g., C1-C3 alkyl, methyl, ethyl, or propyl), wherein the phenyl group is unsubstituted or substituted with one or more halogens or NO2. In some embodiments, u is 1, and R0 It is a methyl group substituted with a phenyl group, wherein the phenyl group is unsubstituted or substituted with one or more halogens or NO2. In some embodiments, R 0 yes or .

[0216] In some implementation schemes, R 1 It was by a C6-C 10 aryl (e.g., phenyl) substituted methyl group, wherein C6-C 10 The aryl group may be optionally substituted by one or more substituents, each substituent being independently -OH or -NHC(O)R. 1a , where R 1a It is a 3- to 8-membered heterocycle (e.g., a 3- to 6-membered heterocycle) optionally substituted with one or more oxygen groups. In some embodiments, R 1 It is a methyl group substituted with a phenyl group, wherein the phenyl group is substituted with one or more -OH groups. In some embodiments, R 1 It is a methyl group substituted with a phenyl group, wherein the phenyl group is replaced by a -NHC(O)R group. 1a Replace, where R 1a It is a 3- to 6-membered heterocycle optionally substituted with one or more oxygen groups. In some embodiments, R 1 It is a methyl group substituted with a phenyl group, wherein the phenyl group is replaced by a methyl group. Replacement. In some implementations, R 1 yes , , or .

[0217] In some implementation schemes, R 2 It was by a C6-C 10 A C1-C6 alkyl group (e.g., C1-C3 alkyl, methyl, ethyl, or propyl) substituted with an aryl or 5- to 12-membered heteroaryl group, each optionally substituted with one or more substituents, each substituent being independently -OH or -NHC(O)NH2. In some embodiments, R 2 It is a C1-C3 alkyl group substituted with a phenyl group, wherein the phenyl group is optionally substituted with one or more -OH or -NHC(O)NH2. In some embodiments, R 2 It is a C1-C3 alkyl group substituted with a 5- to 12-membered heteroaryl group, wherein the 5- to 12-membered heteroaryl group is unsubstituted. In some embodiments, the 5- to 12-membered heteroaryl group is... In some implementations, R 2 yes , or .

[0218] In some implementation schemes, R 3 It is a C1-C6 alkyl group substituted with one or more NH2 molecules. In some embodiments, R 3 It is -CH2CH2CH2CH2NH2.

[0219] In some implementations, x is 0. In some implementations, x is 1. In some implementations, R x yes .

[0220] In some implementations, y is 0. In some implementations, y is 1. In some implementations, R y yes .

[0221] In some implementation schemes, R 4 It is a C1-C3 alkyl group substituted with one or more -OH groups. In some embodiments, R 4 Yes or .

[0222] In some implementation schemes, R z It is -OH.

[0223] In some implementation schemes, R z yes In some implementations, R z1 It is a C1-C6 alkyl group substituted with one or more -OH groups. In some embodiments, R z1 yes In some implementations, R z1 It is a C6-C that is optionally substituted with one or more -OH groups. 10 Alkyl group. In some embodiments, R z1 yes In some implementations, R z2 It is -COOH. In some implementations, R z2 It is a C1-C6 alkyl group substituted with one or more -OH groups. In some embodiments, R z2 It is -CH2OH. In some implementations, R z2 It is -C(O)NH2. In some implementations, R z It is -OH, , or .

[0224] In some implementation schemes, Z is:

[0225] (II-A),

[0226] Where R 3a It is CH2OH, CO2H, or CONH2.

[0227] In some implementation schemes, Z is:

[0228] (TOC)

[0229] (NOC)

[0230] (TATE)

[0231] (octreotide)

[0232] (JR11) or

[0233] (BASS).

[0234] In some embodiments of the compound of formula (I), at least one of (i)-(vii) is satisfied:

[0235] (i)L A It contains 1 to 5 Asp or D-Asp;

[0236] (ii)L A It does not contain Glu, D-Glu, D-γGlu, or γGlu;

[0237] (iii) A is the fatty monocarboxylic acid moiety;

[0238] (iv) A is C8-C 16 Fatty acid portion;

[0239] (v)L Z Contains 1 to 6 Gly; and

[0240] (vi)L Z Does not contain -C2 alkylene O-

[0241] (vii) When T is D-Lys or Lys, L A It is conjugated with the α-amino group of T.

[0242] In some implementations, (i) and (ii) apply. In some implementations, (i) and (iii) apply. In some implementations, (i) and (iv) apply. In some implementations, (i) and (v) apply. In some implementations, (i) and (vi) apply. In some implementations, (i) and (vii) apply. In some implementations, (ii) and (iii) apply. In some implementations, (ii) and (iv) apply. In some implementations, (ii) and (v) apply. In some implementations, (ii) and (vi) apply. In some implementations, (ii) and (vii) apply. In some implementations, (iii) and (iv) apply. In some implementations, (iii) and (v) apply. In some implementations, (iii) and (vi) apply. In some implementations, (iii) and (vii) apply. In some implementations, (iv) and (v) apply. In some implementations, (iv) and (vii) apply. In some implementations, (v) and (vi) apply. In some implementations, (v) and (vii) apply. In some implementations, (vi) and (vii) apply. In some implementations, (i), (ii), and (iii) apply. In some implementations, (i), (ii), and (iv) apply. In some implementations, (i), (ii), and (v) apply. In some implementations, (i), (ii), and (vi) apply. In some implementations, (i), (ii), and (vii) apply. In some implementations, (ii), (iii), and (iv) apply. In some implementations, (ii), (iii), and (v) apply. In some implementations, (ii), (iii), and (vi) apply. In some implementations, (ii), (iii), and (vii) apply. In some implementations, (iii), (iv), and (v) apply. In some implementations, (iii), (iv), and (vi) apply. In some implementations, (iii), (iv), and (vii) apply. In some implementations, (iv), (v), and (vi) apply. In some implementations, (iv), (v), and (vii) apply. In some implementations, (v), (vi), and (vii) apply. In some implementations, (i), (ii), (iii), and (iv) apply. In some implementations, (i), (ii), (iii), and (v) apply. In some implementations, (i), (ii), (iii), and (vi) apply. In some implementations, (i), (ii), (iii), and (vii) apply. In some implementations, (ii), (iii), (iv), and (v) apply.In some implementations, (ii), (iii), (iv), and (vi) apply. In some implementations, (ii), (iii), (iv), and (vii) apply. In some implementations, (iii), (iv), (v), and (vi) apply. In some implementations, (iii), (iv), (v), and (vii) apply. In some implementations, (iv), (v), (vi), and (vii) apply. In some implementations, (i), (ii), (iii), (iv), and (v) apply. In some implementations, (i), (ii), (iii), (iv), and (vii) apply. In some implementations, (i), (ii), (iii), (iv), and (vii) apply. In some implementations, (ii), (iii), (iv), (v), and (vii) apply. In some implementations, (ii), (iv), (v), and (vii) apply. In some implementations, (iii), (iv), (v), (vi), and (vii) apply. In some implementations, (i), (iv), (v), (vi), and (vii) apply. In some implementations, (ii), (iv), (v), (vi), and (vii) apply. In some implementations, (i), (ii), (iv), (v), and (vi) apply. In some implementations, (i), (ii), (iv), (v), and (vii) apply. In some implementations, (ii), (iii), (v), (vi), and (vii) apply. In some implementations, (i), (ii), (iii), (vi), and (vii) apply. In some implementations, (i), (ii), (iv), (vi), and (vii) apply. In some implementations, (i), (ii), (iii), (iv), (v), and (vi) apply. In some implementations, (ii), (iii), (iv), (v), (vi), and (vii) apply. In some implementations, (ii), (iii), (iv), (v), (vi), and (vii) apply. In some implementations, (i), (ii), (iii), (iv), (v), (vi), and (vii) apply.

[0243] In some embodiments, compounds of formula (I) are provided herein, wherein Z is the SSTR2 binding moiety; T is Lys, D-Lys, Amp, Apr, Dab, or Bab; E is an effector moiety comprising a chelating group derived from DOTA or DOTAGA complexed with one or more radionuclides; and A is an unsubstituted or substituted C6-C 24 The fatty acid portion, in which A is connected via linker L A Through the α-amino group of T, T is conjugated with T; L Z L E and L AEach is independently a key or a divalent connector. In some implementations, L A Contains 1 to 5 Asp or D-Asp; and L Z It contains 1 to 6 Gly. In some implementations, L A Contains 1 to 5 Asp or D-Asp and L Z It does not contain -C2 alkylene O-. In some embodiments, L A Contains 1 to 5 Asp or D-Asp, L A It does not contain Glu, D-Glu, D-γGlu, or γGlu, and A is a fatty monocarboxylic acid moiety. In some embodiments, L A Contains 1 to 5 Asp or D-Asp, L Z Contains 1 to 6 Gly, and L Z It does not contain -C2 alkylene O-. In some embodiments, A is an aliphatic monocarboxylic acid moiety and L Z It does not contain -C2 alkylene O-. In some embodiments, A is an aliphatic monocarboxylic acid moiety, and L Z It contains 1 to 6 Gly. In some implementations, L A Contains 1 to 5 Asp or D-Asp, where A is C 12 The fatty monocarboxylic acid moiety, in which A is connected via the linker L A L is conjugated to T via the α-amino group of T. Z Contains 1 to 6 Gly, and L Z It does not contain -C2 alkylene O-. In some embodiments, T is D-Lys or Lys, L A Conjugated with the α-amino group of T, and L A It contains 1 to 5 Asp or D-Asp. In some implementations, T is Amp, Apr, or Bab, and L A It contains 1 to 5 Asp or D-Asp. In some implementations, T is D-Lys or Lys, L A E is conjugated to the α-amino group of T, contains a chelating group derived from DOTA complexed with one or more radionuclides, and A is an aliphatic monocarboxylic acid moiety. In some embodiments, T is D-Lys or Lys, L A With the α-amino group of T conjugated, E contains a chelate group derived from DOTA complexed with one or more radionuclides, and A is C8-C. 12 The fatty monocarboxylic acid moiety, in which A is connected via the linker L A The α-amino group of T is conjugated with T.

[0244] In some embodiments, compounds of formula (I) are provided herein, wherein Z is (TOC) or

[0245] (TATE); T is Lys, D-Lys, Amp, Dab, Apr, or Bab; E is an effector moiety containing a chelating group derived from DOTA or DOTAGA complexed with one or more radionuclides; A is unsubstituted or substituted C6-C 24 The fatty acid portion, in which A is connected via linker L A Through the α-amino group of T, T is conjugated with T; L Z L E and L A Each is independently a key or a divalent connector. In some implementations, L A Contains 1 to 5 Asp or D-Asp; and L Z It contains 1 to 6 Gly. In some implementations, L A Contains 1 to 5 Asp or D-Asp and L Z It does not contain -C2 alkylene O-. In some embodiments, L A Contains 1 to 5 Asp or D-Asp, L A It does not contain Glu, D-Glu, D-γGlu, or γGlu, and A is a fatty monocarboxylic acid moiety. In some embodiments, L A Contains 1 to 5 Asp or D-Asp, L Z Contains 1 to 6 Gly, and L Z It does not contain -C2 alkylene O-. In some embodiments, A is an aliphatic monocarboxylic acid moiety, and L Z It does not contain -C2 alkylene O-. In some embodiments, A is an aliphatic monocarboxylic acid moiety, and L Z It contains 1 to 6 Gly. In some implementations, L A Contains 1 to 5 Asp or D-Asp, where A is C 12 The fatty monocarboxylic acid moiety, in which A is connected via the linker L A L is conjugated to T via the α-amino group of T. Z Contains 1 to 6 Gly, and L Z It does not contain -C2 alkylene O-. In some embodiments, T is D-Lys or Lys, L A Conjugated with the α-amino group of T, and L A It contains 1 to 5 Asp or D-Asp. In some implementations, T is Amp, Apr, or Bab, and L A It contains 1 to 5 Asp or D-Asp. In some implementations, T is D-Lys or Lys, L AIn conjunction with the α-amino group of T, E comprises a chelating group derived from DOTA complexed with one or more radionuclides A, where A is an aliphatic monocarboxylic acid moiety. In some embodiments, T is Lys, E comprises a chelating group derived from DOTA complexed with one or more radionuclides, and A is C8-C 12 The fatty monocarboxylic acid moiety, in which A is connected via the linker L A The α-amino group of T is conjugated with T.

[0246] In some embodiments, compounds of formula (I) are provided herein, wherein Z is (TATE); T is Lys, D-Lys, Dab, Amp, Apr, or Bab; E is an effector moiety containing a chelating group derived from DOTA or DOTAGA complexed with one or more radionuclides; A is unsubstituted or substituted C6-C 24 The fatty acid portion, in which A is connected via linker L A Through the α-amino group of T, T is conjugated with T; L Z L E and L A Each is independently a key or a divalent connector. In some implementations, L A Contains 1 to 5 Asp or D-Asp; and L Z It contains 1 to 6 Gly. In some implementations, L A Contains 1 to 5 Asp or D-Asp and L Z It does not contain -C2 alkylene O-. In some embodiments, L A Contains 1 to 5 Asp or D-Asp, L A It does not contain Glu, D-Glu, D-γGlu, or γGlu, and A is a fatty monocarboxylic acid moiety. In some embodiments, L A Contains 1 to 5 Asp or D-Asp, L Z Contains 1 to 6 Gly, and L Z It does not contain -C2 alkylene O-. In some embodiments, A is an aliphatic monocarboxylic acid moiety, and L Z It does not contain -C2 alkylene O-. In some embodiments, A is an aliphatic monocarboxylic acid moiety, and L Z It contains 1 to 6 Gly. In some implementations, L A Contains 1 to 5 Asp or D-Asp, where A is C 12 The fatty monocarboxylic acid moiety, in which A is connected via the linker L A L is conjugated to T via the α-amino group of T. Z Contains 1 to 6 Gly, and L Z It does not contain -C2 alkylene O-. In some embodiments, T is D-Lys or Lys, LA Conjugated with the α-amino group of T, and L A It contains 1 to 5 Asp or D-Asp. In some implementations, T is Amp, Apr, or Bab, and L A It contains 1 to 5 Asp or D-Asp. In some implementations, T is D-Lys or Lys, L A With the α-amino group of T conjugated, E comprises a chelating group derived from DOTA complexed with one or more radionuclides, and A is an aliphatic monocarboxylic acid moiety. In some embodiments, T is Lys, E comprises a chelating group derived from DOTA complexed with one or more radionuclides, and A is C8-C 12 The fatty monocarboxylic acid moiety, in which A is connected via the linker L A The α-amino group of T is conjugated with T.

[0247] In some embodiments, compounds of formula (Ia) are provided herein:

[0248] (Ia)

[0249] in:

[0250] T is a trivalent part selected from the following group: Lys, D-Lys, Amp, Dab, Apr, and Bab.

[0251] Z is the somatostatin receptor 2 (SSTR2) binding site, where Z is located via the linker L Z Combined with T,

[0252] E is an effector moiety comprising a chelating group derived from DOTA or DOTAGA complexed with one or more radionuclides, wherein E is via a linker L E Adjoining with T.

[0253] A is the unsubstituted or substituted fatty acid moiety, wherein A is via the linker L A Through the α-amino group of T conjugated with T, and

[0254] L Z L E and L A Each is an independent key or a binary connector.

[0255] In some embodiments of the compound of formula (Ia), T is D-Lys or Lys, L A It is conjugated with the α-amino group of T.

[0256] In some embodiments of the compound of formula (Ia), L A It contains 1 to 5 Asp or D-Asp.

[0257] In some embodiments of the compound of formula (Ia), L A Contains 1 to 5 Asp or D-Asp and L A It does not contain Glu, D-Glu, D-γGlu, or γGlu.

[0258] In some embodiments of the compound of formula (Ia), L A It contains 1 to 5 Asp or D-Asp, and A is the fatty monocarboxylic acid moiety.

[0259] In some embodiments of the compound of formula (Ia), L A It does not contain Glu, D-Glu, D-γGlu or γGlu and A is a fatty monocarboxylic acid moiety.

[0260] In some embodiments of the compound of formula (Ia), L A Contains 1 to 5 Asp or D-Asp and L Z It contains 1 to 6 Gly.

[0261] In some embodiments of the compound of formula (Ia), L A Contains 1 to 5 Asp or D-Asp and L Z It does not contain -C2 alkylene O-.

[0262] In some embodiments of the compound of formula (Ia), L A Contains 1 to 5 Asp or D-Asp, L A It does not contain Glu, D-Glu, D-γGlu or γGlu, and A is the fatty monocarboxylic acid portion.

[0263] In some embodiments of the compound of formula (Ia), L A Contains 1 to 5 Asp or D-Asp, L Z Contains 1 to 6 Gly, and L Z It does not contain -C2 alkylene O-.

[0264] In some embodiments of the compound of formula (Ia), A is the fatty monocarboxylic acid moiety, and L Z It does not contain -C2 alkylene O-.

[0265] In some embodiments of the compound of formula (Ia), A is the fatty monocarboxylic acid moiety, and L Z It contains 1 to 6 Gly.

[0266] In some embodiments of the compound of formula (Ia), L A Contains 1 to 5 Asp or D-Asp, where A is C 12 The fatty monocarboxylic acid moiety, in which A is connected via the linker LA L is conjugated to T via the α-amino group of T. Z Contains 1 to 6 Gly, and L Z It does not contain -C2 alkylene O-.

[0267] In some embodiments, the compound of formula (I) comprises a ligand moiety selected from the portions in Table 1.

[0268] Table 1. Structures of exemplary compounds of this application

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290] abbreviation:

[0291] T: Threonine; C: Cysteine; K: Lysine; k: D-Lysine; w: D-Tryptophan; Y: Tyrosine; f: D-Phenylalanine; A: Alanine; G: Glycine; W: Tryptophan; Nle: Non-leucine; D: Aspartic acid; S: Serine; p: D-Proline; R: Arginine

[0292] gE: γ-glutamic acid; eK: ε-lysine

[0293] -OH: C-terminal acid; -NH2: C-terminal amide; Thr(ol): C-terminal alcohol

[0294] [CXXXXC]: Disulfide bond

[0295] DOTA: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid;

[0296] DOTAGA: 2-[1,4,7,10-tetraazacyclododecane-4,7,10-triacetic acid]-glutaric acid

[0297] OEG: H2N-[CH2CH2O]2-CH2CO2H

[0298] In some embodiments, this document provides pharmaceutical compositions comprising any compound described herein, such as a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0299] Stereoisomers, mixtures of stereoisomers, tautomers, isotopically enriched analogs, and pharmaceutically acceptable salts of the compounds described herein, such as compounds of formula (I) or variants thereof described herein.

[0300] In the description herein, it should be understood that each description, variation, implementation, or aspect of a part may be combined with each description, variation, implementation, or aspect of other parts, as each combination of descriptions is specifically and individually listed. For example, each description, variation, implementation, or aspect of A with respect to equation (I) provided herein may be combined with L of equation (I). Z Each description, variation, embodiment, or aspect combination thereof, as if each combination were specifically and individually listed, and such combination is equally applicable to other formulations where the chemical structure permits. For another example, each description, variation, embodiment, or aspect of E relating to formula (I) provided herein may be combined with L of formula (I). AEach description, variation, implementation scheme, or combination of aspects is as specifically and individually listed, and such combination is equally applicable to other formulations where the chemical structure permits.

[0301] The compounds disclosed herein, or pharmaceutically acceptable salts thereof, may include asymmetric centers, thus yielding enantiomers, diastereomers, and other stereoisomers, which may be defined as (R)- or (S)- according to absolute stereochemistry. This disclosure is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), or (R)- and (S)- isomers, can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as chromatography and stepwise crystallization. Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemic mixtures (or racemic mixtures of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). When the compounds described herein contain alkene double bonds or other geometrically asymmetric centers, the compounds are expected to include E and Z geometrical isomers unless otherwise stated. In some embodiments, the compounds of formula (I) provided herein also cover stereoisomers of formula (I) or variants thereof.

[0302] This disclosure also covers tautomers. Tautomers are in equilibrium with each other. For example, amide-containing compounds can exist in equilibrium with imine tautomers. Regardless of which tautomer is shown, and regardless of the equilibrium nature between the tautomers, those skilled in the art will understand that the compound comprises both amide and imine tautomers. Therefore, amide-containing compounds should be understood to include their imine tautomers. Similarly, imine-containing compounds should be understood to include their amide tautomers.

[0303] Any compound or structure described herein is intended to represent both unlabeled and isotopically labeled forms of the compound. These forms of the compound may also be referred to as “isotopically enriched analogs.” Isotopically labeled compounds have the structures described herein, except that one or more atoms are substituted with atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, for example, […]. 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35S, 18 F, 36 Cl、 123 I and 125 I. Various isotope-labeled compounds disclosed herein, such as those doped with radioactive isotopes (e.g., 3 H, 13 C and 14 Compounds of type C). Such isotopically labeled compounds can be used in metabolic studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or for radiotherapy of patients. These compounds may exhibit increased metabolic resistance and therefore can be used to increase the half-life of any compound when administered to mammals, particularly humans. These compounds are synthesized using methods known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0304] Some of the compounds disclosed herein contain one or more ionizable groups (groups from which protons can be removed (e.g., -COOH) or added (e.g., amines) or quaternized (e.g., amines)). All possible ionic forms of such molecules and their salts are intended to be included individually in the disclosure herein. Regarding salts of the compounds described herein, those skilled in the art can select suitable counterions from a variety of available counterions. In specific applications, the selection of a given anion or cation for preparing a salt can result in an increase or decrease in the solubility of that salt.

[0305] In some embodiments, pharmaceutically acceptable salts of the compounds described herein are provided. In some embodiments, the pharmaceutically acceptable salt is an acid addition salt or a base addition salt. The selection of a suitable salt can be made by those skilled in the art (see, for example, SM Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19).

[0306] The description of the compounds disclosed herein is limited by the principles of chemical bonding known to those skilled in the art. Therefore, when a group can be substituted by one or more of a plurality of substituents, such substitution is chosen to conform to the principles of chemical bonding and to provide compounds that are not inherently unstable and / or compounds known to those skilled in the art as potentially unstable under environmental conditions (such as aqueous, neutral, and several known physiological conditions). For example, heterocyclic or heteroaryl groups are linked to the remainder of the molecule via cyclic heteroatoms according to the principles of chemical bonding known to those skilled in the art, thereby avoiding inherently unstable compounds.

[0307] III. Usage Method

[0308] In some respects, this document provides compounds of formula (I) or pharmaceutically acceptable salts thereof for imaging or diagnosis or for treatment, wherein a compound of formula (I) may be any compound or variant described herein.

[0309] In one aspect, this article provides a method for treating a disease or condition in a subject with this need, the method comprising administering to the subject a pharmaceutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or condition is cancer. In some embodiments, the cancer is cancer with high expression of SSTR2. In some embodiments, the cancer is medullary thyroid carcinoma (MTC), small cell lung cancer (SCLC), or a neuroendocrine tumor.

[0310] In some embodiments, this document provides a method for inhibiting cell proliferation activity, which includes administering an effective amount of one or more compounds of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the cells express SSTR2 on their surface.

[0311] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts, stereoisomers, or tautomers thereof, or the pharmaceutical compositions described herein, are cytotoxic and can kill or inhibit the growth of cancer cells. In some embodiments, a method for killing cancer cells is provided herein, comprising contacting cells with an effective amount of the compounds described herein, or pharmaceutically acceptable salts, stereoisomers, or tautomers thereof, or the pharmaceutical compositions described herein. In some embodiments, a method for inhibiting the growth of cancer cells is provided herein, comprising contacting cells with an effective amount of the compounds described herein, or pharmaceutically acceptable salts, stereoisomers, or tautomers thereof, or the pharmaceutical compositions described herein. In some embodiments, a method for killing cancer cells in a person with this need is provided herein, comprising administering to a person a therapeutically effective amount of the compounds described herein, or pharmaceutically acceptable salts, stereoisomers, or tautomers thereof, or the pharmaceutical compositions described herein. In some embodiments, a method for inhibiting the growth of cancer cells in a subject with this need is provided herein, comprising administering to a person a therapeutically effective amount of the compounds described herein, or pharmaceutically acceptable salts, stereoisomers, or tautomers thereof, or the pharmaceutical compositions described herein.

[0312] In some implementations, this document provides a method for imaging the tissues of a subject by administering to the subject in need an imaging-effective amount of one or more compounds of formula (I) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or the pharmaceutical composition described herein, and applying imaging techniques to detect emitted gamma rays.

[0313] In some implementations, this document provides a method for diagnosing cancer in a subject by administering a diagnostically effective amount of one or more compounds of formula (I) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition described herein, and by applying imaging techniques to detect emitted gamma rays.

[0314] IV. Reagent Kit

[0315] This document also provides kits for carrying out the methods described herein, comprising one or more of the compounds described herein, or pharmaceutically acceptable salts, stereoisomers, or tautomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the compounds described herein. The kit may use any of the compounds disclosed herein. In one variation, the kit uses the compounds described herein or pharmaceutically acceptable salts thereof: the kit may be used for any one or more of the purposes described herein, and may therefore contain instructions for use in diagnosing or treating cancer.

[0316] In some respects, this document provides a kit comprising a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, or a pharmaceutical composition described herein, and instructions for use of the kit to diagnose a disease or condition in a subject who requires such diagnosis.

[0317] In some respects, this document provides a kit comprising a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, or a pharmaceutical composition described herein, and instructions for use of the kit to treat a disease or condition in a subject who requires such treatment.

[0318] In some embodiments, the kit may contain one or more containers containing any of the compounds described herein. Each component (if more than one component is present) may be packaged in a separate container, or, where cross-reactivity and shelf life permit, some components may be combined in one container. One or more components of the kit may be sterile and / or may be contained in sterile packaging.

[0319] In some implementations, the kit may include a set of instructions relating to the use of the components of the methods described herein, typically in written form, although electronic storage media containing the instructions (e.g., disks or optical discs) are also acceptable. The instructions included with the kit typically include information about the components and their administration to an individual.

[0320] V. Preparation method

[0321] The compounds described herein can be prepared by a variety of synthetic methods. The choice of specific structural features and / or substituents can influence the choice of one method relative to another. The choice of a specific method for preparing a given compound is within the scope of those skilled in the art. Some starting materials used to prepare the compounds of this application are available from commercial chemical sources. Other starting materials, such as those described below, can be readily prepared from available precursors using direct transformations known in the art.

[0322] In some embodiments, the compound of formula (I) may be prepared, in whole or in part, using solid-phase peptide synthesis (SPPS) or solution-phase coupling techniques known in the art, for example, using the synthetic procedure found in Stewart and Young, 1984, SolidPhase Synthesis, Second Edition, Pierce Chemical Co., Rockford, Ill.; Fieldsand Noble, 1990, “Solid phase peptide synthesis utilizing 9-fluorenylmethyloxycarbonyl amino acids,” Int. J. Pept. Protein Res. 35:161-214; Geysen et al., 1987, J. Immunol. Methods 102:259-274.

[0323] Therefore, in some embodiments, in SPPS, an Nα-protected linker group, such as a tert-butoxycarbonyl (Boc) or 9-fluorenylmethoxycarbonyl (Fmoc) amino acid linker group, can be activated at the α-carbonyl group and coupled to the deprotected Nα function of the solid support. Then, if desired, a newly added Nα-protected linker group can be deprotected and coupled to the next Nα-protected linker group until the final cleavage step. Those skilled in the art will understand that the chemical nature of the linker coupling from the solid support, deprotection, and final cleavage steps depends on the choice of the αN-protecting group. In some embodiments, cleavage can be accomplished by treatment with an acid (e.g., trifluoroacetic acid (TFA)) in the optional presence of a scavenging agent (e.g., triisopropylsilane). In some embodiments, when the αN-protecting group is Fmoc, cleavage in acid can also result in the deprotection of the side chain.

[0324] Therefore, in exemplary embodiments, compounds of formula (I) can be prepared using fluorene methoxycarbonyl (Fmoc) solid-phase peptide synthesis chemistry known in the art. Thus, in some embodiments, compounds of formula (I) or fragments thereof can be prepared manually or by using an automated multi-solid-phase peptide synthesizer, using Wang resin, Rink amide-MBHA or equivalent resin, and Fmoc-protected linker group derivatives with suitable side chain protection, such as Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc-Ala-OH, Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc-Ala-OH, Fmoc-Gly-OH, Fmoc-Ala-OH, Fmoc-Gly-OH, Fmoc-Ala-OH, Fmoc-Gly-OH, Fmoc-Gly-OH, Fmoc-Ala-OH, Fmoc-Gly-OH, Fmoc-Gly-OH, Fmoc-Gly-OH, Fmoc-Gly-OH, Fmoc-Gly-OH, Fmoc-Gly-Hys(Trt)-OH, Fmoc-Ala ... c-Ile-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Fmoc-Met-OH, Fmoc-Phe-OH, Fmoc-Pro-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Trp(Boc)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Val-OH, Fmoc-Lys(Mtt)-OH, Fmoc-Lys(ivDde)-OH, Fmoc-Nle-OH, Fmoc-8-amino-3,6-dioxooctanoic acid (Fmoc-OEG-OH), Fmoc-Glu-OtBu. In some embodiments, the resin can be swelled using a suitable solvent (such as a combination of dichloromethane (DCM) and dimethylformamide (DMF). Prior to each coupling step, the base-unstable Nα-protecting group Fmoc can be cleaved from the Fmoc-protected linker group using a suitable base (e.g., piperidine) in a suitable solvent (e.g., DMF) for, for example, about 10-15 minutes. In some embodiments, the resin can then be washed with a suitable solvent (e.g., DMF) to remove piperidine, for example. In some embodiments, excess Fmoc-linker groups (e.g., 4 to 810 molar equivalents) can then be coupled for about 1 to about 2 hours using coupling agents known in the art (e.g., N,N'-diisopropylcarbodiimide (DIC) and ethyl cyanohydroxyimino(Oxyma, e.g., Oxyma Pure®) or (benzotriazoloxy)tripyrrolidinephosphine hexafluorophosphate (PyBOP) and (1-hydroxybenzotriazole (HOBt)) in a suitable solvent (e.g., DMF), followed by further washing with a suitable solvent (e.g., DMF). The coupling step is repeated once for each linker group.

[0325] In some embodiments, if necessary, the deprotected Lys(Mtt) residues in the methyltriphenylmethyl (Mtt) group of the Fmoc-Lys(Mtt)-OH (i.e., N-α-Fmoc-N-ε-4-methyltriphenylmethyl-L-lysine) linker group or in the linker fragment can be removed by treating the resin with hexafluoroisopropanol (HFIP) in a suitable solvent (such as dichloromethane (DCM)) (e.g., 20 about 30% v / v) for a suitable amount of time, such as about 1 hour, followed by washing the resin with a suitable solvent and repeating the HFIP treatment in DCM, and finally washing with DCM after treatment.

[0326] In some embodiments, after coupling, the compound of formula (I) or a fragment thereof can be cleaved from the solid phase by treatment with a suitable acid (e.g., trifluoroacetic acid (TFA)) and optionally in the presence of a trialkylsilane (e.g., triisopropylsilane (TIP)) and water, followed by precipitation with a suitable solvent (e.g., diethyl ether). The product can be dissolved in a suitable solvent such as water and acetonitrile and purified using high-performance liquid chromatography (HPLC) such as reversed-phase HPLC using a suitable solvent or solvent mixture such as water with acetonitrile and TFA with an increasing acetonitrile gradient. In some embodiments, the relevant fractions can be examined by analytical UPLC. Fractions containing the purified target compound are combined and lyophilized.

[0327] In some embodiments, chelating groups such as DOTA can be chemically conjugated to the linker fragment using active esters known in the art, for example, an ε-amine of a lysine residue of the linker fragment or a linker fragment connected to the SSTR2 binding moiety and / or effector moiety. For example, DOTA can be combined with the linker fragment in the presence of a base (such as an amine).

[0328] In some embodiments, the chelating group can be synthesized by methods known in the art or is commercially available. For example, DOTA is available from Sigma-Aldrich (St. Louis, Missouri, USA).

[0329] In some implementations, the desired compound salt can be formed using standard techniques. For example, a neutral compound can be treated with an acid or base in a suitable solvent, and the formed salt can be separated by filtration, extraction, or any other suitable method.

[0330] In some embodiments, the formation of solvates can vary depending on the compound and the solvate. Typically, solvates can be formed by dissolving the compound in a suitable solvent and separating the solvate by cooling or using an antisolvent. In some embodiments, the solvate can be dried or azeotropic under ambient conditions. In some embodiments, those skilled in the art can select suitable conditions for the formation of a particular solvate. Examples of suitable solvents are ethanol, water, etc. When water is used as the solvent, the molecule is referred to as a "hydrate". The formation of solvates of the compounds in this application will vary depending on the compound and the solvate. In some embodiments, solvates can be formed by dissolving the compound in a suitable solvent and separating the solvate by cooling or using an antisolvent. In some embodiments, the solvate can be dried or azeotropic under ambient conditions.

[0331] In some embodiments, where appropriate, suitable protecting groups can be added to various reactants and intermediates in a manner readily understood by those skilled in the art, and subsequently removed from these reactants and intermediates. Conventional procedures using such protecting groups, and examples of suitable protecting groups, are described, for example, in “Protective Groups in Organic Synthesis,” TW Green, PGM Wuts, Wiley-Interscience, New York, (1999). It should also be understood that the conversion of one group or substituent to another can be carried out by chemical manipulation on any intermediate or final product along the synthetic pathway toward the final product, wherein the possible types of conversion are limited only by the inherent incompatibility of other functionalities carried by the molecule at that stage with the conditions or reagents used in the conversion. Such inherent incompatibility, and methods for circumventing them by performing suitable conversion and synthetic steps in a suitable order, will be readily understood by those skilled in the art. Examples of conversions are given herein, and it should be understood that the conversions described are not limited to general groups or substituents exemplified by example. References and descriptions of other suitable transformations are given in “Comprehensive Organic Transformations – A Guide to Functional Group Preparations”, RC Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions are found in organic chemistry textbooks such as “Advanced Organic Chemistry”, March, 4th ed. McGraw Hill (1992) or “Organic Synthesis”, Smith, McGraw Hill, (1994). Techniques for purifying intermediates and final products include, for example, normal and reversed-phase chromatography on columns or rotating plates, recrystallization, distillation, and liquid-liquid or solid-liquid extraction, which are readily understood by those skilled in the art. Example

[0332] The following embodiments are provided to provide a complete disclosure and description of how to prepare and use the invention to those skilled in the art, and these embodiments are not intended to limit the scope of the invention as the inventors believe, nor are they intended to represent all or only the experiments conducted below. The following embodiments are intended only to illustrate this application and should not be construed as limiting the application in any way. The following embodiments and detailed descriptions are provided by way of illustration rather than limitation.

[0333] Example 1. Synthesis of Compound of Exemplary Formula I

[0334] 1.1 Reagents

[0335] Unless otherwise specified, the Fmoc-protected amino acid derivatives used are the recommended standards: Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Fmoc-Leu-OH, Fmoc-Met-OH, Fmoc-Phe-OH, Fmoc-D-Phe-OH, Fmoc- Pro-OH, Fmoc-D-Pro-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Trp(Boc)-OH, Fmoc-D-Trp(Boc)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Val-OH, Fmoc-Lys(Mtt)-OH, Fmoc-Lys(ivDde)-OH, Fmoc-Glu-OtBu, Fmoc-Thr(tBu)-ol(CAS#189337-28-8), Fmoc-8-amino-3,6-dioxaoctanoic acid (Fmoc-OEG-OH), Fmoc-8-amino-octanoic acid (Fmoc-Aoc-OH), Fmoc-PEG1-OH (Fmoc-HN-CH2CH2O-CH2CH2CO2H), Fmoc-PEG3-OH (Fmoc-HN-[CH2CH2O]3-CH2CH2CO2H), Fmoc-PEG6-OH (Fmoc-HN-[CH2CH2O]6-CH2CH2CO2H), etc. Other reagents used include DOTA-tris(tert-butyl ester) and DOTAGA-tetra(tert-butyl ester).

[0336] 1.2 C-terminal acidic peptide

[0337] C-terminal acidic peptides were prepared using Wang resin. Coupling of the first C-terminal residue began by swelling Wang resin (1.1 mmol / g, 5.0 mmol) in a 50 mL DCM solution within a SPPS reaction vessel and bubbling with N2 for 30 min. The resin was then drained and washed three times with DMF (50 mL). In a separate flask, a mixture of Fmoc-Thr(tBu)-OH (15 mmol), DIC (15 mmol), and 4-dimethylaminopyridine (DMAP) (0.5 mmol) was stirred in DMF (60 mL) at room temperature for 15 min and then transferred to the aforementioned reaction vessel. The resulting mixture was bubbled with N2 for 4 h, drained, and washed six times with DMF (50 mL), followed by the addition of DMF (60 mL), acetic anhydride (50 mmol), and DMAP (0.50 mmol). The resulting mixture was bubbled with N2 for 2 h, drained, and the resin washed six times with DMF (50 mL).

[0338] 1.3 C-terminal amide peptide

[0339] C-terminal amide peptides were prepared using Rink amide-MBHA resin. The first C-terminal residue (Fmoc-Thr(tBu)-OH) was linked using PyBOP / HOBt / DIEA as the coupling agent under standard amide coupling conditions. The resin was washed six times with DMF before coupling the second residue.

[0340] 1.4 C-terminal alcohol peptide

[0341] C-terminal alcohol peptides were prepared using chlorotriphenylmethyl chloride (CTC) resin. The first C-terminal residue, Fmoc-Thr(tBu)-ol, was linked to the CTC resin by mixing 2 equivalents of Fmoc-Thr(tBu)-ol with the resin and maintaining the mixture in DMF at room temperature for 4 h in the presence of 3 equivalents of DIEA. The resin was then washed and blocked with 50% MeOH / DMF at room temperature for 1 h. The resin was then washed 6 times with DMF.

[0342] 1.5 Standard Solid-Phase Assembly Scheme

[0343] The synthesis was performed manually using Fmoc-based chemical methods. Step-by-step assembly was carried out following these steps:

[0344] 1) Use DCM and DMF pre-expanded resin;

[0345] 2) Remove the Fmoc group with 20% piperidine; treat twice, 10 minutes each time;

[0346] 3) Wash the resin with DMF to remove piperidine;

[0347] 4) Add Fmoc-amino acid (1 mmol), PyBOP (1 mmol), HOBt (0.2 mmol) and DMF (5 mL) to a reaction vessel containing 0.20 mmol of resin, then add DIEA (2 mmol), and mix the resulting mixture by bubbling nitrogen gas for 1-2 h;

[0348] 5) Drain the resin and wash it 6 times with DMF.

[0349] 6) When necessary, the N-ε-lysine Mtt protecting group can be removed by treating the resin twice in DCM with 30% (v / v) HFIP for 1 h; drain the resin and wash with DCM and DMF.

[0350] 7) Perform final washing of the resin before cutting using DMF (3 times), DCM (3 times), and MeOH (3 times).

[0351] 1.6 Resin cutting and disulfide bridge formation conditions and purification

[0352] After solid-phase peptide assembly, the resin was treated with TFA / triisopropylsilane (TIS) / H2O (95:2.5:2.5, v / v / v) for 1.5–3 h. The resin was filtered off and washed once with TFA. The combined filtrate was treated with methyl tert-butyl ether (MTBE) to precipitate the crude peptide from the solution. The precipitate was collected by centrifugation, washed three times with diethyl ether, briefly dried, and then dissolved in acetonitrile (ACN) and H2O to a concentration of 1 mM or lower. The volume ratio of ACN to H2O could be adjusted to a relatively low percentage of ACN while ensuring a completely clear solution. The pH of the resulting solution was adjusted to 4–5 by adding acetic acid, and then a methanol solution of iodine (1.0 g iodine in 100 mL methanol) was added dropwise until the iodine purple color was maintained. The slightly purple mixture was then gently stirred for another 30 minutes, and then ascorbic acid solid (a few mg per serving) was added until the purple color completely disappeared. The crude product was purified using a reversed-phase preparative HPLC system (Waters Delta Prep 4000) with a C18 reversed-phase column. Mobile phases: A: 0.1% TFA / H2O; B: 0.1% TFA / ACN. The fractions were analyzed by analytical ultra-high performance liquid chromatography (UPLC). The purified fractions were combined and lyophilized to obtain a white lyophilized powder.

[0353] 1.7 LC-MS conditions

[0354] Instrument: Agilent Prime-6125B_2LCMS

[0355] Column: Boltimate EXT C18 CoreShell 4.6 x 50 mm, 2.7 µm

[0356] Detection: UV (254 nm, 214 nm, 280 nm) and MS (ESI, 100 to 2000 amu)

[0357] Mobile phase: A: H2O (0.05% formic acid); B: ACN (0.05% formic acid)

[0358] Flow rate: 2.0 mL / min

[0359] Column temperature: 45℃

[0360] Gradient: From 10% to 95% B in 1.5 minutes, then reaching 95% B in 1.0 minute.

[0361] 1.8 Analytical HPLC conditions

[0362] Instrument: WATERS ARC UPLC

[0363] Column: XBridge BEH peptide BEH C18, 3.5 µm, 2.1 mm x 150 mm

[0364] Detection: UV 254 nm, 214 nm, 280 nm

[0365] Mobile phase: A: H2O (0.1% TFA); B: ACN (0.1% TFA)

[0366] Column temperature: 40℃

[0367] Flow rate: 0.6 mL / min

[0368] gradient:

[0369]

[0370] 1.9 Radiochemical Methods

[0371] Add 4 μL of the reference compound or the exemplary compound of this application from a 2000 μM DMSO stock solution to 20-50 μL of 0.5 M NaOAc buffer (pH=4.5), followed by 2 mCi 177Lu (ITM Isotope Technologies Munich). The resulting mixture was heated to 95°C and held for 15 minutes, then analyzed by radiometric TLC and radiometric HPLC (column: Shim-pack GIST 5 μm 4.6 x 150 mm; buffer A: 0.2% formic acid H₂O; buffer B: 0.1% formic acid acetonitrile; flow rate: 1 mL / min; gradient: 0–5 min: 10% B to 95% B; then 5–8 min: 95% B). Radiolabeled compounds were used immediately or diluted with PBS buffer containing freshly added 3 mg / mL ascorbate.

[0372] 1.10 Synthesis of the exemplary compound (I)

[0373] The following exemplary compound (I) was prepared using the method described above and further characterized by LC-MS, as shown in Table 2.

[0374] Table 2. Synthesis and characterization of exemplary compounds of this application.

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386] abbreviation:

[0387] T: Threonine; C: Cysteine; K: Lysine; k: D-Lysine; w: D-Tryptophan; Y: Tyrosine; f: D-Phenylalanine; A: Alanine; G: Glycine; W: Tryptophan; Nle: Non-leucine; D: Aspartic acid; S: Serine; p: D-Proline; R: Arginine

[0388] gE: γ-glutamic acid; eK: ε-lysine

[0389] -OH: C-terminal acid; -NH2: C-terminal amide; Thr(ol): C-terminal alcohol

[0390] [CXXXXC]: Disulfide bond

[0391] DOTA: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid;

[0392] DOTAGA: 2-[1,4,7,10-tetraazacyclododecane-4,7,10-triacetic acid]-glutaric acid

[0393] OEG: H2N-[CH2CH2O]2-CH2CO2H

[0394] Example 2. Binding affinity and binding selectivity of exemplary compounds

[0395] HEK 293T cells were transfected with a plasmid expressing SSTR2 using Lipofectamine 2000 reagent. Twenty-four hours post-transfection, cells were harvested and resuspended in assay buffer (1% OVA in DMEM). Cells were then seeded into 96-well plates with Cy5-labeled DOTATATE (Seq: Cy5-OEG-Lys(DOTA)-f[CYwKTC]T-OH) as a competitive ligand. Test compounds were further added to the wells at different concentrations. After incubation in the dark for 1 hour, cells were washed and resuspended in FACS buffer (1% OVA in DPBS). Fluorescence signals were detected by flow cytometry, and the IC50 of the competitive binding of the test compound to the competing ligand was calculated. 50 To evaluate the binding affinity of the test compound.

[0396] As shown in Table 3, the exemplary compounds of this application all exhibit specific binding to SSTR2, and in the assays described above, IC50... 50 The values ​​range from approximately 0.1 nM to approximately 10 nM, where:

[0397] Category A represents the IC of the reference compound. 50 IC of an exemplary compound 50 The value is less than 1.0.

[0398] Category B represents the IC of the reference compound. 50 IC of an exemplary compound 50 The value is between 1.0 and 2.0.

[0399] Category C represents the IC of the reference compound. 50 IC of an exemplary compound50 The value is between 2.0 and 4.0.

[0400] Category D represents the IC of the reference compound. 50 IC of an exemplary compound 50 The value is between 4.0 and 8.0.

[0401] Category E represents the IC of the reference compound. 50 IC of an exemplary compound 50 The value is ≥8.0.

[0402] Table 3. Binding affinity of exemplary compounds of this application

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409] abbreviation:

[0410] T: Threonine; C: Cysteine; K: Lysine; k: D-Lysine; w: D-Tryptophan; Y: Tyrosine; f: D-Phenylalanine; A: Alanine; G: Glycine; W: Tryptophan; Nle: Non-leucine; D: Aspartic acid; S: Serine; p: D-Proline; R: Arginine

[0411] gE: γ-glutamic acid; eK: ε-lysine

[0412] -OH: C-terminal acid; -NH2: C-terminal amide; Thr(ol): C-terminal alcohol

[0413] [CXXXXC]: Disulfide bond

[0414] DOTA: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid;

[0415] DOTAGA: 2-[1,4,7,10-tetraazacyclododecane-4,7,10-triacetic acid]-glutaric acid

[0416] OEG:H2N-[CH2CH2O]2-CH2CO2H

[0417] Based on Table 3, it was surprisingly found that compounds with fatty acid moiety A conjugated to a trivalent group (such as the alpha(α) amino group of Lys or D-Lys) resulted in higher binding affinity compared to exemplary compounds with A conjugated to an epsilon(ε) amino group, as exemplarily shown in Table 4.

[0418] Table 4: Binding Affinity of Representative Compounds in this Application

[0419]

[0420] Furthermore, compounds containing A as a fatty monocarboxylic acid moiety exhibit higher binding affinity compared to those containing A as a dicarboxylic acid moiety with the same carbon chain length, as shown in Table 5.

[0421] Table 5: Binding Affinity of Representative Compounds in this Application

[0422]

[0423] In addition, compounds containing fatty acid moieties with 12-16 carbons showed stronger binding to the target, as shown in Table 6.

[0424] Table 6: Binding Affinity of Representative Compounds in this Application

[0425]

[0426] Compound 027 is further used 175 Lu and 139 La labeling was used to evaluate the effect of metal-pair binding affinity after metal chelation. In short, for 175 Lu-labeled compound O27 (15 mg, 0.007 mmol) was added to 15 mL of 0.5 M NaOAc buffer (pH 4.5) containing a solution of compound O27 (15 mg, 0.007 mmol). The mixture was stirred at 55 °C for 30 min, and then LC-MS was performed to confirm the completion of the reaction (MW 2319.4; 1159.8 (M+2H)). + ),773.9(M+3H + (From LCMS). After cooling, the reaction mixture was purified by prep-HPLC to give 11.5 mg of white powder. 175 Lu-labeled compounds (purity > 99%).

[0427] for 139La-labeled compound O27 (15 mg, 0.007 mmol) was added to 15 mL of 0.5 M NaOAc buffer (pH 4.5) containing a solution of compound O27 (15 mg, 0.007 mmol). The mixture was stirred at 55 °C for 30 min, and then LC-MS was performed to confirm the completion of the reaction (MW 2283.3; 1142.2 (M+2H)). + ), 761.8 (M+3H + ), 571.7(M+4H + (From LCMS). After cooling, the reaction mixture was purified by prep-HPLC to give 6.9 mg of white powder. 139 La-labeled compounds (purity > 99%).

[0428] Further analysis was conducted using the same method described in Example 2 above. 175 Lu and 139 The binding affinity of La-labeled compound 027 is shown in Table 7. 175 Lu or 139 After La chelation, the compound exhibited binding affinity comparable to that of the unlabeled compound.

[0429] Table 7. Binding affinity of metal-labeled compounds

[0430]

[0431] To analyze the binding selectivity of the compounds, HEK 293T cells were transfected with plasmids expressing SSTR1, 2, 3, 4, or 5 using Lipofectamine 2000 reagent. Twenty-four hours post-transfection, cells were harvested and resuspended in assay buffer (1% OVA in DMEM). Cells were then seeded into 96-well plates containing the Cy5-labeled somatostatin peptide SST-14 (Seq: Cy5-OEG-OEG-Ala-Gly-[Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys]-OH) as a competitive ligand. Compound 027 was then added to the wells at different concentrations. After incubation in the dark for 1 hour, cells were washed and resuspended in FACS buffer (1% OVA in DPBS). Fluorescence signals were detected by flow cytometry, and the IC50 was calculated by measuring the competitive binding of the test compound to the competing ligand. 50 The binding affinity of compound 027 was evaluated. As shown in Table 8, compound 027 exhibited >500-fold selectivity for SSTR1, 3, 4 and 5 compared to SSTR2.

[0432] Table 8. Binding selectivity of compounds

[0433]

[0434] To analyze the cross-reactivity of the compound with SSTR2, HEK 293T cells were transfected with plasmids expressing SSTR2 from humans, mice, rats, or dogs using Lipofectamine 2000 reagent. Twenty-four hours post-transfection, cells were harvested and resuspended in assay buffer (1% OVA in DMEM). Cells were then seeded into 96-well plates containing Cy5-labeled DOTATATE (Seq: Cy5-OEG-Lys(DOTA)-f[CYwKTC]T-OH) as a competitive ligand. Compound 027 was then added to the wells at varying concentrations. After incubation in the dark for 1 hour, cells were washed and resuspended in FACS buffer (1% OVA in DPBS). Fluorescence signals were detected by flow cytometry, and the IC50 of the test compound against the competitive ligand was calculated. 50 The binding affinity of compound 027 was evaluated. As shown in Table 9, compound 027 exhibited considerable binding affinity for SSTR2 from humans, mice, rats, and dogs.

[0435] Table 9 Cross-reactivity of compounds in different species

[0436]

[0437] Example 3. 177 Biodistribution study of Lu-labeled compounds

[0438] All animal care and experimental procedures were performed in accordance with animal protocols approved by Kyinno Biotechnology and the Ethics Committee of the Institute of Radiation Protection, China. NOD SCID mice (Kyinno Biotechnology, Beijing) were used for these studies. Mice were kept in sterile microisolation cages at a rate of no more than 5 mice per cage under controlled temperature and humidity conditions using a 12-hour light / 12-hour dark schedule and were randomly fed irradiated rodent food and reverse osmosis (RO) sterile water. In preparation for tumor cell inoculation, mice were anesthetized with isoflurane (RWD Life Science Inc.) at a 4% induction rate and maintained with 0.4 L of oxygen at a rate of 2.5% via a precision vaporizer and non-rebreathing device. Mice received a subcutaneous injection of approximately 4 × 10⁴ mmol / L of oxygen in the posterior region. 6AR42J (human pancreatic cancer cell line) or H524 (human small cell lung cancer cell line) cells were suspended in 200 μL phosphate-buffered saline (PBS) and Matrigel (Corning) (1 / 1). Xenograft tumors were allowed to grow for ~2–4 weeks post-inoculation until the average tumor size reached ~200 mm. 3 .

[0439] Then, add 100 μL of 0.9% NaCl to each 177 Lu-labeled compounds were administered to mice via tail vein injection at doses of ~10–50 μCi (~0.37–1.85 MBq), with specific activities of 50–1000 µCi / nmol. Following administration, mice were euthanized at different time points including 1, 4, 24, 72, and 168 h, and tissues and organs were excised from the animals. Tissues and organs were weighed, counted in a PerkinElmer 2480 Wizard2γ counter, and the percentage dose (%ID) and %ID / g of each organ or tissue were calculated.

[0440] As shown in Tables 9-10 and Figure 1 As shown, all tested compounds exhibited high levels of radionuclide uptake in tumors, while showing acceptable uptake in normal tissues, including blood, kidneys, and liver. Surprisingly, the connector L of the exemplary compound was found... Z and L A The chemical structure and net charge of these compounds have a significant impact on their biodistribution in vivo. For example, compared to the reference compound, the amino acid linker -Asp-Asp- as L A and with -Gly-Gly-Gly- as L Z Compound 027 showed higher tumor uptake, as well as higher T / K and T / B, indicating superior efficacy and improved safety.

[0441] Table 9. This application 177 Biodistribution of Lu-labeled compounds 24 h after administration in the H524 xenograft model

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455] T / K: Tumor / Kidney; T / L: Tumor / Liver; T / B: Tumor / Blood.

[0456] Table 10. The application's 177 Biodistribution of Lu-labeled compounds 24 h after administration in the AR42J xenograft model

[0457]

[0458]

[0459]

[0460]

[0461]

[0462] T / K: Tumor / Kidney; T / L: Tumor / Liver; T / B: Tumor / Blood

[0463] Further evaluation of AR42J tumor-bearing mice 177 Lu-labeled compound 027 and 177 Biological distribution of Lu-labeled reference compounds at different time points. See Table 11 and... Figure 2A and Figure 2B As shown, apply 177 Following administration of Lu-labeled compound 027, high tumor uptake was observed at 1 h (56.32% ID / g), peaking at 24 h (102.65% ID / g). Durable tumor uptake was identified, decreasing to 59.65% ID / g and 40.25% ID / g at 72 h and 168 h, respectively. In the pancreas, kidneys, and blood, the highest non-tumor uptake was observed at early time points, but was rapidly cleared to low or undetectable levels by 168 h.

[0464] The area under the plasma drug concentration-time curve (AUC), which reflects the actual physical exposure to the drug, was further calculated, and 177 The tumor-to-organ AUC ratio of Lu-labeled compound 027 in the AR42J xenograft model is summarized in Table 12.

[0465] Table 11. 177 Biodistribution of Lu-labeled compound 027 in AR42J tumor-bearing mice (n=3 / time point)

[0466]

[0467] Table 12. Mean AUC (Area Under the Curve) and AUC Ratio (Tumor / Organ)

[0468]

[0469] In addition, the H524 tumor-bearing mice were evaluated 177 Lu-labeled compound 027 and 177 Biological distribution of Lu-labeled reference compounds at different time points. See Table 13 and... Figure 3A and Figure 3B As shown, high tumor uptake was observed at 1 h (29.41% ID / g), peaking at 4 h (46.98% ID / g). Durable tumor uptake was identified, decreasing to 39.18% ID / g, 12.83% ID / g, and 2.95% ID / g at 24 h, 72 h, and 168 h, respectively. In the pancreas, kidneys, and blood, the highest non-tumor uptake was observed at early time points, but was rapidly cleared to low or undetectable levels by 168 h.

[0470] The area under the plasma drug concentration-time curve (AUC), which reflects the actual physical exposure to the drug, was further calculated, and 177 The tumor-to-organ AUC ratio of Lu-labeled compound 027 in the H524 xenograft model is summarized in Table 14.

[0471] Table 13. 177 Biodistribution of Lu-labeled compound 027 in H524 tumor-bearing mice (n=3 / time point)

[0472]

[0473] Table 14. Mean AUC (Area Under the Curve) and AUC Ratio (Tumor / Organ)

[0474]

[0475] Example 4177 SPECT / CT Imaging Study of Lu-labeled Compounds

[0476] An exemplary case of intravenous injection of approximately 300 μCi into AR42J tumor-bearing mice. 177 Lu-labeled compounds, using ( Figure 4B ) or not using ( Figure 4A 1000 times the additional amount of unlabeled DOTATATE. Four hours later, mice were anesthetized with 2% isoflurane / oxygen and placed on a scanner. SPECT / CT images were acquired for 30 minutes at three beds using a MILabs SPECT scanner.

[0477] Figure 4A and Figure 4B Proved 177 The Lu-labeled compound 027 was taken up by tumors with high specificity in an SSTR2-dependent manner.

[0478] Example 5 177 In vivo efficacy studies of Lu-labeled compounds

[0479] 5.1 177 In vivo efficacy study of Lu-labeled compound 027 in an AR42J rat model of pancreatic cancer cell xenograft expressing SSTR2.

[0480] The vector was administered via a single tail vein injection to female Balb / c nude mice carrying AR42J tumors expressing SSTR2. 177 Lu-DOTATATE (18.5 MBq or 37 MBq / mouse, 18.5 MBq / nmol) or 177 Lu-labeled compound 027 (18.5 MBq or 37 MBq / mouse, 18.5 MBq / nmol) (N=4-5 / group). Efficacy was assessed by measuring tumor volume twice weekly. Tolerability was assessed by measuring body weight twice weekly.

[0481] Tumor growth inhibition (TGI) is calculated as follows:

[0482] TGI%=100%×[1-(tvt(t)-tvinitial(t)) / (tvt(v)-tvinitial(v)))],

[0483] in

[0484] tvt(t) is the mean tumor volume in the treatment group on the test day.

[0485] tvinitial(t) is the mean tumor volume in the first day of treatment.

[0486] tvt(v) is the mean tumor volume of the mediator group on the test day, and

[0487] tvt(t) is the average tumor volume of the mediator group on day 1.

[0488] On day 12, the mean tumor volume (TV) in the mediator group reached 2,041 mm. 3 Significant antitumor activity was observed in all treatment groups (p<0.0001, univariate ANOVA using Tukey's multiple comparison test). 18.5 MBq and 37 MBq... 177 The average TV of Lu-labeled compound 027 was 115 mm. 3 and 85 mm 3 The tumor growth inhibition (TGI) values ​​were 99% and 100%, respectively. Figure 5A (Accepting 18.5 MBq and 37 MBq) 177 In mice treated with Lu-labeled compound 027, tumor regression was observed in 2 / 5 and 4 / 5 of the mice, respectively.

[0489] 18.5 MBq and 37 MBq 177 The average TV of Lu-DOTATATE is 120 mm. 3 and 131 mm 3 The TGI values ​​were 98% and 98% respectively. Figure 5A Only 1 / 5 of 37 MBq 177 Lu-DOTATATE was observed to cause tumor regression.

[0490] On day 24, when no mice in the treatment group discontinued treatment due to TV, the levels of 18.5 MBq and 37 MBq were [data missing]. 177 The average TV of Lu-labeled compound 027 was 100 mm. 3 and 58 mm 3 ( Figure 5A (Accepting 18.5 MBq and 37 MBq) 177 In mice treated with the Lu-labeled compound 027, tumor regression was observed in 2 / 5 and 4 / 5 of the mice, respectively. Specifically, in mice receiving 37 MBq... 177 In mice treated with Lu-labeled compound 027, tumor shrinkage >30% was observed in 4 / 5 of the mice.

[0491] 18.5 MBq and 37 MBq 177 The average TV of Lu-DOTATATE was 1,181 mm. 3 and 1,033 mm 3 ( Figure 5A ). 177No tumor regression was observed in the Lu-DOTATATE treatment group.

[0492] and 177 Compared to Lu-DOTATATE 177 Treatment with Lu-labeled compound 027 showed significantly better efficacy at the same dose level (p<0.01, using Tukey's multiple comparison test in a one-way ANOVA).

[0493] 177 The best response (BOR) to Lu-labeled compound 027 treatment occurred on day 20, with the highest response rates observed in patients receiving 18.5 MBq and 37 MBq of the compound. 177 In mice treated with Lu-labeled compound 027, tumor shrinkage of 30% was observed in 2 / 5 and 4 / 5 of the mice, respectively. Specifically, in mice receiving 37 MBq... 177 In mice treated with Lu-labeled compound 027, complete tumor regression was observed in 1 / 5 of the mice. On the same day, mice receiving 37 MBq... 177 In mice treated with Lu-DOTATATE, tumor regression was observed in only 1 / 5 of them.

[0494] No significant weight loss was observed in any of the mice during the study period. Figure 5B ).

[0495] 5.2 In 177 After initial Lu-DOTATATE treatment 177 Lu-DOTATATE and 177 In vivo efficacy study of Lu-labeled compound 027 in an AR42J rat model of pancreatic cancer cell xenograft expressing SSTR2.

[0496] The vector was administered via a single tail vein injection to female Balb / c nude mice carrying AR42J tumors expressing SSTR2 (N=5). 177 Lu-DOTATATE (18.5 MBq / mouse, 18.5 MBq / nmol, N=15). When 177 After the average TV in the Lu-DOTATATE group increased by >3 times compared to day 1, 10 mice were selected and randomly divided into two groups (N=5) for use. 177 Lu-DOTATATE (18.5 MBq / mouse, 18.5 MBq / nmol) or 177 Treatment with Lu-labeled compound 027 (18.5 MBq / mouse, 18.5 MBq / nmol) was administered. Efficacy was assessed by measuring tumor volume twice weekly. Tolerability was assessed by measuring body weight twice weekly.

[0497] On day 17, the mean tumor volume (TV) in the mediator group reached 2,206 mm. 3 hour, 177 Lu-DOTATATE showed significant antitumor activity (p<0.0001, univariate ANOVA with Tukey multiple comparison test). 18.5 MBq 177 The average TV of Lu-DOTATATE is 146 mm. 3 The tumor growth inhibition (TGI) value was 97%. Figure 6A One 177 Mice in the Lu-DOTATATE group died on day 17, and no significant findings were found during gross necropsy.

[0498] On the 19th day, when 18.5 MBq 177 The average TV of Lu-DOTATATE increased by more than 3 times compared to the first day (391 mm). 3 vs 92 mm 3 At that time, 10 mice were selected and randomly divided into two groups, one group receiving 18.5 MBq of treatment. 177 Lu-DOTATATE or 177 Treatment of Lu-labeled compound 027.

[0499] On the 38th day, when 1 77 In the Lu-DOTATATE retreatment group, one mouse achieved a TV of 2000 mm. 3 When above, 177 Lu-DOTATATE and 177 The mean TV in the Lu-labeled compound 027 retreatment group was 1379 mm. 3 and 284 mm 3 . 177 Lu-labeled compound 027 showed significantly better re-treatment results than 177 The efficacy of Lu-DOTATATE retreatment (p<0.01, Student's t-test). Compared with day 19, on day 38, 177 Two-fifths of mice retreated with Lu-labeled compound 027 showed tumor regression, while 177 No tumor regression was observed in mice that were retreated with Lu-DOTATATE. Figure 6A ).

[0500] remove 177 Except for one mouse in the Lu-DOTATATE retreatment group that showed a >15% weight loss from day 31 to day 38, no significant weight loss was observed in any of the mice during the study period. Figure 6B and Figure 6C ).

[0501] 5.3 Evaluation in an H524 human lung cancer cell xenograft model expressing SSTR2 (moderate SSTR2 expression) 177 Lu-DOTATATE and 177 In vivo efficacy study of Lu-labeled compound 027

[0502] The vector was administered via a single tail vein injection to female Balb / c nude mice carrying H524 tumors expressing SSTR2. 177 Lu-DOTATATE (18.5 MBq or 37 MBq / mouse, 18.5 MBq / nmol) or 177 Lu-labeled compound 027 (18.5 MBq or 37 MBq / mouse, 18.5 MBq / nmol) (N=5 / group). Efficacy was assessed by measuring tumor volume twice weekly. Tolerability was assessed by measuring body weight twice weekly.

[0503] On day 24, when the mean tumor volume in the vector group reached 1,630 mm 3 Significant antitumor activity was observed in all treatment groups (p<0.0001, univariate ANOVA using Tukey's multiple comparison test). 18.5 MBq and 37 MBq 177 The average TV of Lu-labeled compound 027 was 0 mm. 3 and 1 mm 3 The tumor growth inhibition (TGI) values ​​were 106% and 106% ( Figure 7A (At 18.5 MBq and 37 MBq) 177 In mice treated with Lu-labeled compound 027, tumor regression was observed in 5 / 5 and 5 / 5 of the mice, respectively. Specifically, at 18.5 MBq and 37 MBq... 177 In mice treated with Lu-labeled compound 027, complete tumor regression was observed in 5 / 5 and 4 / 5 mice, respectively. (18.5 MBq and 37 MBq) 177 The average TV of Lu-DOTATATE is 447 mm. 3 and 205 mm 3 The TGI values ​​were 77% and 93% respectively. Figure 7A ). In 37 MBq 177 Only 1 / 5 of the tumors were observed to regress in Lu-DOTATATE, which is considered to be the extent of complete tumor regression.

[0504] 177 The best response (BOR) to treatment with the Lu-labeled compound 027 occurred on day 20, with the best response occurring at 18.5 MBq and 37 MBq. 177In mice treated with Lu-labeled compound 027, complete tumor regression was observed in 5 / 5 and 5 / 5 of the mice, respectively. On the same day, 37 MBq... 177 Only two-fifths of the Lu-DOTATATE mice showed tumor regression, with one showing complete tumor regression.

[0505] remove 177 Except for one mouse in the Lu-labeled compound 027 18.5 MBq group that showed a >10% weight loss on day 24, no significant weight loss was observed in any of the mice during the study period. Figure 7B ).

[0506] 5.4 Evaluation in an H69 human lung cancer cell xenograft model expressing SSTR2 (low SSTR2 expression) 177 Lu-DOTATATE and 177 In vivo efficacy study of Lu-labeled compound 027

[0507] The vector was administered via a single tail vein injection to female Balb / c nude mice carrying H69 tumors expressing SSTR2. 177 Lu-DOTATATE (18.5 MBq or 37 MBq / mouse, 18.5 MBq / nmol) or 177 Lu-labeled compound 027 (18.5 MBq or 37 MBq / mouse, 18.5 MBq / nmol) (N=5 / group). Efficacy was assessed by measuring tumor volume twice weekly. Tolerability was assessed by measuring body weight twice weekly.

[0508] On day 27, when the mean tumor volume in the vector group reached 1,098 mm 3 Significant antitumor activity was observed in all treatment groups (for 18.5 MBq and 37 MBq). 177 Lu-DOTATATE, p<0.05, for 18.5 MBq 177 The Lu-labeled compound 027, p < 0.001, for 37 MBq 177 The Lu-labeled compound 027 (p < 0.0001, using a one-way ANOVA with Tukey's multiple comparison test) was used. The values ​​of 18.5 MBq and 37 MBq were... 177 The average TV of Lu-labeled compound 027 was 528 mm. 3 and 248 mm 3 The tumor growth inhibition (TGI) values ​​were 56% and 84% ( Figure 8A ). In 37 MBq 177In mice treated with Lu-labeled compound 027, complete tumor regression was observed in 1 / 5 of the mice. (18.5 MBq and 37 MBq) 177 The average TV of Lu-DOTATATE is 711 mm. 3 and 686 mm 3 The TGI values ​​were 38% and 41% respectively. Figure 8A When comparing tumor volumes, 177 The Lu-labeled compound 027 showed higher levels than 37 MBq. 177 Lu-DOTATATE showed better efficacy (p<0.05, using Tukey's multiple comparison test in a one-way ANOVA).

[0509] 177 The best response (BOR) to treatment with the Lu-labeled compound 027 occurred on day 16, during which... 177 In mice treated with Lu-labeled compound 027 37 MBq, 30% tumor shrinkage was observed in 4 / 5 of the mice, with one mouse showing complete tumor regression. No tumor regression was observed in the other groups on the same day.

[0510] During the research period, 177 The Lu-labeled compound 027 treatment group and 177 No significant weight loss was observed in any of the Lu-DOTATATE 37 MBq groups. 177 Three mice in the Lu-DOTATATE 18.5 MBq group showed a transient >10% weight loss on day 16, but recovered from day 20. 177 One mouse in the Lu-DOTATATE 18.5 MBq group died on day 27, and no significant findings were found during gross necropsy. Figure 8B ).

[0511] In summary, the test object 177 The Lu-labeled compound 027 exhibited significant antitumor efficacy in different SSTR2-expressing xenograft models at dose levels of 18.5 Mbq and 37 MBq. At the same dose level, observed... 177 Lu-labeled compound 027 and 177 Lu-DOTATATE demonstrates superior efficacy. Specifically, in the AR42J model expressing SSTR2, when the tumor is initially... 177 When progression occurs after Lu-DOTATATE treatment 177 Retreatment with Lu-labeled compound 027 compared to the same dose level 177Retreatment with Lu-DOTATATE demonstrated significantly stronger antitumor activity, and tumor regression was observed. Mice treated with 18.5 MBq and 38 Mbq levels... 177 The Lu-labeled compound 027 was well tolerated, with no significant weight loss.

[0512] Example 6 225 Biodistribution study of Lu-labeled compounds

[0513] Further evaluation of AR42J tumor-bearing mice 225 Biological distribution of Ac-labeled compound 027 at different time points. See Table 15 and... Figure 9 As shown, apply 225 Following administration of the Ac-labeled compound 027, high tumor uptake was achieved within 4 h, reaching 55.87% ID / g, followed by durable tumor retention at 24 h and 72 h at 51.77% ID / g and 53.89% ID / g, respectively. For non-tumor organs, relatively high uptake was observed in the pancreas, kidney, and stomach at 4 h, but rapid clearance to lower levels was observed after 24 h.

[0514] Table 15. Biota distribution in the NET AR42J xenograft model (n=5 / time point)

[0515]

[0516] Example 7 225 In vivo efficacy studies of Ac-labeled compounds

[0517] Evaluate 225 The in vivo efficacy of Ac-labeled compound 027 in an AR42J rat xenograft model of pancreatic cancer cells expressing SSTR2. In short, the agent was administered via a single tail vein injection to female Balb / c nude mice carrying AR42J tumors expressing SSTR2. 225 Ac-labeled compound 027 (18.5 kBq or 37 kBq / mouse, 18.5 kBq / nmol) (N=5 / group). Tumor volume was measured twice weekly for efficacy assessment. Tolerability was assessed by measuring body weight twice weekly.

[0518] On day 14, when the mean tumor volume (TV) in the mediator group reached 1,359 mm 3 hour, 225 Significant antitumor activity was observed in the Ac-compound 027 treatment group (p<0.0001, using Tukey's multiple comparison test and one-way ANOVA). 18.5 MBq and 37 kBq 225 The average TV of Ac-labeled compound 027 was 15 mm.3 and 7 mm 3 The tumor growth inhibition (TGI) values ​​were 106% and 106%, respectively. Figure 10A ). At 18.5 kBq and 37 kBq 225 Tumor regression was observed in all mice in which Lu-labeled compound 027 was used.

[0519] 225 The best response (BOR) to treatment with the Ac-labeled compound 027 occurred on day 28, with the best response occurring at 18.5 kBq and 37 kBq. 225 Tumor shrinkage of 30% was observed in all mice with Ac-labeled compound 027. Additionally, tumor shrinkage was observed at 18.5 kBq and 37 kBq. 225 In mice treated with Ac-labeled compound 027, complete tumor regression was observed in 4 / 5 and 3 / 5 of the mice, respectively.

[0520] No significant weight loss was observed in any of the mice during the study period. Figure 10B This indicates the application 225 Safety of Ac-labeled compounds.

[0521] Example 8 68 PET / CT Imaging Study of Ga-labeled Compounds

[0522] SCLC-21H tumor-bearing mice were IV-injected with approximately 100 μCi of 68 Ga-labeled compound 027. Twenty minutes (0.33 hours) later, mice were anesthetized with 2% isoflurane / oxygen and placed on a scanner. PET / CT images were acquired at 0.33 h, 1 h, and 3 h post-injection.

[0523] like Figure 11 As shown, apply 68 The Ga-labeled compound 027 demonstrates its promising potential for diagnostic purposes by inducing rapid and specific tumor uptake and rapid clearance of the radioisotope from normal tissue within 3 hours.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: (I) in: T is the trivalent component. Z is the somatostatin receptor 2 (SSTR2) binding site, where Z is located via the linker L Z Combined with T, E is the effector part, where E is connected via the connector L. E Combined with T, A is the unsubstituted or substituted fatty acid moiety, wherein A is via the linker L A With T, and L Z L E and L A Each is an independent key or a binary connector.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein L A Is it a key or a binary connector: –(Y) n -, in: n is an integer from 1 to 20, and Each Y is independently selected from amino acid residues and -N(R) N (C2 alkylene Y) a ) y1 Y b The group consisting of C(O)-, where R N Is it H or C? 1- C6 alkyl, wherein Y a It is -O-, -S-, -NH- or -N(C 1- C6 alkyl)-, where y1 is an integer from 1 to 10, and where Y b It is C 1- C3 alkylene 3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein L A It contains one or more amino acid residues.

4. The compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein L A Contains one or more amino acid residues, each independently selected from the group consisting of: alanine (Ala, A), asparagine (Asn, N), aspartic acid (Asp, D), glutamine (Gln, Q), glutamic acid (Glu, E), γGlu, glutamine (Gln), glycine (Gly, G), isoleucine (Ile, I), leucine (Leu, L), εLys, methionine (Met, M), phenylalanine (Phe, F), proline (Pro, P), serine (Ser, S), threonine (Thr, T), tryptophan (Trp, W), tyrosine (Tyr, Y), valine (Val, V), pyrrolidone (Pyl, O), pyrrolidone-carboxy-lysine (PCL), γ-carboxyglutamic acid (Gla), NR 5 C5 alkylene C(O)(Ahx), cysteine ​​(Cya), leucine (Nle), valine (Nva), 2-aminooctanoic acid (Aoc), 2-naphthylalanine (2-Nal), 3-(trifluoromethyl)phenylalanine (TFP), homophenylalanine (hPhe), cyclohexylalanine (Cha), 1-naphthylalanine (1-Nal), 4-benzoyl-L-phenylalanine (Bpa), 2-methoxy-4-vinylphenylalanine (MvF), 4-fluorophenylalanine (Bpa), 4-phenyl-2, 3-Dihydroxy-6-nitrophenylalanine (pNIPA), 2-(2-naphthyl)alanine (2-Nal-ala), 4-(4-propoxyphenyl)alanine (Ppa), 4-carboxyphenylalanine (4-CPA), 4-butylphenylalanine (Bua), 2-nitrophenylalanine (2-Npa), 4-azidophenylalanine (4-AzF), 2-(4-nitrophenyl)ethylalanine (2-Npe), 3-iodo-L-tyrosine (Ity), 5,5,5-trifluoroleucine (TFL) or their D enantiomers.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein L A It comprises one or more negatively charged amino acid residues, wherein each negatively charged amino acid residue is independently and optionally selected from the group consisting of D-Asp, Asp, D-Glu, Glu, D-γGlu, γGlu and Cya.

6. The compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof, wherein L A It contains one or more D-Asp, Asp, or any combination thereof.

7. The compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, wherein L A It contains one or more neutral amino acid residues, wherein each amino acid residue is independently and optionally selected from the group consisting of Gly, D-Pro, Pro, D-Ser and Ser.

8. The compound of any one of claims 1-7 or a pharmaceutically acceptable salt thereof, wherein L A It contains one or more neutral amino acid residues, wherein each amino acid residue is independently and optionally selected from the group consisting of Gly and Ser.

9. The compound of any one of claims 1-8 or a pharmaceutically acceptable salt thereof, wherein L A Includes -N(R) N (C2-alkyleneO) y1 Y b C(O)-, where R N Let H be an integer from 1 to 10, and Y be a integer from 1 to 10. b It is C 1- C3 alkylene 10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein the -N(R) N (C2 alkylene Y) a ) y1 Y b C(O)- is -NH(C2alkyleneO)2C1alkyleneC(O)(OEG), -NH(C2alkyleneO)C2alkyleneC(O)(PEG1), -NH(C2alkyleneO)3C2alkyleneC(O)(PEG3) or -NH(C2alkyleneO)6C2alkyleneC(O)(PEG6).

11. The compound of any one of claims 2-10 or a pharmaceutically acceptable salt thereof, wherein n is an integer from 1 to 15, and each Y is independently selected from the group consisting of: Ahx, Cya, Gla, Gly, D-Ala, Ala, D-Val, Val, D-Leu, Leu, D-Phe, Phe, D-Pro, Pro, D-Met, Met, D-Trp, Trp, D-Thr, Thr, D-Tyr, Tyr, D-Nle, Nle, D-Ser, Ser, D-Asp, Asp, D-Glu, Glu, D-γGlu, γGlu, OEG, and PEG1.

12. The compound of any one of claims 2-11 or a pharmaceutically acceptable salt thereof, wherein each Y is independently selected from the group consisting of Gly, D-Asp, Asp, D-Glu, Glu, D-γGlu, γGlu and OEG.

13. The compound of any one of claims 2-12 or a pharmaceutically acceptable salt thereof, wherein n is an integer from 1 to 10.

14. The compound of any one of claims 2-13 or a pharmaceutically acceptable salt thereof, wherein n is an integer from 1 to 5.

15. The compound of any one of claims 1-14 or a pharmaceutically acceptable salt thereof, wherein L A It is a bivalent connector containing 1 to 5 Asp.

16. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein L A It includes –(Asp) 2-5 – a bivalent connector.

17. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein L A It contains –(D-Asp) 2-5 – a bivalent connector.

18. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein L A It contains 2 to 5 Asp, and said 2 to 5 Asp are in L A It is discontinuous.

19. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein L A Yes bond, -γGlu-γGlu-, -Glu-γGlu-, -Asp-, -Asp-Asp-, -γGlu-, -Gly-Ser-Gly-, -Asp-Asp-Asp-, -γGlu-γGlu-OEG-OEG-, -Asp-Asp-Gly-Gly-Gly-, -A sp-, -Glu-Glu-, -(D-Asp)-(D-Asp)-, -Gly-Gly-, -Asp-Asp-Asp-Asp-, -Cya-, -Gla-, -eLys-eLys-, -Ahx-Ahx-, -Gly-Ser-Gly-, or -Asp-Asp-OEG-.

20. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein L A Is -Asp-Asp-, -Asp-Asp-Asp-, -(D-Asp)-(D-Asp)-, or -Asp-Asp-Asp-Asp-.

21. The compound of any one of claims 1-20 or a pharmaceutically acceptable salt thereof, wherein T comprises one or more amino acid residues, each of which is independently selected from the group consisting of: Lys, D-Lys, ornithine (Orn), homolysine, 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab), cysteine, homocysteine, glutamine, glutamic acid, asparagine, aspartic acid, 3,5-bis(aminomethyl)benzoic acid (Bab), 4-aminomethylphenylalanine (Amp), 4R-4-aminoproline (Apr), 4-(2-aminoethoxy)phenylalanine, 4-aminopiperidine-4-carboxylic acid (Apc), and 2-((1,3-diaminoprop-2-yl)oxy)acetic acid (Dpa).

22. The compound of any one of claims 1-21 or a pharmaceutically acceptable salt thereof, wherein T is Lys, D-Lys, Amp, Apr or Bab.

23. The compound of any one of claims 1-21 or a pharmaceutically acceptable salt thereof, wherein T comprises Lys or D-Lys.

24. The compound of any one of claims 1-21 or a pharmaceutically acceptable salt thereof, wherein... When T contains any of the following amino acid residues selected from the group consisting of: Lys, D-Lys, Orn, high-lysine, 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab), cysteine, homocysteine, glutamine, glutamic acid, asparagine, aspartic acid, 4R-4-aminoproline (Apr), and 4-(2-aminoethoxy)phenylalanine; then α-amino conjugation of A with T.

25. The compound of any one of claims 1-21 or a pharmaceutically acceptable salt thereof, wherein... When T contains Lys or D-Lys; then A is conjugated with the α-amino group of Lys or D-Lys.

26. The compound of any one of claims 1-25 or a pharmaceutically acceptable salt thereof, wherein A is a fatty acid moiety.

27. The compound of claim 26 or a pharmaceutically acceptable salt thereof, wherein A is a saturated fatty acid moiety.

28. The compound of claim 26 or a pharmaceutically acceptable salt thereof, wherein A is a fatty monocarboxylic acid moiety.

29. The compound of claim 28 or a pharmaceutically acceptable salt thereof, wherein A is an unsubstituted or substituted C8-C compound. 18 Fatty monocarboxylic acid portion.

30. The compound of claim 28 or a pharmaceutically acceptable salt thereof, wherein A is unsubstituted or substituted C. 10 -C 16 Fatty monocarboxylic acid portion.

31. The compound of claim 28 or a pharmaceutically acceptable salt thereof, wherein A is unsubstituted or substituted C. 10 Fatty monocarboxylic acid portion.

32. The compound of claim 28 or a pharmaceutically acceptable salt thereof, wherein A is unsubstituted or substituted C. 12 Fatty monocarboxylic acid portion.

33. The compound of claim 28 or a pharmaceutically acceptable salt thereof, wherein A is unsubstituted or substituted C. 14 Or C 16 Fatty monocarboxylic acid portion.

34. The compound of any one of claims 1-28 or a pharmaceutically acceptable salt thereof, wherein A is -C(O)A a A a It is unsubstituted or substituted C3-C 23 alkyl.

35. The compound of claim 34 or a pharmaceutically acceptable salt thereof, wherein A a It is C7 alkyl, C8 alkyl, C9 alkyl, C 10 Alkyl, C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl, C 16 Alkyl or C 17 Alkyl groups, each of which may be unsubstituted or substituted.

36. The compound of any one of claims 1-35 or a pharmaceutically acceptable salt thereof, wherein L Z Is it a key or a binary connector: –(X) m -, in: m is an integer from 1 to 20, and Each X is independently selected from amino acid residues and -N(R) N (C2 alkylene X) a ) x1 Y b The group consisting of C(O), where R N Is it H or C? 1-6 Alkyl, wherein X a It is -O-, -S-, -NH- or -N(C 1-6 Alkyl)-, where x1 is an integer from 1 to 10, and where X b It is C 1-3 Alkylene.

37. The compound of any one of claims 1-36 or a pharmaceutically acceptable salt thereof, wherein L Z It is a divalent linker containing one or more amino acid residues.

38. The compound of claim 37 or a pharmaceutically acceptable salt thereof, wherein L Z Contains one or more amino acid residues, each independently selected from the group consisting of: alanine (Ala, A), asparagine (Asn, N), glutamine (Gln, Q), glycine (Gly, G), isoleucine (Ile, I), leucine (Leu, L), methionine (Met, M), phenylalanine (Phe, F), proline (Pro, P), serine (Ser, S), threonine (Thr, T), tryptophan (Trp, W), tyrosine (Tyr, Y), valine (Val, V), pyrrolidone (Pyl, O), pyrrolidone-carboxy-lysine (PCL), NR 5 C5 alkylene C(O) (Ahx), leucine (Nle), valine (Nva), 2-aminooctanoic acid (Aoc), 2-naphthylalanine (2-Nal), 3-(trifluoromethyl)phenylalanine (TFP), homophenylalanine (hPhe), cyclohexylalanine (Cha), 1-naphthylalanine (1-Nal), 4-benzoyl-L-phenylalanine (Bpa), 2-methoxy-4-vinylphenylalanine (MvF), 4-fluorophenylalanine (Bpa), 4-phenyl-2,3- -Dihydroxy-6-nitrophenylalanine (pNIPA), 2-(2-naphthyl)alanine (2-Nal-ala), 4-(4-propoxyphenyl)alanine (Ppa), 4-carboxyphenylalanine (4-CPA), 4-butylphenylalanine (Bua), 2-nitrophenylalanine (2-Npa), 4-azidophenylalanine (4-AzF), 2-(4-nitrophenyl)ethylalanine (2-Npe), 3-iodo-L-tyrosine (Ity), and 5,5,5-trifluoroleucine (TFL).

39. The compound of claim 37 or 38 or a pharmaceutically acceptable salt thereof, wherein L Z It contains one or more neutral amino acid residues.

40. The compound of claim 39 or a pharmaceutically acceptable salt thereof, wherein each of the neutral amino acid residues is independently Gly, D-Pro, Pro, D-Ser, or Ser.

41. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt thereof, wherein L Z It contains one or more Gly.

42. The compound of any one of claims 1-36 or a pharmaceutically acceptable salt thereof, wherein L Z Includes -N(R) N (C2 alkylene X) a ) x1 X b C(O), where R N Let H be an integer from 1 to 10, and let X be a variable. b It is C 1- C3 alkylene 43. The compound of claim 42 or a pharmaceutically acceptable salt thereof, wherein R N It's H.

44. The compound of claim 42 or 43 or a pharmaceutically acceptable salt thereof, wherein L Z It comprises one or more portions, each of which is independently selected from -NH(C2alkyleneO)2C1alkyleneC(O) (OEG), -NH(C2alkyleneO)C2alkyleneC(O) (PEG1), -NH(C2alkyleneO)3C2alkyleneC(O) (PEG3) or -NH(C2alkyleneO)6C2alkyleneC(O) (PEG6).

45. The compound of claim 36 or a pharmaceutically acceptable salt thereof, wherein each X is independently selected from the group consisting of: Ahx, Gly, D-Ala, Ala, D-Val, Val, D-Leu, Leu, D-Phe, Phe, D-Pro, Pro, D-Met, Met, D-Trp, Trp, D-Thr, Thr, D-Tyr, Tyr, D-Nle, Nle, D-Ser, Ser, OEG and PEG1.

46. ​​The compound of claim 36 or claim 45 or a pharmaceutically acceptable salt thereof, wherein each X is independently selected from the group consisting of Gly, Pro, Ser and OEG.

47. The compound of any one of claims 36, 45 or 46, or a pharmaceutically acceptable salt thereof, wherein m is an integer from 1 to 15.

48. The compound of any one of claims 36, 45 or 46, or a pharmaceutically acceptable salt thereof, wherein m is an integer from 1 to 10.

49. The compound of any one of claims 36, 45 or 46, or a pharmaceutically acceptable salt thereof, wherein m is an integer from 1 to 6.

50. The compound of any one of claims 1-49 or a pharmaceutically acceptable salt thereof, wherein L Z It is a bivalent connector containing 1 to 6 OEGs.

51. The compound of any one of claims 1-49 or a pharmaceutically acceptable salt thereof, wherein L Z It is a bivalent connector containing 1 to 6 Gly.

52. The compound of claim 51 or a pharmaceutically acceptable salt thereof, wherein L Z Yes – (Gly) 2-5 – 53. The compound of claim 51 or a pharmaceutically acceptable salt thereof, wherein L Z It contains 2 to 5 Gly, and the 2 to 5 Gly are not consecutive.

54. The compound of any one of claims 1-53 or a pharmaceutically acceptable salt thereof, wherein L Z Yes key, -OEG-OEG-, -OEG-, -Gly-Gly-Gly-, -Gly-Ser-Gly-Ser-Gly-Ser-, - Pro-Gly-Pro-Gly-Pro-Gly-, -γGlu-γGlu -OEG-OEG-, - Asp-Asp-Gly-Gly-Gly-, -Gly-Gly-Gly-Gly-Gly-Gly-, -Gly-Tyr-Gly-, -Gly-Ser-Gly-, -Gly- or -Gly-Gly-.

55. The compound of any one of claims 1-53 or a pharmaceutically acceptable salt thereof, wherein L Z It is -Gly-Gly-Gly-.

56. The compound of any one of claims 1-55 or a pharmaceutically acceptable salt thereof, wherein E comprises a chemotherapeutic agent, a toxin, an immunomodulator, a diagnostic agent, a radionuclide, or a chelating group.

57. The compound of claim 56, wherein E comprises a radionuclide selected from: 14 C 15 N、 18 F, 75 Br、 76 Br、 77 Br、 123 I, 124 I, 125 I, 131 I, 35 S, 18 F, 211 At、 32 P, 33 P and 125 I.

58. The compound of any one of claims 1-56 or a pharmaceutically acceptable salt thereof, wherein E comprises a chelating group derived from a chelating agent.

59. The compound of claim 58 or a pharmaceutically acceptable salt thereof, wherein the chelating agent is selected from the group consisting of: 1,4,7-triazacyclononane (TACN), 1,4,7-triazacyclononane-triacetic acid (NOTA), 1,4,7-triazacyclononane-N-succinic acid-N',N''-diacetic acid (NOTASA), 1,4,7-triazacyclononane-N-glutamic acid-N',N''-diacetic acid (NODAGA), 1,4,7-triazacyclononane-N,N',N''-tris(methylenephosphonic acid) acid (NOTP), 1,4,7,10-tetraazacyclododecane ([1 2]aneN4)(cyclen), 1,4,7,10-tetraazacyclotridecane ([13]aneN4), 1,4,7,11-tetraazacyclotetradecane (iso-cyclam), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 2-(1,4,7,10-tetraazacyclododecane-1-yl)acetate (DO1A), 2,2'-(1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid (DO2A), 2,2',2''-(1,4,7,10-tetraazacyclododecane-1 ,4,7-triyl)triacetic acid (DO3A), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylphosphonic acid) (DOTP), 1,4,7,10-tetraazacyclododecane-1,7-bis(methylphosphonic acid) (DO2P), 1 ,4,7,10-Tetraazacyclododecane-1,4,7-tris(methylphosphonic acid) (DO3P), 1,4,7,10-tetraazacyclododecane-1-glutamic acid-4,7,10-triacetic acid (DOTAGA), 1,4,7,10-tetraazacyclododecane-1-succinic acid-4,7,10-triacetic acid (DOTASA), 1,4,8,11-tetraazacyclotetradecane ([14]aneN4) (cyclam), 1,4,8,12-tetraazacyclopentadecane ([15]aneN4), 1,5,9,13-tetraazacyclohexadecane ([16]aneN4), 1,4- Ethylene-1,4,8,11-tetraazacyclotetradecane (et-cyclam), 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA), 2-(1,4,8,11-tetraazacyclotetradecane-1-yl)acetic acid (TE1A), 2,2'-(1,4,8,11-tetraazacyclotetradecane-1,8-diyl)diacetic acid (TE2A), 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CB-TE2A), 3,6,10,13,16,19-hexaazabicyclo[6.6.2].6] Eicosane (Sar), 1,4,7,10-tetra-(2-carbamoyl-methyl)-cyclododecane (TCMC), N,N'-bis[(6-carboxy-2-pyridine)methyl]-4,13-diaza-18-crown ether-6 (macropa), phthalocyanine, porphyrin, PCTA (3,6,9,15-tetraazabicyclo[9.3.1]pentadecano-1(15),11,13-trien-3,6,9-triacetic acid), DEPA (7-[2-(biscarboxymethylamino)ethyl]-4,10-biscarboxymethyl-1,4,7,10-tetraazacyclododecane-1-yl-acetic acid), DTPA (1,1,4,7,7-diethylenetriaminepentaacetic acid), CHX-DTPA (cyclohexane-1,2 1,2-diamine N,N,N',N'-tetraacetic acid, BATPA (1,2-bis[2-aminophenoxy]ethane-N,N,N',N'-tetraacetic acid), TTHA (triethylenetetramine N,N,N',N'',N''',N'''-hexaacetic acid), HBED (N,N'-bis[2-hydroxybenzyl]ethylenediamine-N,N'-diaacetic acid), EGTA (ethylene glycol bis[2-aminoethyl ether]-N,N,N',N'-tetraacetic acid), EDTMP (ethylenediamine tetra- [Methylenephosphonic acid]), TRAP (triazacyclononanoic acid), SHBED (N,N'-bis[2-hydroxy-5-sulfobenyl]ethylenediaminediacetic acid), H6Sbbpen (N,N'-bis-[2-hydroxy-5-sulfobenyl]-N,N'-bis[2-methylpyridine]ethylenediamine), THP (tris(3,4-hydroxypyridinone)), DFO (deferroamine), FSC (fusarium oxychloride), 6SS (N,N'-bis[2,2-dimethyl-2- ... [-mercaptoethyl]ethylenediamine-N,N'-diacetic acid), ECC (ethylene cysteine), ECD (cysteine ​​ethyl ester dimer), NETA ([2-{4,7-biscarboxymethyl(1,4,7)triazacyclononane-1-yl-ethyl}carbonylmethylamino]acetic acid), THPN (tetra(3-hydroxy-4-pyridinone)), H2dedpa (1,2-[{6-(carboxylic acid-)pyridin-2-yl}methylamino]ethane), H4octapa (N,N'-bis[6-carboxy-2-pyridinylmethyl]ethylenediamine-N,N'-diacetic acid), H2bispa2 (6,6'-[{9-hydroxy-1,5-bis-(methoxycarbonyl)-2,4-bis(pyridin-2-yl)-3,7-diazabicyclo[3.3]).[1] Nonane-3,7-diyl}bis(methylene)]pyridine dicarboxylic acid), DOTMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl-tetra(methylphosphonic acid)), PEPA (1,4,7,10,13-pentazocyclopentadecanoacetic acid), HEHA (1,4,7,10,13,16-hexazocyclooctadecanehexaacetic acid), H2hox, H2CHXhox, H2octox, H2pyhox, H4neunopa, TETPA, H4pypa, H4py4pa, DTPAM, EGTAM, ampam, Me-3,2-HOPO, 3,4,3-(LI-1,2-HOPO) and macrocyclic tetraphthalimide.

60. The compound of claim 59 or a pharmaceutically acceptable salt thereof, wherein the chelating group is derived from DOTA or DOTAGA.

61. The compound of any one of claims 58-60, wherein the chelating group is further complexed with one or more radionuclides, wherein each radionuclide is independently a radioisotope of As, Se, K, Sc, Ti, Cr, Mn, Fe, Co, Ni, Cu, Ga, Ge, Rb, Sr, Y, Zr, Nb, Tc, Rh, Pd, In, Sn, Sb, Zn, Ta, W, Re, Os, Ir, Pt, Au, Hg, Tl, Pb, Bi, Po, Fr, Pm, lanthanides, actinides, Mg, Al, Ca, Cd, or Ba.

62. The compound of claim 61 or a pharmaceutically acceptable salt thereof, wherein the lanthanide element is Lu, Sm, Ho or Tb.

63. The compound of claim 61 or a pharmaceutically acceptable salt thereof, wherein the actinide element is Ac, Th or U.

64. The compound of claim 61 or 62 or a pharmaceutically acceptable salt thereof, wherein the one or more radionuclides are each independently selected from the group consisting of: 99 Tc, 99m Tc, 188 Re、 186 Re、 153 Sm、 66 Ga、 67 Ga、 68 Ga、 111 In、 123 In、 59 Fe、 63 Zn, 52 Fe、 52 Mn, 45 Ti、 60 Cu、 61 Cu、 67 Cu、 64 Cu、 62 Cu、 82 Rb、 195m Pt, 191m Pt, 193m Pt, 117m Sn、 89 Zr、 177 Lu、 18 F, 188 Re、 186 Re、 153 Sm、 66 Ho、 86 Y、 87 Y、 90 Y、 89 Sr、 153 Gd, 159 Gd, 225 Ac、 212 Bi、 213 Bi、 198 Au、 199 Au、 193m Pt, 197 Pt, 103 Pd, 109 Pd, 105 Rh、 101m Rh、 103m Rh、 223 Ra、 224 Ra、 97 Ru、 227 Th、 229 Th、 161 Tb, 149 Tb, 203 Pb, 212 Pb, 201 TI, 119 Sb, 58m Co, 55 Co, 57 Co, 47 Sc, 149 Pm, 142 Pr, 161 Ho, 166 Ho, 175 Yb and 51 Cr.

65. The compound of any one of claims 1-56 or 57-64, or a pharmaceutically acceptable salt thereof, wherein E is 77 Lu-DOTA-、 177 Lu-DOTAGA-、 225 Ac-DOTA- or 225 Ac-DOTAGA-.

66. The compound of any one of claims 1-65 or a pharmaceutically acceptable salt thereof, wherein Z is: (II), in: u is 0 or 1; R 0 It was by a C6-C 10 Aryl-substituted C1-C6 alkyl groups, and the C6-C 10 The aryl group may optionally be substituted by one or more substituents, each substituent being independently a halogen or NO2; R 1 It was by a C6-C 10 aryl-substituted C1-C6 alkyl groups, wherein the C6-C 10 The aryl group may be optionally substituted by one or more substituents, each substituent being independently -OH, -O (C1-C6 alkyl), or -N (R). a )C(O)R 1a And R 1a It is a 3- to 8-membered heterocycle optionally substituted with one or more oxygens; R 2 It was by a C6-C 10 aryl or 5 to 12 heteroaryl substituted C1-C6 alkyl groups, wherein the C6-C 10 The aryl or 5- to 12-membered heteroaryl group is optionally substituted by one or more substituents, each substituent being independently -OH, -O (C1-C6 alkyl) or -N (R a )C(O)NH(R a ); x is 0 or 1; R x It is -N(R) a )C(O)-(C6-C 10 (Aromatic); R 3 It is caused by one or more -NH((R) a ) substituted C1-C6 alkyl groups; R 4 It is a C1-C6 alkyl group substituted with one or more -OH groups; y is 0 or 1; R y It was by a C6-C 10 Aryl-substituted C1-C6 alkyl groups; R z Is -OH or , where R z1 It is a C1-C6 alkyl group substituted with one or more substituents, each substituent being independently selected from -OH and optionally substituted with one or more -OH groups. 10 Group composed of aryl groups; R z2 It is -COOH, -C(O)NH2, or a C1-C6 alkyl group substituted with one or more -OH groups; and R a Each time it appears, it is independently H or C1-C3 alkyl.

67. The compound of claim 66 or a pharmaceutically acceptable salt thereof, wherein u is 1 and R 0 It is a C1-C6 alkyl group substituted with a phenyl group, wherein the phenyl group is either unsubstituted or substituted with one or more halogens.

68. The compound of claim 66 or 67 or a pharmaceutically acceptable salt thereof, wherein R 1 It was by a C6-C 10 aryl-substituted methyl group, wherein the C6-C 10 The aryl group may be optionally substituted by one or more substituents, each substituent being independently -OH or -NHC(O)R. 1a , where R 1a It is a 3- to 8-membered heterocycle that is optionally substituted with one or more oxygens.

69. The compound of any one of claims 66-68 or a pharmaceutically acceptable salt thereof, wherein R 2 It was by a C6-C 10 aryl or 5 to 12 heteroaryl substituted C1-C6 alkyl groups, wherein the C6-C 10 The aryl group may optionally be substituted by one or more substituents, each substituent being independently -OH or -NHC(O)NH2.

70. The compound of any one of claims 66-69 or a pharmaceutically acceptable salt thereof, wherein R 3 It is a C1-C6 alkyl group substituted with one or more NH2.

71. The compound of any one of claims 66-70 or a pharmaceutically acceptable salt thereof, wherein R 4 It is a C1-C3 alkyl group substituted with one or more -OH groups.

72. The compound of any one of claims 1-65 or a pharmaceutically acceptable salt thereof, wherein Z is: (TOC)、 (NIGHT) (TATE)、 (Octreotide) (JR11) or (BASS)。 73. The compound of any one of claims 1-66 or a pharmaceutically acceptable salt thereof, wherein Z is: (II-A), Where R 3a It is CH2OH, CO2H, or CONH2.

74. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound comprises a structure selected from any one of Table 1.

75. The compound of any one of claims 1-74 or a pharmaceutically acceptable salt thereof, used for imaging or diagnosis, or for treatment.

76. A pharmaceutical composition comprising the compound of any one of claims 1-74 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

77. A kit comprising any one of claims 1-74, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 76, and instructions for using the kit to diagnose a disease or condition in a subject with such need.

78. A kit comprising a compound of any one of claims 1-74 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 76, and instructions for using the kit to treat a disease or condition of a subject in need of such treatment.

79. A method for treating a disease or condition in a subject who requires such treatment, the method comprising administering to the subject a pharmaceutically effective amount of one or more of the compounds of any one of claims 1-74 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 76.

80. The method of claim 79, wherein the disease or condition is cancer.

81. The method of claim 79, wherein the cancer is a cancer with high expression of SSTR2.

82. The method of claim 79, wherein the cancer is medullary thyroid carcinoma (MTC), small cell lung cancer (SCLC), or a neuroendocrine tumor.

83. A method for inhibiting cell proliferation activity, said method comprising administering an effective amount of one or more of the compounds or salts thereof as described in any one of claims 1-74.

84. A method for imaging the tissues of a subject, the method being performed by administering to the subject in need of imaging an effective amount of one or more of the compounds of any one of claims 1-74 or a pharmaceutically acceptable salt thereof, and applying imaging techniques to detect emitted gamma rays.

85. A method for diagnosing cancer in a subject, the method being performed by administering a diagnostically effective amount of one or more compounds of any one of claims 1-74 or a pharmaceutically acceptable salt thereof, and applying imaging techniques to detect the emitted gamma rays.

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