Radiolabelled compounds targeting prostate specific membrane antigens

Abstract

The present invention provides a compound comprising a prostate specific membrane antigen (PSMA) targeting moiety of the formula or a salt or solvate thereof. And R0 is O or S. For example, each of R1a, R1b, and R1c may be-CO2H,-SO2H,-SO3H,-PO2H, or-PO3H2, for example. R2 may be methylene or a derivative thereof, propylene or a derivative thereof, or a derivative of ethylene, optionally substituted. And R3 is a linker. When the PSMA targeting moiety is linked to a radiolabelling group, the compounds may be used as imaging or therapeutic agents for PSMA expressing diseases / conditions. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to radiolabeled compounds useful for in vivo imaging or treatment of diseases or conditions characterized by expression of prostate specific membrane antigen, particularly compounds having low uptake in the salivary glands and / or kidneys. Background Art

[0002] Prostate-specific membrane antigen (PSMA) is a transmembrane protein that catalyzes the hydrolysis of N-acetyl-aspartylglutamate to glutamate and N-acetylaspartate. PSMA is selectively overexpressed in certain diseases and conditions compared to most normal tissues. For example, PSMA is overexpressed up to 1,000-fold in prostate tumors and metastases. Due to its pathological expression pattern, various radiolabeled PSMA-targeting constructs have been designed and evaluated for imaging of PSMA-expressing tissues and / or for treatment of diseases or conditions characterized by PSMA expression.

[0003] Many radiolabeled PSMA-targeting derivatives of Lys-ureido-Glu have been developed, including 18 F-DCFBC, 18 F-DCFPyL, 68 Ga-PSMA-HBED-CC, 68 Ga-PSMA-617, 68 Ga-PSMA I and T (see Figure 1) and the aforementioned α-emitters (such as 225 Ac) or beta emitters (e.g. 177 Lu or 90 Y) version.

[0004] In clinical trials, therapeutic radionuclides (such as 177 Lu and 225Ac) radiolabeled PSMA-617 has shown promise as an effective systemic treatment for metastatic castration-resistant prostate cancer (mCRPC). However, due to the high salivary gland and kidney accumulation of radiotracers, dry mouth (dry mouth), taste changes, and renal adverse events are common side effects of this treatment (Hofman et al., 2018 The Lancet 16 (6): 825-833; Rathke et al. 2019 Eur J Nucl Med Mol Imaging 46 (1): 139-147; Sathekge et al. 2019 Eur J Nucl Med Mol Imaging 46 (1): 129-138). The accumulation of radiotracers in the kidneys and salivary glands is therefore a limiting factor, which reduces the maximum cumulative administration activity that can be safely given to patients, which limits the potential therapeutic effect of Lys-urea-Glu-based radiopharmaceuticals (Violet et al. 2019 J Nucl Med. 60 (4): 517-523). Therefore, there is a need for new radiolabeled PSMA-targeting compounds, particularly those with low accumulation in the salivary glands and / or kidneys.

[0005] It is not necessarily intended, nor should it be construed, that any prior information constitutes prior art against the present invention. Summary of the invention

[0006] Various embodiments disclosed herein relate to a compound, wherein the compound has Formula I or a salt or solvate of Formula I:

[0007]

[0008] in:

[0009] n is 0 or 1;

[0010] R 1a , R 1b and R 1c Each is independently -CO2H, -SO2H, -SO3H, -SO4H, -PO2H, -PO3H or -PO4H;

[0011] When n is 0, R 2 is -CH2-, -CHOH-, -CHF-, -CH2CHOH-, -CH2CHF-, -CH2CHOHCH2-, -CH2CHFCH2-, -(CH2)2CHOH-, -(CH2)2CHF-, -(CH2)3-, -CH2OCH2- or -CH2SCH2-;

[0012] When n is 1, R 2is -CH2-, -CHOH-, -CHF-, -CH2CHOH-, -CH2CHF- or -(CH2)2-;

[0013] R 3 It is a C1-C2- 20 Alkylene or alkenylene, or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 20 heteroalkylene or heteroalkenylene;

[0014] R 4 :-O-、-S-、-NHC(O)-、-C(O)NH-、

[0015] R 5 It is a C1-C2- 30 Alkylene, alkenylene or alkynylene, or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 30 heteroalkylene, heteroalkenylene, or heteroalkynylene;

[0016] R 6 is hydrogen or methyl;

[0017] XA 1 It is a compound having the formula -N(R 8 )R 9 C(O)-amino acids, where each R 8 are independently hydrogen or methyl, and wherein each R 9 are independently: linear or branched, cyclic or acyclic and / or aromatic or non-aromatic C1-C 20 Alkylene, alkenylene or alkynylene; or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 20 heteroalkylene, heteroalkenylene, or heteroalkynylene;

[0018] At least one R 9 or R 5 yes

[0019] At least one R 9 or R 5 Yes - (CH2) 0-3 CH(R 10 )(CH2) 0-3 -, where R 10 It is a C2-C3 straight chain or branched, cyclic or acyclic and / or aromatic or non-aromatic 19 Alkyl, alkenyl or alkynyl, or R 10is a linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X having only 1 to 3 heteroatoms 19 heteroalkyl, heteroalkenyl or heteroalkynyl;

[0020] R 7 YesR X -(Xaa 2 ) 0-4 -、

[0021] R 11 does not exist,

[0022] R 12 is I, Br, F, Cl, H, OH, OCH3, NH2, NO2 or CH3;

[0023] XA 2 , when present, is -N(R 13 )R 14 C(O)-, where each R 13 are independently hydrogen or methyl, and wherein each R 14 are independently: linear or branched, cyclic or acyclic and / or aromatic or non-aromatic C1-C 20 Alkylene, alkenylene or alkynylene; or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 20 heteroalkylene, heteroalkenylene, or heteroalkynylene; and

[0024] Each R X is a radiolabeling group independently selected from: a radiometal chelator optionally bound by a radiometal; an aryl group substituted with a radioisotope; a prosthetic group containing a trifluoroborate; and a prosthetic group containing a silicon-fluorine-acceptor moiety.

[0025] Various embodiments disclosed herein relate to a compound, wherein the compound has Formula II or a salt or solvate of Formula II:

[0026]

[0027] in:

[0028] R 0 is O or S;

[0029] R 1a is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, OPO3H2, OSO3H, -B(OH)2 or

[0030] R 1b is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -B(OH)2 or R 1c is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -B(OH)2 or

[0031] R 2 is -CH2-, -CH(OH)-, -CHF-, -CF2-, -CH(CH3)-, -C(CH3)2-, -CH2CH(OH)-, -CH2CHF-, -CHFCH2-, -CF2CH2-, -CH2C F2-, -CH(OH)CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-, -CH2CH(OH)CH2-, -CH2CHFCH2 -, -(CH2)2CH(OH)-, -(CH2)2CHF-, -(CH2)3-, -CH2OCH2-, -CH2SCH2-, -CHFCH2CH2-, -CH(OH)CH2CH2-, -CH(CH3) CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-, -CH(C H3)-O-CH2-, -C(CH3)2-O-CH2-, -CH2-O-CH(CH3)-, -CH2-OC(CH3)2-, -CH2-S(O)-CH2-, -CH2-S(O)2-CH2-, -CH( CH3)-S-CH2-, -C(CH3)2-S-CH2-, -CH2-S-CH(CH3)-, -CH2-SC(CH3)2-, -CH(CH3)-S(O)-CH2-, -C(CH3)2-S(O)-C H2-, -CH2-S(O)-CH(CH3)-, -CH2-S(O)-C(CH3)2-, -CH(CH3)-S(O)2-CH2-, -C(CH3)2-S(O)2-CH2-, -CH2-S(O)2- CH(CH3)-, -CH2-S(O)2-C(CH3)2-, -CH2-NH-C(O)-, -C(O)-NH-CH2-, -C(O)-NH-CH(CH3)- or -C(O)-NH-C(CH3)2-;

[0032] R 3 It is a C1-C2-20 alkylene, alkenylene or alkynylene, or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 20 heteroalkylene, heteroalkenylene, or heteroalkynylene;

[0033] R 4 is -O-, -S-, -Se-, -S(O)-, -S(O)2-, -NHC(O)-, -C(O)NH-, -C(O)-(NH)2-C(O)-, -OC(O)NH, -NHC(O)O-, -NHC(O)NH-, -OC(S)NH, -NHC(S)O-, -NHC(S)NH-, -NHC(O)C(O)NH-, -SS-, -S-CH2-S-, -NH-NH-C(O)-, -C(O)-NH-NH;

[0034] R 5 It is a C1-C2- 30 Alkylene, alkenylene or alkynylene, or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 30 heteroalkylene, heteroalkenylene, or heteroalkynylene;

[0035] R 6 is hydrogen or methyl or ethyl;

[0036] XA 1 It is a compound having the formula -N(R 8 )R 9 C(O)-amino acids, where each R 8 are independently hydrogen or methyl, and wherein each R 9 are independently: linear or branched, cyclic or acyclic and / or aromatic or non-aromatic C1-C 20 Alkylene, alkenylene or alkynylene; or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 20 heteroalkylene, heteroalkenylene, or heteroalkynylene;

[0037] At least one R 9 or R 5 Yes - (CH2) 0-3 CH(R 10 )(CH2) 0-3 -, where R 10 yes:

[0038] Straight or branched, cyclic or acyclic and / or aromatic or non-aromatic C2-C 19alkyl, alkenyl or alkynyl; linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X3 having only 1 to 3 heteroatoms 19 heteroalkyl, heteroalkenyl or heteroalkynyl;

[0039] -CH2R 23 , where R 23 is an optionally substituted C4-C 16 an aromatic ring or a partially or fully aromatic fused ring system, wherein 0-3 carbons in the aromatic ring or the partially or fully aromatic fused ring system are replaced by N, S and / or O heteroatoms, and wherein the optional substituents are selected from OH, NH2, NO2, halogen, C1-C6 alkyl and / or C1-C6 alkoxy; or

[0040] Selected from:

[0041]

[0042] Optionally modified with one, more than one, or a combination of: halogen, OMe, SMe, NH2, NO2, CN, OH, or another endocyclic nitrogen atom;

[0043] R 7 YesR X -(Xaa 2 ) 0-4 -、

[0044] R 28 It is an albumin binder;

[0045] XA 2 and Xaa 3 , when present, is independently -N(R 13 )R 14 C(O)-, where each R 13 are independently hydrogen or methyl, and wherein each R 14 are independently: linear or branched, cyclic or acyclic and / or aromatic or non-aromatic C1-C 20 Alkylene, alkenylene or alkynylene; or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 20 heteroalkylene, heteroalkenylene, or heteroalkynylene; and

[0046] Each R X is a radiolabeling group independently selected from the following: a radiometal chelator optionally bound by a radiometal; an aryl or heteroaryl group substituted with a radiohalogen; a prosthetic group containing a trifluoroborate; a prosthetic group containing a silicon-fluorine-acceptor moiety; or a prosthetic group containing a fluorophosphate, a fluorosulfate, a sulfonyl fluoride or a combination thereof.

[0047] In some embodiments of the compound, salt or solvate of Formula II:

[0048] R 0 It is O;

[0049] R 1a , R 1b and R 1c Each is independently -CO2H, -SO2H, -SO3H, -SO4H, -PO2H, -PO3H or -PO4H;

[0050] R 2 is -CH2-, -CH(OH)-, -CHF-, -CF2-, -CH(CH3)-, -C(CH3)2-, -CH2CH(OH)-, -CH2CHF-, -CHFCH2-, -CF2CH2-, -CH2C F2-, -CH(OH)CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-, -CH2CH(OH)CH2-, -CH2CHFCH2 -, -(CH2)2CH(OH)-, -(CH2)2CHF-, -(CH2)3-, -CH2OCH2-, -CH2SCH2-, -CHFCH2CH2-, -CH(OH)CH2CH2-, -CH(CH3) CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-, -CH(C H3)-O-CH2-, -C(CH3)2-O-CH2-, -CH2-O-CH(CH3)-, -CH2-OC(CH3)2-, -CH2-S(O)-CH2-, -CH2-S(O)2-CH2-, -CH( CH3)-S-CH2-, -C(CH3)2-S-CH2-, -CH2-S-CH(CH3)-, -CH2-SC(CH3)2-, -CH(CH3)-S(O)-CH2-, -C(CH3)2-S(O)-C H2-, -CH2-S(O)-CH(CH3)-, -CH2-S(O)-C(CH3)2-, -CH(CH3)-S(O)2-CH2-, -C(CH3)2-S(O)2-CH2-, -CH2-S(O)2- CH(CH3)-, -CH2-S(O)2-C(CH3)2-, -CH2-NH-C(O)-, -C(O)-NH-CH2-, -C(O)-NH-CH(CH3)- or -C(O)-NH-C(CH3)2-;

[0051] R 3 It is a C1-C2- 20 Alkylene or alkenylene, or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 20 heteroalkylene or heteroalkenylene;

[0052] R 4 Is -O-, -S-, -S(O)-, -S(O)2-, -NHC(O)-, -C(O)NH-,

[0053] R 5 It is a C1-C2- 30 Alkylene, alkenylene or alkynylene, or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 30 heteroalkylene, heteroalkenylene, or heteroalkynylene;

[0054] R 6 is hydrogen or methyl;

[0055] XA 1 It is a compound having the formula -N(R 8 )R 9 C(O)-amino acids, where each R 8 are independently hydrogen or methyl, and wherein each R 9 are independently: linear or branched, cyclic or acyclic and / or aromatic or non-aromatic C1-C 20 Alkylene, alkenylene or alkynylene; or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 20 heteroalkylene, heteroalkenylene, or heteroalkynylene;

[0056] At least one R 9 or R 5 Yes - (CH2) 0-3 CH(R 10 )(CH2) 0-3 -, where R 10 is: linear or branched, cyclic or acyclic and / or aromatic or non-aromatic C2-C 19 alkyl, alkenyl or alkynyl; linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X3 having only 1 to 3 heteroatoms 19 heteroalkyl, heteroalkenyl or heteroalkynyl; or -CH2R 23 , where R 23 is an optionally substituted C4-C 16an aromatic ring or a partially or fully aromatic fused ring system, wherein 0-3 carbons in the aromatic ring or the partially or fully aromatic fused ring system are replaced by N, S and / or O heteroatoms, and wherein the optional substituents are selected from OH, NH2, NO2, halogen, C1-C6 alkyl and / or C1-C6 alkoxy;

[0057] R 7 YesR X -(Xaa 2 ) 0-4 -、

[0058] R 11 does not exist,

[0059]

[0060] R 12 is I, Br, F, Cl, H, OH, OCH3, NH2, NO2 or CH3;

[0061] XA 2 , when present, is -N(R 13 )R 14 C(O)-, where each R 13 are independently hydrogen or methyl, and wherein each R 14 are independently: linear or branched, cyclic or acyclic and / or aromatic or non-aromatic C1-C 20 Alkylene, alkenylene or alkynylene; or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 20 heteroalkylene, heteroalkenylene, or heteroalkynylene; and

[0062] Each R X is a radiolabeling group independently selected from: a radiometal chelator optionally bound by a radiometal; an aryl group substituted with a radioisotope; a prosthetic group containing a trifluoroborate; and a prosthetic group containing a silicon-fluorine-acceptor moiety.

[0063] Various embodiments disclosed herein relate to a compound comprising a prostate specific membrane antigen (PSMA) targeting moiety of Formula III or a salt or solvate of Formula III:

[0064]

[0065] in:

[0066] R 0 is O or S;

[0067] R 1ais -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, OPO3H2, OSO3H, -B(OH)2 or

[0068] R 1b is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -B(OH)2 or R 1c is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -B(OH)2 or

[0069] R 2 is -CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-, -CH(CH3)-O-CH2-, -C (CH3)2-O-CH2-, -CH2-O-CH(CH3)-, -CH2-OC(CH3)2-, -CH2-S(O)-CH2-, -CH2-S(O)2-CH2-, -CH(CH3)-S-CH2-, -C(CH3)2-S-CH2-, -CH2-S-C H(CH3)-, -CH2-SC(CH3)2-, -CH(CH3)-S(O)-CH2-, -C(CH3)2-S(O)-CH2-, -CH2-S(O)-CH(CH3)-, -CH2-S(O)-C(CH3)2-, -CH(CH3)-S(O)2-C and

[0070] R 3 It's a connector.

[0071] In some embodiments of the compound, salt or solvate of Formula III:

[0072] R 0 It is O;

[0073] R 1a , R 1b and R 1c Each is independently -CO2H, -SO2H, -SO3H, -SO4H, -PO2H, -PO3H or -PO4H;

[0074] R 2 is -CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-, -CH(CH3)-O-CH2-, -C(CH3)2-O- CH2-, -CH2-O-CH(CH3)-, -CH2-OC(CH3)2-, -CH2-S(O)-CH2-, -CH2-S(O)2-CH2-, -CH(CH3)-S-CH2-, -C(CH3)2-S-CH2-, -CH2-S-CH(CH3)-, -CH2-SC(C H3)2-, -CH(CH3)-S(O)-CH2-, -C(CH3)2-S(O)-CH2-, -CH2-S(O)-CH(CH3)-, -CH2-S(O)-C(CH3)2-, -CH(CH3)-S(O)2-CH2-, -C(CH3)2-S(O)2-CH2-, -C and

[0075] R 3 It's a connector.

[0076] Various embodiments disclosed herein relate to a compound, wherein the compound has Formula IV or a salt or solvate of Formula IV:

[0077]

[0078] in:

[0079] R 0 is S or O;

[0080] R 1a is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -OPO3H2, -OSO3H, -B(OH)2 or

[0081] R 1b is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -B(OH)2 or

[0082] R 1cis -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -B(OH)2 or

[0083] R 2 is -CH2-, -CH(OH)-, -CHF-, -CF2-, -CH(CH3)-, -C(CH3)2-, -CH2CH(OH)-, -CH2CHF-, -CHFCH2-, -CF2CH2-, -CH2CF2-, -CH(OH)CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-, -CH2CH(OH)CH2-, -CH2CHFCH2-, -(CH2)2CH(OH)-, -(CH2)2CHF-, -(CH2)3-, -CH2OCH2-, -CH2SCH2-, -CHFCH2CH2-, -CH(OH)CH2CH2-, -CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-, -CH(CH3)-O-CH2-, -C(CH3)2-O-CH2-, -CH2-O-CH(CH3)-, -CH2-O-C(CH3)2-, -CH2-S(O)-CH2-, -CH2-S(O)2-CH2-, -CH(CH3)-S-CH2-, -C(CH3)2-S-CH2-, -CH2-S-CH(CH3)-, -CH2-S-C(CH3)2-, -CH(CH3)-S(O)-, -CH2-, -C(CH3)2-S(O)-CH2-, -CH2-S(O)-CH(CH3)-, -CH2-S(O)-C(CH3)2-, -CH(CH3)-S(O)2-CH2-, -C(CH3)2-S(O)2-CH2-, -CH2-S(O)2-CH(CH3)-, -CH2-S(O)2-C(CH3)2-, -CH2-NH-C(O)-, -C(O)-NH-CH2-, -C(O)-NH-CH(CH3)-, -C(O)-NH-C(CH3)2-, -CH2SeCH2-, -CH(COOH)-, -CH2CH(COOH)-, -CH2CH(COOH)CH2-, -CH2CH2CH(COOH)-, -CH=CH-, -CH=CHCH2-, –C≡CCH2-, -HC[CH2]CH- or -HC[CH2]CHCH2-, where HC[CH2]CH represents a cyclopropyl ring;

[0084] R 3 It is a C1-C2- 20 Alkylene or alkenylene, or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 20 heteroalkylene or heteroalkenylene;

[0085] R 4 Is -O-, -S-, -Se-, -S(O)-, -S(O)2-, -NHC(O)-, -C(O)NH-, -C(O)-(NH)2-C(O)-, -OC(O)NH-, -NHC(O)O-, -NHC(O)NH-, -OC(S)NH-, -NHC(S)O-, -NHC(S)NH-, -NHC(O)C(O)NH-, -SS-, -S-CH2-S-, -NH-NH-C(O)-, -C(O)-NH-NH-,

[0086]

[0087] R 5 It is a C1-C2- 30 Alkylene, alkenylene or alkynylene, or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 30 heteroalkylene, heteroalkenylene, or heteroalkynylene;

[0088] R 6 is hydrogen or methyl or ethyl;

[0089] XA 1 It is a compound having the formula -N(R 8 )R 9 C(O)-amino acids, where each R 8 are independently hydrogen or methyl, and wherein each R 9 are independently: linear or branched, cyclic or acyclic and / or aromatic or non-aromatic C1-C 20 Alkylene, alkenylene or alkynylene; or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 20 heteroalkylene, heteroalkenylene, or heteroalkynylene;

[0090] At least one R 9 or R 5 Yes - (CH2) 0-3 CH(R 10 )(CH2) 0-3 -, where R10 yes:

[0091] Straight or branched, cyclic or acyclic and / or aromatic or non-aromatic C2-C 19 alkyl, alkenyl or alkynyl; linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X3 having only 1 to 3 heteroatoms 19 heteroalkyl, heteroalkenyl or heteroalkynyl;

[0092] -CH2R 23 , where R 23 is an optionally substituted C4-C 16 an aromatic ring or a partially or fully aromatic fused ring system, wherein 0-3 carbons in the aromatic ring or the partially or fully aromatic fused ring system are replaced by N, S and / or O heteroatoms, and wherein the optional substituents are selected from OH, NH2, NO2, halogen, C1-C6 alkyl and / or C1-C6 alkoxy; or

[0093] Selected from:

[0094]

[0095]

[0096] Optionally modified with one, more than one, or a combination of: halogen, OMe, SMe, NH2, NO2, CN, OH, or another endocyclic nitrogen atom;

[0097] R 7 YesR X -(Xaa 2 ) 0-4 -、

[0098] R 28 It is an albumin binder;

[0099] XA 2 and Xaa 3 , when present, is independently -N(R 13 )R 14 C(O)-, where each R 13 are independently hydrogen or methyl, and wherein each R 14 are independently: linear or branched, cyclic or acyclic and / or aromatic or non-aromatic C1-C 20 Alkylene, alkenylene or alkynylene; or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 20 heteroalkylene, heteroalkenylene, or heteroalkynylene; and

[0100] Each RX is a radiolabeling group independently selected from: a radiometal chelator optionally bound to a metal; an aryl or heteroaryl group substituted with a radioisotope; a prosthetic group containing a trifluoroborate; or a prosthetic group containing a silicon-fluorine-acceptor moiety, a fluorophosphate, a fluorosulfate or a sulfonyl fluoride;

[0101] And where R 7 -(Xaa 1 ) 1-4 -N(R 6 )-R 5 -R 4 -R 3 Any amide linkage or combination thereof within is optionally replaced by one or a combination selected from the group consisting of: -O-, -S-, -Se-, -S(O)-, -S(O)2-, -NHC(O)-, -C(O)NH-, -C(O)-, -(NH)2-C(O)-, -OC(O)NH-, -NHC(O)O-, -NHC(O)NH-, -OC(S)NH-, -NHC(S)O -, -NHC(S)NH-, -NHC(O)C(O)NH-, -SS-, -S-CH2-S-, -NH-NH-C(O)-, and -C(O)-NH-NH-.

[0102] Various embodiments disclosed herein relate to a compound, wherein the compound has Formula V or a salt or solvate of Formula V:

[0103]

[0104] in:

[0105] R 0 is S or O;

[0106] R 1a is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -OPO3H2, -OSO3H, -B(OH)2 or

[0107] R 1b is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -B(OH)2 or

[0108] R 1c is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -B(OH)2 or

[0109] R 2is -CH2-, -CH(OH)-, -CHF-, -CF2-, -CH(CH3)-, -C(CH3)2-, -CH2CH(OH)-, -CH2CHF-, -CHFCH2-, -CF2CH2-, -CH2CF2-, -CH(OH)CH2-, -CH (CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-, -CH2CH(OH)CH2-, -CH2CHFCH2-, -(CH2)2CH(OH)-, -(CH2)2CHF-, -(CH2)3- , -CH2OCH2-, -CH2SCH2-, -CHFCH2CH2-, -CH(OH)CH2CH2-, -CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2- , -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-, -CH(CH3)-O-CH2-, -C(CH3)2-O-CH2-, -CH2-O-CH(CH3)-, -CH2-OC(CH3)2-, -CH2-S(O)-CH2-, -CH2-S(O)2-CH2-, -CH(CH3)-S-CH2-, -C(CH3)2-S-CH2-, -CH2-S-CH(CH3)-, -CH2-SC(CH3)2-, -CH(CH3)-S(O)-, -CH2-, -C(CH3)2-S( O)-CH2-, -CH2-S(O)-CH(CH3)-, -CH2-S(O)-C(CH3)2-, -CH(CH3)-S(O)2-CH2-, -C(CH3)2-S(O)2-CH2-, -CH2-S(O)2-CH(CH3)-, -CH2- S(O)2-C(CH3)2-, -CH2-NH-C(O)-, -C(O)-NH-CH2-, -C(O)-NH-CH(CH3)-, -C(O)-NH-C(CH3)2-, -CH2SeCH2-, -CH(COOH)-, -CH2CH(COOH)-, -CH2CH(COOH)CH2-, -CH2CH2CH(COOH)-, -CH=CH-, -CH=CHCH2-, –C≡CCH2-, -HC[CH2]CH- or -HC[CH2]CHCH2-, wherein HC[CH2]CH represents a cyclopropyl ring;

[0110] R 3 It is a C1-C2- 20Alkylene or alkenylene, or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 20 heteroalkylene or heteroalkenylene;

[0111] R 4 is -O-, -S-, -Se-, -S(O)-, -S(O)2-, -NHC(O)-, -C(O)NH-, -C(O)-(NH)2-C(O)-, -OC(O)NH-, -NHC(O)O-, -NHC(O)NH-, -OC(S)NH-, -NHC(S)O-, -NHC(S)NH-, -NHC(O)C(O)NH-, -SS-, -S-CH2-S-, -NH-NH-C(O)-, -C(O)-NH-NH-,

[0112] R 5 It is a C1-C2- 30 Alkylene, alkenylene or alkynylene, or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 30 heteroalkylene, heteroalkenylene, or heteroalkynylene;

[0113] R 6 is optionally a carbonyl, phosphoryl or sulfonyl group, which is 1 or alternatively: -NHC(O)-, -(NH)2-C(O)-, -C(O)-(NH)2-C(O)-, -OC(O)-, -OC(S)-, -NHC(S)-, -NHC(O)C(O)-, -NH-NH-C(O)-, to attach Xaa 1 Alpha nitrogen in.

[0114] XA 1 It is a compound having the formula -N(R 8 )R 9 C(O)-amino acids, where each R 8 are independently hydrogen or methyl, and wherein each R 9 are independently: linear or branched, cyclic or acyclic and / or aromatic or non-aromatic C1-C 20 Alkylene, alkenylene or alkynylene; or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 20 heteroalkylene, heteroalkenylene, or heteroalkynylene;

[0115] At least one R 9 or R5 Yes - (CH2) 0-3 CH(R 10 )(CH2) 0-3 -, where R 10 yes:

[0116] Straight or branched, cyclic or acyclic and / or aromatic or non-aromatic C2-C 19 Alkyl, alkenyl or alkynyl; linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X3 having only 1 to 3 heteroatoms 19 heteroalkyl, heteroalkenyl or heteroalkynyl;

[0117] -CH2R 23 , where R 23 is an optionally substituted C4-C 16 an aromatic ring or a partially or fully aromatic fused ring system, wherein 0-3 carbons in the aromatic ring or the partially or fully aromatic fused ring system are replaced by N, S and / or O heteroatoms, and wherein the optional substituents are selected from OH, NH2, NO2, halogen, C1-C6 alkyl and / or C1-C6 alkoxy; or

[0118] Selected from:

[0119]

[0120] optionally modified with one, more than one, or a combination of: halogen, OMe, SMe, NH2, NO2, CN, OH, or another endocyclic nitrogen atom;

[0121] R 7 YesR X -(Xaa 2 ) 0-4 -、

[0122] R 28 It is an albumin binder;

[0123] XA 2 and Xaa 3 , when present, is independently -N(R 13 )R 14 C(O)-, where each R 13 are independently hydrogen or methyl, and wherein each R 14 are independently: linear or branched, cyclic or acyclic and / or aromatic or non-aromatic C1-C 20 Alkylene, alkenylene or alkynylene; or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 20heteroalkylene, heteroalkenylene, or heteroalkynylene; and

[0124] Each R X is a radiolabeling group independently selected from: a radiometal chelator optionally bound to a metal; an aryl or heteroaryl group substituted with a radioisotope; a prosthetic group containing a trifluoroborate; or a prosthetic group containing a silicon-fluorine-acceptor moiety, a fluorophosphate, a fluorosulfate or a sulfonyl fluoride.

[0125] Various embodiments can be used to image PSMA-expressing tissue in a subject. Various embodiments can be used to treat a PSMA-expressing condition or disease in a subject. BRIEF DESCRIPTION OF THE DRAWINGS

[0126] Features of the present invention will become apparent from the following description with reference to the accompanying drawings, in which:

[0127] FIG. 1 shows examples of prior art PSMA-targeted compounds for prostate cancer imaging.

[0128] Figure 2 Shown is a synthetic scheme for HTK03149 using a solid phase method.

[0129] Figure 3 Shown is a general synthetic scheme for several exemplary compounds incorporating a Lys-ureido-Aad PSMA binding moiety.

[0130] Figure 4 A general synthetic scheme for exemplary compounds having two BF3 labeling groups is shown.

[0131] Figure 5 The injection is shown 68 Reconstitution of Ga-HTK03149 mice 68 Ga-labeled PET images. Images were taken after intravenous injection of 68 Ga-HTK03149 was obtained 1 and 3 hours after administration into immunodeficient mice bearing LNCaP xenografts. Solid arrows point to very high tumor accumulation. Dashed arrows point to minimal kidney accumulation.

[0132] Figure 6 The chemical structures of the following compounds are shown: HTK03041, HTK03149, HTK03169, HTK03161, HTK03177, HTK03187, HTK03153, HTK03170, HTK03189A, HTK03189B, HTK04033, HTK04036, HTK04037, HTK04040, HTK04041, HTK04053, HTK03162, and HTK04055.

[0133] Figure 7 The following maximum intensity projection PET / CT image obtained 1 h after injection is shown: 68 Ga-HTK03041, 68 Ga-HTK03149, 68 Ga-HTK03161, 68 Ga-HTK03169, 68 Ga-HTK03177, 68 Ga-HTK03187, 68 Ga-HTK03189A, 68 Ga-HTK03189B, 68 Ga-HTK04033, 68 Ga-HTK04036, 68 Ga-HTK04037, 68 Ga-HTK04040, 68 Ga-HTK04041 and 68 Ga-HTK04053.

[0134] Figure 8 The results obtained at 1 h, 4 h, 24 h, 72 h and 120 h after injection are shown. 177 Maximum intensity projection SPECT / CT images of Lu-HTK03149 (t: tumor, k: kidney, b: bladder).

[0135] Fig. 9 The results obtained at 1 h, 4 h, 24 h, 72 h and 120 h after injection are shown. 177 Maximum intensity projection SPECT / CT images of Lu-HTK03153 (t: tumor, k: kidney, b: bladder).

[0136] Fig.10 The results obtained at 1 h, 4 h, 24 h, 72 h and 120 h after injection are shown. 177 Maximum intensity projection SPECT / CT images of Lu-HTK03170 (t: tumor, k: kidney, b: bladder).

[0137] Fig.11 The results obtained at 1 h, 4 h, 24 h, 72 h and 120 h after injection are shown. 177 Maximum intensity projection SPECT / CT images of Lu-HTK04028 (t: tumor, k: kidney, b: bladder).

[0138] Fig.12 The results obtained at 1 h, 4 h, 24 h, 72 h and 120 h after injection are shown. 177Maximum intensity projection SPECT / CT images of Lu-HTK04048 (t: tumor, k: kidney, b: bladder).

[0139] Fig.13 The results obtained 1 and 2 h after injection are shown. 18 F-HTK03162 and 18 F - Maximum intensity projection PET / CT image of HTK04055 (t: tumor, k: kidney, b: bladder). DETAILED DESCRIPTION

[0140] As used herein, the terms "comprising," "having," "including," and "containing," and grammatical variations thereof, are inclusive or open-ended and do not exclude additional, unrecited elements and / or method steps, even if the features / components defined as a part thereof consist of or consist essentially of the specified one or more features / components. The term "consisting essentially of," if used herein in conjunction with a compound, composition, use, or method, indicates that additional elements and / or method steps may be present, but these additional elements and / or method steps do not materially affect the manner in which the compound, composition, method, or use functions. The term "consisting of," if used herein in conjunction with a feature of a composition, use, or method, excludes the presence of additional elements and / or method steps in that feature. A compound, composition, use, or method described herein as comprising certain elements and / or steps may also consist essentially of those elements and / or steps in certain embodiments, and consist of those elements and / or steps in other embodiments, whether or not those embodiments are specifically referred to. Uses or methods described herein as comprising certain elements and / or steps may also consist essentially of those elements and / or steps in certain embodiments, and consist of those elements and / or steps in other embodiments, whether or not specifically referred to those embodiments.

[0141] Furthermore, unless the context clearly requires that there is one and only one element, reference to an element by the indefinite article "a" does not exclude the possibility that more than one element is present. As used herein, the singular forms "a", "an", and "the" include plural referents unless the context clearly indicates otherwise. The word "a" or "an" when used herein in conjunction with the term "comprising" may mean "one", but it is also consistent with the meaning of "one or more", "at least one", and "one or more than one".

[0142] In this disclosure, the recitation of numerical ranges by endpoints includes all numbers subsumed within that range, including all whole numbers, all integers, and all intermediate fractions where appropriate (e.g., 1 to 5 may include 1, 1.5, 2, 2.75, 3, 3.80, 4, and 5, etc.).

[0143] Unless otherwise indicated, "certain embodiments," "various embodiments," "embodiments," and similar terms include particular features described for that embodiment alone or in combination with any other embodiment or embodiments described herein, whether or not such other embodiments are referenced directly or indirectly and whether or not the feature or embodiment is described in the context of a method, product, use, composition, compound, etc.

[0144] As used herein, the terms "treat," "treatment," "therapeutic" and the like include alleviating symptoms, reducing disease progression, improving prognosis and reducing recurrence.

[0145] As used herein, the term "diagnostic agent" includes "imaging agents." Thus, a "diagnostic radiometal" includes radiometals suitable for use as imaging agents.

[0146] The term "subject" refers to an animal (e.g., a mammal or non-mammal). The subject can be a human or a non-human primate. The subject can be a laboratory mammal (e.g., a mouse, a rat, a rabbit, a hamster, etc.). The subject can be an agricultural animal (e.g., a horse, a sheep, a cow, a pig, a camel, etc.) or a domestic animal (e.g., a dog, a cat, etc.). In some embodiments, the subject is a human.

[0147] The compounds disclosed herein may also include their free base form, salts or pharmaceutically acceptable salts. Unless otherwise indicated, the compounds claimed and described herein are intended to include all racemic mixtures and all individual enantiomers or combinations thereof, whether or not they are explicitly indicated herein.

[0148] Compounds disclosed herein may be shown as having one or more charged groups, may be shown under an ionizable group in an uncharged (e.g., protonated) state, or may be shown without specifying a formal charge. As will be appreciated by those skilled in the art, the ionization state of certain groups within a compound (e.g., but not limited to, CO2H, PO3H2, SO2H, SO3H, SO4H, OPO3H2, etc.) depends in particular on the pKa of the group and the pH at the position. For example, but not limited to, a carboxylic acid group (i.e., COOH) will be understood to be generally deprotonated (and negatively charged) at neutral pH and at most physiological pH, unless the protonation state is stable. Similarly, OSO3H (i.e., SO4H) groups, SO2H groups, SO3H groups, OPO3H2 (i.e., PO4H2) groups, and PO3H groups will generally be deprotonated (and negatively charged) at neutral and physiological pH values.

[0149] As used herein, the terms "salt" and "solvate" have their usual meanings in chemistry. Therefore, when a compound is a salt or a solvate, it is associated with a suitable counterion. How to prepare salts or exchange counterions is well known in the art. Generally, such salts can be prepared by reacting these compounds in free acid form with a stoichiometric amount of a suitable base (such as, but not limited to, hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg, or K), or by reacting these compounds in free base form with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Counterions can be changed, for example, by ion exchange techniques such as ion exchange chromatography. Unless a particular form is specifically indicated, all zwitterions, salts, solvates, and counterions are intended.

[0150] In certain embodiments, the salt or counterion may be pharmaceutically acceptable for administration to a subject. More generally, with respect to any pharmaceutical composition disclosed herein, non-limiting examples of suitable excipients include any suitable buffer, stabilizer, salt, antioxidant, complexing agent, tonicity agent, cryoprotectant, lyophilization protectant, suspending agent, emulsifier, antimicrobial agent, preservative, chelating agent, adhesive, surfactant, wetting agent, non-aqueous vehicle (such as fixed oil) or polymer for maintaining or controlling release. See, for example, Berge et al. 1977. (J. Pharm Sci. 66: 1-19), or Remington - The Science and Practice of Pharmacy, 21st edition (Gennaro et al., ed. Lippincott Williams & Wilkins Philadelphia), each of which is incorporated by reference in its entirety.

[0151] As used herein, the expression "Xy-Xz" wherein y and z are integers (e.g., X1-X 15 、X1-X 30 、X1-X 100 , etc.), refers to the number of carbons in a compound, R-group or substituent (for alkyl (whether saturated or unsaturated) or aryl), or refers to the number of carbons plus heteroatoms in a compound, R-group or substituent (for heteroalkyl (whether saturated or unsaturated) or heteroaryl). The heteroatoms may include any, some or all possible heteroatoms. For example, in some embodiments, the heteroatoms are selected from N, O, S, P and Se. In some embodiments, the heteroatoms are selected from N, O, S and P. Such embodiments are non-limiting. Alkyl and aryl may alternatively be referred to using the expression "Cy-Cz", where y and z are integers (e.g., C3-C 15 wait).

[0152] Unless otherwise expressly stated, the terms "alkyl" and "heteroalkyl" each include any reasonable combination of the following: (1) saturated alkyl and unsaturated (including partially unsaturated) alkyl (e.g., alkenyl and alkynyl); (2) straight chain or branched; (3) acyclic or cyclic (aromatic or non-aromatic), the latter of which may include polycyclic (fused ring, multiple non-fused rings or combinations thereof); and (4) unsubstituted or substituted. For example, according to the skills of those skilled in the art, an alkyl or heteroalkyl (i.e., "alkyl / heteroalkyl") may be saturated, branched and cyclic, or unsaturated, branched and cyclic, or straight chain and unsaturated, or any other reasonable combination. If not specified, the size of the alkyl / heteroalkyl is what is deemed reasonable by those skilled in the art. For example, but not limited to, if not specified, according to the common knowledge of those skilled in the art, the size (length) of the alkyl group can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 94, 95, 96, 97, 98, 99, 100 or more carbon atoms. In addition, but not limited to, if not specified, the size (length) of the heteroalkyl group can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75 97, 98, 99, 100 or more than 100 carbon atoms and heteroatoms. In the context of the expression "alkyl, alkenyl or alkynyl" and similar expressions, "alkyl" is understood to mean a saturated alkyl group.Likewise, in the context of the expression "heteroalkyl, heteroalkenyl or heteroalkynyl" and similar expressions, "heteroalkyl" is to be understood as a saturated heteroalkyl group.

[0153] As used herein, in the context of alkyl / heteroalkyl groups of compounds, the term "linear" may be used as generally understood by those skilled in the art and generally refers to a chemical entity comprising a backbone or main chain that does not break down into more than one continuous chain. Non-limiting examples of linear alkyl groups include methyl, ethyl, n-propyl, and n-butyl.

[0154] As used herein, the term "branched" may be used as generally understood by those skilled in the art and generally refers to a chemical entity comprising a backbone or main chain that decomposes into more than one continuous chain. The portion of the backbone or main chain that decomposes in more than one direction may be linear, cyclic, or any combination thereof. Non-limiting examples of branched alkyl groups include tert-butyl and isopropyl.

[0155] The term "alkylene" refers to a divalent analog of an alkyl group. In the context of the expression "alkylene, alkenylene, or alkynylene," "alkylene or alkenylene," and similar expressions, "alkylene" is understood to be a saturated alkylene group. The term "heteroalkylene" refers to a divalent analog of a heteroalkyl group. In the context of the expression "heteroalkylene, heteroalkenylene, or heteroalkynylene," "heteroalkylene or heteroalkenylene," and similar expressions, "heteroalkylene" is understood to be a saturated heteroalkylene group.

[0156] As used herein, the term "saturated" when referring to a chemical entity may be used as generally understood by those skilled in the art, and generally refers to a chemical entity that contains only single bonds, and may contain linear, branched, and / or cyclic groups. 20 Non-limiting examples of alkyl groups may include methyl, ethyl, n-propyl, isopropyl, sec-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, tert-pentyl, n-hexyl, isohexyl, 1,2-dimethylpropyl, 2-ethylpropyl, 1-methyl-2-ethylpropyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1,2-triethylpropyl, 1,1-dimethylbutyl, 2,2- dimethylbutyl, 2-ethylbutyl, 1,3-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, sec-hexyl, tert-hexyl, n-heptyl, isoheptyl, sec-heptyl, tert-heptyl, n-octyl, isooctyl, sec-octyl, tert-octyl, n-nonyl, isononyl, sec-nonyl, tert-nonyl, n-decyl, isodecyl, sec-decyl, tert-decyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, etc. Unless otherwise specified, C1-C 20 Alkylene thus encompasses, but is not limited to, all divalent analogs of the saturated alkyl groups listed above.

[0157] As used herein, the term "unsaturated" when referring to a chemical entity may be used as generally understood by those skilled in the art, and generally refers to a chemical entity that contains at least one double bond or triple bond, and may contain linear, branched, and / or cyclic groups. 20 Non-limiting examples of alkenyl groups may include vinyl, allyl, isopropenyl, 1-propen-2-yl, 1-buten-1-yl, 1-buten-2-yl, 1-buten-3-yl, 2-buten-1-yl, 2-buten-2-yl, octenyl, decenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl, and the like. Unless otherwise specified, C1-C 20 Alkenylene thus encompasses, but is not limited to, all divalent analogs of the alkenyl groups listed above. 20 Non-limiting examples of alkynyl groups can include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, and the like. Unless otherwise specified, C1-C 20 Alkyne groups thus encompass, but are not limited to, all divalent analogs of the alkynyl groups listed above. Without limitation, unless otherwise indicated, the saturated C1-C 20 Alkyl, C2-C 20 Alkenyl and C2-C 20 Alkynyl groups are all encompassed by the term "X1-X 20 Without limitation, unless otherwise specified, the saturated C1-C 20 Alkylene, C2-C 20 Alkenylene and C2-C 20 Alkyne groups are all encompassed by the term "X1-X 20 "Alkylene"

[0158] Without limitation, the term "X1-X 20 The term "heteroalkyl" shall encompass the saturated C1-C 20 Alkyl, C2-C 20 Alkenyl and C2-C 20 Each of the alkynyl groups, wherein one or more carbon atoms are independently replaced by heteroatoms. Likewise, without limitation, the term "X1-X 20 The term "heteroalkylene" shall encompass the saturated C1-C 20 Alkylene, C2-C 20 Alkenylene and C2-C 20Each in alkynylene, wherein one or more carbon atoms are independently replaced by heteroatoms. It will be appreciated by those skilled in the art that various combinations of different heteroatoms can be used. The limiting examples of non-aromatic heterocyclic groups include aziridine, azetidinyl, diazetidinyl, pyrrolidinyl, pyrrolinyl, piperidinyl, piperazinyl, imidazolinyl, pyrazolidinyl, imidazolidinyl, phthalimide, succinimidyl, oxiranyl, tetrahydropyranyl, oxetanyl, dioxane, thietanyl, thiepitrienyl, morpholinyl, oxathiolanyl etc.

[0159] Unless otherwise specified, "aryl" includes both single aromatic rings and fused rings containing at least one aromatic ring. 20 Non-limiting examples of aryl groups include phenyl (Ph), pentalenyl, indenyl, naphthyl, and azulenyl. 20 Non-limiting examples of aromatic heterocyclic groups include pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, acridinyl, indolyl, isoindolyl, indolizinyl, purinyl, carbazolyl, indazolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, phenanthridinyl, phenazinyl, phenanthrolinyl, furidinyl, furanyl, dibenzofuranyl, xanthenyl, benzofuranyl, thienyl, thianthrenyl, benzothienyl, phosphoryl, phospholinyl, phosphadolyl, thiazolyl, oxazolyl, isoxazolyl, and the like.

[0160] As used herein, the term "substituted" is used as commonly understood by those skilled in the art, and generally refers to a compound or chemical entity in which one chemical group is replaced by a different chemical group. Unless otherwise specified, a substituted alkyl group is an alkyl group in which one or more hydrogen atoms are independently replaced by a non-hydrogen atom. For example, chloromethyl is a non-limiting example of a substituted alkyl group, more specifically an example of a substituted methyl group. Aminoethyl is another non-limiting example of a substituted alkyl group, more specifically an example of a substituted ethyl group. Unless otherwise specified, a substituted compound or group (such as an alkyl group, assorted alkyl groups, aryl groups, heteroaryl groups, etc.) can be replaced by any chemical group that is reasonable to those skilled in the art. For example, but not limited to, hydrogen bonded to carbon or a heteroatom (such as N) can be replaced by halogen groups (such as F, I, Br, Cl), amines, amides, oxo, hydroxyl, thiol, phosphate groups, phosphonate groups, sulfate groups, SO2H, SO3H, alkyl, assorted alkyl groups, aryl groups, heteroaryl groups, ketones, formaldehyde, carboxylate groups, formamides, nitrile, monohalomethyl, dihalomethyl or trihalomethyl groups.

[0161] As used herein, the term "unsubstituted" is used as commonly understood by those skilled in the art. Non-limiting examples of unsubstituted alkyl include methyl, ethyl, tert-butyl, pentyl, etc. The expression "optionally substituted" is used interchangeably with the expression "unsubstituted or substituted".

[0162] In the structures provided herein, hydrogen may or may not be shown. In some embodiments, hydrogen (whether shown or implied) may be protium (i.e. 1 H), deuterium (i.e. 2 H) or 1 H and 2 H combination. 2 H Exchange 1 H methods are well known in the art. For solvent exchangeable hydrogen, use 2 H Exchange 1 H occurs readily in the presence of a suitable deuterium source without the need for any catalyst. The use of acids, bases, or metal catalysts, combined with conditions of elevated temperature and pressure, can promote the exchange of non-exchangeable hydrogen atoms, usually resulting in the removal of all deuterium atoms from the molecule. 1 H is exchanged for 2 H.

[0163] The term "Xaa" refers to an amino acid residue in a peptide chain or an amino acid that is otherwise part of a compound. An amino acid has both an amino group and a carboxylic acid group, one or both of which can be used for covalent attachment. When attached to the rest of the compound, the amino group and / or the carboxylic acid group can be converted to an amide or other structure; for example, the carboxylic acid group of a first amino acid is converted to an amide (i.e., a peptide bond) when bonded to the amino group of a second amino acid. Thus, Xaa can have the formula -N(R a )R b C(O)-, where R a and R b is an R group. aUsually it will be hydrogen or methyl. The amino acid residue of a peptide may include a typical peptide (amide) bond and may also include a bond between a side chain functional group and a side chain or main chain functional group of another amino acid. For example, a side chain carboxylate of an amino acid residue (e.g., Asp, Glu, etc.) in a peptide may be bonded to an amine of another amino acid residue (e.g., Dap, Dab, Orn, Lys) in a peptide. Further details are provided below. Unless otherwise indicated, "Xaa" may be any amino acid, including protein amino acids and non-protein amino acids. Non-limiting examples of non-protein amino acids are shown in Table 1 and include: D-amino acids (including but not limited to any D-form of the following amino acids), ornithine (Orn), 3-(1-naphthyl)alanine (Nal), 3-(2-naphthyl)alanine (2-Nal), α-aminobutyric acid, norvaline, norleucine (Nle), homonorleucine, β-(1,2,3-triazole-4-yl)-L-alanine, 1,2,4-triazole-3-alanine, Phe ( 4-F), Phe(4-Cl), Phe(4-Br), Phe(4-I), Phe(4-NH2), Phe(4-NO2), homoarginine (hArg), 2-amino-4-guanidinobutyric acid (Agb), 2-amino-3-guanidinopropionic acid (Agp), β-alanine, 4-aminobutyric acid, 5-aminopentanoic acid, 6-aminohexanoic acid, 7-aminoheptanoic acid, 8-aminooctanoic acid, 9-aminononanoic acid, 10-aminodecanoic acid, 2-aminooctanoic acid, 2-amino 2-amino-3-(anthracen-2-yl)propionic acid, 2-amino-3-(anthracen-9-yl)propionic acid, 2-amino-3-(pyrene-1-yl)propionic acid, Trp(5-Br), Trp(5-OCH3), Trp(6-F), Trp(5-OH) or Trp(CHO), 2-aminoadipic acid (2-Aad), 3-aminoadipic acid (3-Aad), propargylglycine (Pra), homopropargylglycine (Hpg), β-homopropargylglycine (Bpg) , 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab), azidolysine (Lys(N3)), azidoornithine (Orn(N3)), 2-amino-4-azidobutyric acid Dab(N3), Dap(N3), 2-(5'-azidopentyl)alanine, 2-(6'-azidohexyl)alanine, 4-amino-1-carboxymethyl-piperidine (Pip), 4-(2-aminoethyl)-1-carboxymethyl-piperazine (Acp) and tranexamic acid. If not specified as L-amino acid or D-amino acid, amino acid is understood to cover both L-amino acid and D-amino acid.

[0164] Table 1. List of non-limiting examples of non-proteinogenic amino acids.

[0165]

[0166]

[0167] In a chemical formula (e.g., in formula I, etc., R 4 , R 6 , R 7 , R 9 and R 11 ), a wavy line through the key or shown at the end of the key The notation is intended to define the R group on one side of the wavy line without modifying the definition of the structure on the other side of the wavy line. 11 ), any atoms shown outside the wavy lines are intended to clarify the orientation of the R group. Thus, only the atoms between the two wavy lines constitute the definition of the R group. When atoms are not shown outside the wavy lines, or for chemical groups that do not show wavy lines but do have bonds on multiple sides (e.g., -C(O)NH-, etc.), the chemical group should be read from left to right, matching the orientation in the formula associated with the group (e.g., for the formula -R a -R b -R c -, R b Defined as -C(O)NH-, when incorporated into the formula it becomes -R a -C(O)NH-R c -Rather than being -R a -NHC(O)-R c -).

[0168] In various aspects, disclosed are compounds of Formula I (as defined below), Formula II (as defined below), Formula IV (as defined below), or Formula V (as defined below), or compounds comprising a PSMA targeting moiety of Formula III (as defined below), including salts or solvates of the foregoing.

[0169] The following definitions apply to the compounds of formula I (and their salts / solvates).

[0170] In some embodiments, the compound has Formula I or is a salt or solvate of Formula I:

[0171]

[0172] in:

[0173] n is 0 or 1;

[0174] R 1a , R 1b and R 1c Each is independently -CO2H, -SO2H, -SO3H, -SO4H, -PO2H, -PO3H or -PO4H;

[0175] When n is 0, R 2 is -CH2-, -CHOH-, -CHF-, -CH2CHOH-, -CH2CHF-, -CH2CHOHCH2-, -CH2CHFCH2-, -(CH2)2CHOH-, -(CH2)2CHF-, -(CH2)3-, -CH2OCH2- or -CH2SCH2-;

[0176] When n is 1, R 2 is -CH2-, -CHOH-, -CHF-, -CH2CHOH-, -CH2CHF- or -(CH2)2-;

[0177] R 3 It is a C1-C2- 20 Alkylene or alkenylene, or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 20 heteroalkylene or heteroalkenylene;

[0178] R 4 It is -O-, -S-, -NHC(O)-, -C(O)NH-,

[0179] R 5 It is a C1-C2- 30 Alkylene, alkenylene or alkynylene, or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 30 heteroalkylene, heteroalkenylene, or heteroalkynylene;

[0180] R 6 is hydrogen or methyl;

[0181] XA 1 It is a compound having the formula -N(R 8 )R 9 C(O)-amino acids, where each R 8 are independently hydrogen or methyl, and wherein each R 9 are independently: linear or branched, cyclic or acyclic and / or aromatic or non-aromatic C1-C 20 Alkylene, alkenylene or alkynylene; or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 20 heteroalkylene, heteroalkenylene, or heteroalkynylene;

[0182] At least one R 9 or R 5 yes

[0183] At least one R9 or R 5 Yes - (CH2) 0-3 CH(R 10 )(CH2) 0-3 -, where R 10 It is a C2-C3 straight chain or branched, cyclic or acyclic and / or aromatic or non-aromatic 19 Alkyl, alkenyl or alkynyl, or R 10 is a linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X having only 1 to 3 heteroatoms 19 heteroalkyl, heteroalkenyl or heteroalkynyl;

[0184] R 7 YesR X -(Xaa 2 ) 0-4 -、

[0185] R 11 does not exist,

[0186] R 12 is I, Br, F, Cl, H, OH, OCH3, NH2, NO2 or CH3;

[0187] XA 2 , when present, is -N(R 13 )R 14 C(O)-, where each R 13 are independently hydrogen or methyl, and wherein each R 14 are independently: linear or branched, cyclic or acyclic and / or aromatic or non-aromatic C1-C 20 Alkylene, alkenylene or alkynylene; or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 20 heteroalkylene, heteroalkenylene, or heteroalkynylene; and

[0188] Each R X is a radiolabeling group independently selected from: a radiometal chelator optionally bound by a radiometal; an aryl group substituted with a radioisotope; a prosthetic group containing a trifluoroborate; and a prosthetic group containing a silicon-fluorine-acceptor moiety.

[0189] In some embodiments, the compound is a salt or solvate of Formula I.

[0190] In some embodiments, the compound of Formula I is a compound of Formula Ia:

[0191]

[0192] Where R 1a , R 1b , R 1c , R 2 , R 3 , R 4 , R 5 , R 6 , Xaa 1 and R 7 As defined for Formula I. In some embodiments, the compound is a salt or solvate of Formula Ia.

[0193] In some embodiments, n is 0. In some embodiments, n is 1.

[0194] In some embodiments, R 1a is -CO2H. In some embodiments, R 1b is -CO2H. In some embodiments, R 1c is -CO2H. In some embodiments, R 1a and R 1b Each is -CO2H. In some embodiments, R 1a and R 1c Each is -CO2H. In some embodiments, R 1b and R 1c Each is -CO2H. In some embodiments, R 1a , R 1b and R 1c Each is –CO2H.

[0195] In some embodiments, R 2 It is –CH2OCH2– or –CH2SCH2–.

[0196] In some embodiments, n is 0 and R 2 is -CH2-. In some embodiments, n is 0 and R 2 is -CHOH-. In some embodiments, n is 0 and R 2 is -CHF-. In some embodiments, n is 0 and R 2 is -CH2CHOH-. In some embodiments, n is 0 and R 2 is -CH2CHF-. In some embodiments, n is 0 and R 2 is -CH2CHOHCH2-. In some embodiments, n is 0 and R 2 is -CH2CHFCH2-. In some embodiments, n is 0 and R 2 is -(CH2)2CHOH-. In some embodiments, n is 0 and R2 is -(CH2)2CHF-. In some embodiments, n is 0 and R 2 is -(CH2)3-. In some embodiments, n is 0 and R 2 is -CH2OCH2-. In some embodiments, n is 0 and R 2 It is –CH2SCH2–.

[0197] In some embodiments, n is 1 and R 2 is -CH2-. In some embodiments, n is 1 and R 2 is -CHOH-. In some embodiments, n is 1 and R 2 is -CHF-. In some embodiments, n is 1 and R 2 is -CH2CHOH-. In some embodiments, n is 1 and R 2 is -CH2CHF-. In some embodiments, n is 1 and R 2 It is –(CH2)2–.

[0198] In some embodiments, n is 0, R 1a is –CO2H and R 2 is -(CH2)3-. In some embodiments, n is 0, R 1a is –CO2H and R 2 is -CH2-. In some embodiments, n is 0, R 1a Yes – CO2H, R 1b Yes – CO2H, R 1c is –CO2H and R 2 is -(CH2)3-. In some embodiments, n is 0, R 1a is -CO2H and R 2 It is -CH2-.

[0199] In some embodiments, R 3 It is a straight-chain non-cyclic C3-C 15 In some embodiments, R 3 is a straight-chain non-cyclic C3-C 15 In some embodiments, R 3 It is a straight chain non-cyclic saturated C3-C 10 alkylene, optionally substituted with 1-5 amino, amide, oxo, hydroxyl, thiol, methyl or ethyl groups. 3 Yes - (CH2) 3-15 -. In some embodiments, R 3 is -CH2-. In some embodiments, R3 is -(CH2)2-. In some embodiments, R 3 is -(CH2)3-. In some embodiments, R 3 is -(CH2)4-. In some embodiments, R 3 is -(CH2)5-. In some embodiments, R 3 is -CH2-O-CH2-. In some embodiments, R 3 It is -CH2-S-CH2-.

[0200] In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 is -NHC(O)-. In some embodiments, R 4 is -C(O)NH-. In some embodiments, R 4 yes In some embodiments, R 4 yes

[0201] In some embodiments, R 3 Yes - (CH2) 3-15 - and R 4 is -C(O)NH-. In some embodiments, R 3 Yes - (CH2) 3-5 - and R 4 is -C(O)NH-. In some embodiments, R 3 is -(CH2)4- and R 4 It is -C(O)NH-.

[0202] In some embodiments, R 5 Yes - (CH2) 0-3 CH(R 10 )(CH2) 0-3 -. In some embodiments, R 5 Yes -CH(R 10 )-. In some embodiments, R 5 It is -CH2CH(R 10 )-. In some embodiments, R 5 Yes -CH(R 10 )CH2-. In some embodiments, R 5 Yes -CH(R 10 )-.

[0203] In some embodiments, R 10 Contains C6-C 16Aryl or X6-X having 1-3 heteroatoms independently selected from N, S and / or O 16 In some embodiments, C6-C 16 Aryl is benzyl. In some embodiments, X6-X 16 Heteroaryl is benzyloxy or benzylthio. In some embodiments, R 10 yes:

[0204] In some embodiments, R 10 yes In some embodiments, R 10 yes: In some embodiments, R 10 yes

[0205] In some embodiments, R 5 Yes -CH(R 10 )-, where R 10 As defined in any of the above embodiments.

[0206] In some embodiments, R 5 Yes - (CH2) 0-3 CH(R 10 )(CH2) 0-3 - and R 10 is -(CH2)5CH3. In some embodiments, R 5 Yes -CH(R 10 )-and R 10 It is -(CH2)5CH3.

[0207] In some embodiments, R 5 yes In some embodiments, R 5 yes

[0208] In some embodiments, R 6 is hydrogen. In some embodiments, R 6 It's methyl.

[0209] In some embodiments, (Xaa 1 ) 1-4 In some embodiments, (Xaa 1 ) 1-4 is a dipeptide in which each Xaa 1 Can be the same or different. In some embodiments, (Xaa 1 ) 1-4 is a tripeptide in which each Xaa1 Can be the same, different or a combination thereof. In some embodiments, (Xaa 1 ) 1-4 It is composed of four amino acid residues linked by peptide bonds, each of which is Xaa 1 Can be the same, different or a combination thereof. In some embodiments, each Xaa 1 R is independently selected from the proteinogenic amino acids and non-proteinogenic amino acids listed in Table 1, wherein each peptide backbone amino group is optionally methylated. 9 yes In some embodiments, at least one R 9 yes In some embodiments, at least one R 8 is hydrogen. In some embodiments, all R 8 In some embodiments, at least one Xaa 1 is a tranexamic acid residue. In some embodiments, (Xaa 1 ) 1-4 It is composed of a single tranexamic acid residue.

[0210] In some embodiments, R 3 is -(CH2)4- and -(Xaa 1 ) 1-4 N(R 6 )R 5 R 4 -yes

[0211] In some embodiments, R 3 is -(CH2)4- and -(Xaa 1 ) 1-4 N(R 6 )R 5 R 4 -yes

[0212] The following definitions apply to the compounds of formula II (and their salts / solvates).

[0213] In some embodiments, the compound is a compound of Formula II or a salt or solvate of Formula II:

[0214]

[0215] in:

[0216] R 0 is O or S;

[0217] R 1ais -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -OPO3H2, -OSO3H, -B(OH)2 or

[0218] R 1b is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -B(OH)2 or

[0219] R 1c is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -B(OH)2 or

[0220] R 2is -CH2-, -CH(OH)-, -CHF-, -CF2-, -CH(CH3)-, -C(CH3)2-, -CH2CH(OH)-, -CH2CHF-, -CHFCH2-, -CF2CH2-, -CH2C F2-, -CH(OH)CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-, -CH2CH(OH)CH2-, -CH2CHFCH2 -, -(CH2)2CH(OH)-, -(CH2)2CHF-, -(CH2)3-, -CH2OCH2-, -CH2SCH2-, -CHFCH2CH2-, -CH(OH)CH2CH2-, -CH(CH3) CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-, -CH(C H3)-O-CH2-, -C(CH3)2-O-CH2-, -CH2-O-CH(CH3)-, -CH2-OC(CH3)2-, -CH2-S(O)-CH2-, -CH2-S(O)2-CH2-, -CH( CH3)-S-CH2-, -C(CH3)2-S-CH2-, -CH2-S-CH(CH3)-, -CH2-SC(CH3)2-, -CH(CH3)-S(O)-CH2-, -C(CH3)2-S(O)-C H2-, -CH2-S(O)-CH(CH3)-, -CH2-S(O)-C(CH3)2-, -CH(CH3)-S(O)2-CH2-, -C(CH3)2-S(O)2-CH2-, -CH2-S(O)2- CH(CH3)-, -CH2-S(O)2-C(CH3)2-, -CH2-NH-C(O)-, -C(O)-NH-CH2-, -C(O)-NH-CH(CH3)- or -C(O)-NH-C(CH3)2-;

[0221] R 3 It is a C1-C2- 20 alkylene, alkenylene or alkynylene, or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 20 heteroalkylene, heteroalkenylene, or heteroalkynylene;

[0222] R 4 Is -O-, -S-, -Se-, -S(O)-, -S(O)2-, -NHC(O)-, -C(O)NH-, -C(O)-(NH)2-C(O)-, -OC(O)NH, -NHC(O)O-, -NHC(O)NH-, -OC(S)NH, -NHC(S)O-, -NHC(S)NH-, -NHC(O)C(O)NH-, -SS-, -S-CH2-S-, -NH-NH-C(O)-, -C(O)-NH-NH;

[0223] R 5 It is a C1-C2- 30 Alkylene, alkenylene or alkynylene, or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 30 heteroalkylene, heteroalkenylene, or heteroalkynylene;

[0224] R 6 is hydrogen or methyl or ethyl;

[0225] XA 1 It is a compound having the formula -N(R 8 )R 9 C(O)-amino acids, where each R 8 are independently hydrogen or methyl, and wherein each R 9 are independently: linear or branched, cyclic or acyclic and / or aromatic or non-aromatic C1-C 20 Alkylene, alkenylene or alkynylene; or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 20 heteroalkylene, heteroalkenylene, or heteroalkynylene;

[0226] At least one R 9 or R 5 Yes - (CH2) 0-3 CH(R 10 )(CH2) 0-3 -, where R 10 yes:

[0227] Straight or branched, cyclic or acyclic and / or aromatic or non-aromatic C2-C 19 alkyl, alkenyl or alkynyl; linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X3 having only 1 to 3 heteroatoms 19 heteroalkyl, heteroalkenyl or heteroalkynyl;

[0228] -CH2R 23 , where R 23 is an optionally substituted C4-C 16an aromatic ring or a partially or fully aromatic fused ring system, wherein 0-3 carbons in the aromatic ring or the partially or fully aromatic fused ring system are replaced by N, S and / or O heteroatoms, and wherein the optional substituents are selected from OH, NH2, NO2, halogen, C1-C6 alkyl and / or C1-C6 alkoxy; or

[0229] Selected from:

[0230]

[0231] optionally modified with one, more than one, or a combination of: halogen, OMe, SMe, NH2, NO2, CN, OH, or one or more additional endocyclic nitrogen atoms;

[0232] R 7 YesR X -(Xaa 2 ) 0-4 -、

[0233] R 28 It is an albumin binder;

[0234] XA 2 and Xaa 3 , when present, is independently -N(R 13 )R 14 C(O)-, where each R 13 are independently hydrogen or methyl, and wherein each R 14 are independently: linear or branched, cyclic or acyclic and / or aromatic or non-aromatic C1-C 20 Alkylene, alkenylene or alkynylene; or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 20 heteroalkylene, heteroalkenylene, or heteroalkynylene; and

[0235] Each R X is a radiolabeling group independently selected from the following: a radiometal chelator optionally bound by a radiometal; an aryl or heteroaryl group substituted with a radiohalogen; a prosthetic group containing a trifluoroborate; a prosthetic group containing a silicon-fluorine-acceptor moiety; or a prosthetic group containing a fluorophosphate, a fluorosulfate, a sulfonyl fluoride or a combination thereof.

[0236] In some embodiments, the compound of Formula II is a compound of Formula IIa:

[0237]

[0238] Where R 1a , R 1b , R1c , R 2 , R 3 , R 4 , R 5 , R 6 , Xaa 1 and R 7 As defined for Formula II. In some embodiments, the compound is a salt or solvate of Formula IIa.

[0239] In some embodiments, R 2 is -CH2-. In some embodiments, R 2 is -CH(OH)-. In some embodiments, R 2 is -CHF-. In some embodiments, R 2 is -CF2-. In some embodiments, R 2 is -CH(CH3)-. In some embodiments, R 2 It is -C(CH3)2-.

[0240] In some embodiments, R 2 is -CH2CH(OH)-. In some embodiments, R 2 is -CH2CHF-. In some embodiments, R 2 is -CHFCH2-. In some embodiments, R 2 is -CF2CH2-. In some embodiments, R 2 is -CH2CF2-. In some embodiments, R 2 is -CH(OH)CH2-. In some embodiments, R 2 is -CH(CH3)CH2-. In some embodiments, R 2 is -CH2CH(CH3)-. In some embodiments, R 2 is -C(CH3)2CH2-. In some embodiments, R 2 It is -CH2C(CH3)2-.

[0241] In some embodiments, R 2is -CH2-, -CH(OH)-, -CHF-, -CF2-, -CH(CH3)-, -C(CH3)2-, -CH2CH(OH)-, -CH2CHF-, -CHFCH2-, -CF2CH2–, –CH2CF2–, –CH(OH)CH2–, –CH(CH3)CH2–, –CH2CH(CH3)–, –C(CH3)2CH2–, –CH2C(CH3)2–, –CH2CH(OH)CH2–, –CH2CHFCH2–, –(CH2)2CH(OH)–, –(CH2)2CHF–, –(CH2)3–, –CH2OCH2–, –CH2SCH2–, –CHFCH2CH2–, –CH(OH)CH2CH2–, –CH(CH3)CH2CH2–, –CH2CH(CH3)CH2–, –CH2CH2CH(CH3)–, –C(CH3)2CH2CH2–, –CH2C(CH3)2CH2–, –CH2CH2C(CH3)2–, –CH(CH3)–O–CH2–, –C(CH3)2–O–CH2–, –CH2–O–CH(CH3)–, –CH2–O–C(CH3)2–, –CH2–S(O)–CH2–, –CH2–S(O)2–CH2–, –CH(CH3)–S–CH2–, –C(CH3)2–S–CH2–, –CH2–S–CH(CH3)–, –CH2–S–C(CH3)2–, –CH(CH3)–S(O)–CH2–, –C(CH3)2–S(O)–CH2–, –CH2–S(O)–CH(CH3)–, –CH2–S(O)–C(CH3)2–, –CH(CH3)–S(O)2–CH2–, –C(CH3)2–S(O)2–CH2–, –CH2–S(O)2–CH(CH3)–, –CH2–S(O)2–C(CH3)2–, –C(O)–NH–CH2–, –C(O)–NH–CH(CH3)– or –C(O)–NH–C(CH3)2–.

[0242] In some embodiments, R 2are –CH2CH(OH)CH2–, –CH2CHFCH2–, –(CH2)2CH(OH)–, –(CH2)2CHF–, –(CH2)3–, –CH2OCH2–, –CH 2SCH2–, –CHFCH2CH2–, –CH(OH)CH2CH2–, –CH(CH3)CH2CH2–, –CH2CH(CH3)CH2–, –CH2CH2CH(CH 3)–, –C(CH3)2CH2CH2–, –CH2C(CH3)2CH2–, –CH2CH2C(CH3)2–, –CH(CH3)–O–CH2–, –C(CH3)2– O–CH2–, –CH2–O–CH(CH3)–, –CH2–O–C(CH3)2–, –CH2–S(O)–CH2–, –CH2–S(O)2–CH2–, –CH(CH3) –S–CH2–, –C(CH3)2–S–CH2–, –CH2–S–CH(CH3)–, –CH2–S–C(CH3)2–, –CH(CH3)–S(O)–CH2–, –C (CH3)2–S(O)–CH2–, –CH2–S(O)–CH(CH3)–, –CH2–S(O)–C(CH3)2–, –CH(CH3)–S(O)2–CH2–, –C( In some embodiments, R 2 It is –CH2OCH2– or –CH2SCH2–.

[0243] In some embodiments, R 2are –CH2–, –CH(OH)–, –CHF–, –CF2–, –CH(CH3)–, –C(CH3)2–, –CHFCH2–, –CF2CH2–, –CH(OH)CH2–, –CH(CH3)CH2–, –C(CH3)2CH2–, –(CH2)2CH(OH)–, –(CH2)2CHF–, –(CH2)3–, –CH2OCH2–, –CH2SCH 2–, –CHFCH2CH2–, –CH(OH)CH2CH2–, –CH(CH3)CH2CH2–, –CH2CH2CH(CH3)–, –C(CH3)2CH2CH2–, – CH2CH2C(CH3)2–, –CH(CH3)–O–CH2–, –C(CH3)2–O–CH2–, –CH2–O–CH(CH3)–, –CH2–O–C(CH3)2–, –CH2–S(O)–CH2–, –CH2–S(O)2–CH2–, –CH(CH3)–S–CH2–, –C(CH3)2–S–CH2–, –CH2–S–CH(CH3)– , –CH2–S–C(CH3)2–, –CH(CH3)–S(O)–CH2–, –C(CH3)2–S(O)–CH2–, –CH2–S(O)–CH(CH3)–, –CH2– S(O)–C(CH3)2–, –CH(CH3)–S(O)2–CH2–, –C(CH3)2–S(O)2–CH2–, –CH2–S(O)2–CH(CH3)–, –CH2– S(O)2–C(CH3)2–, –CH2–NH–C(O)–, –C(O)–NH–CH2–, –C(O)–NH–CH(CH3)–, or –C(O)–NH–C(CH3)2–.

[0244] In some embodiments, R 2are –(CH2)2CHF–, –(CH2)3–, –CH2OCH2–, –CH2SCH2–, –CHFCH2CH2–, –CH(OH)CH2CH2–, –CH(CH3)CH2CH2–, CH2CH2CH(CH3)–, –C(CH3)2CH2CH2–, –CH2CH2C (CH3)2–, –CH(CH3)–O–CH2–, –C(CH3)2–O–CH2–, –CH2–O–CH(CH3)–, –CH2–O–C(CH3)2–, –CH2–S(O)–CH2–, –CH2–S(O)2–CH2–, –CH(CH3)–S–CH2–, –C(CH 3)2–S–CH2–, –CH2–S–CH(CH3)–, –CH2–S–C(CH3)2–, –CH(CH3)–S(O)–CH2–, –C(CH3)2–S(O)–CH2–, –CH2–S(O)–CH(CH3)–, –CH2–S(O)–C(CH3)2–, –CH(C H3)–S(O)2–CH2–, –C(CH3)2–S(O)2–CH2–, –CH2–S(O)2–CH(CH3)–, –CH2–S(O)2–C(CH3)2–, –C(O)–NH–CH2–, –C(O)–NH–CH(CH3)–, or –C(O)–NH–C(CH3)2–.

[0245] In some embodiments, R 2 is –CH2CH(OH)–, –CH2CHF–, –CH2CH(CH3)–, –CH2CH(COOH)–, –CH2CH(OH)CH2–, –CH2CH(F)CH2–, or –CH2CH(CH3)CH2–, where R 2 The second carbon in has an R-configuration. In some embodiments, R 2 is –CH2CH(OH)–, –CH2CHF–, or –CH2CH(CH3)–, where R 2 The second carbon in has an R-configuration. In some embodiments, R 2 is –CH2CHF–, where R 2 The second carbon in has the R-configuration.

[0246] In some embodiments, R 2 is -CH2CH(OH)CH2-. In some embodiments, R 2 is -CH2CHFCH2-. In some embodiments, R 2 is -(CH2)2CH(OH)-. In some embodiments, R 2is -(CH2)2CHF-. In some embodiments, R 2 is -(CH2)3-. In some embodiments, R 2 is -CH2OCH2-. In some embodiments, R 2 is -CH2SCH2-. In some embodiments, R 2 is -CHFCH2CH2-. In some embodiments, R 2 is -CH(OH)CH2CH2-. In some embodiments, R 2 is -CH(CH3)CH2CH2-. In some embodiments, R 2 is -CH2CH(CH3)CH2-. In some embodiments, R 2 is -CH2CH2CH(CH3)-. In some embodiments, R 2 is -C(CH3)2CH2CH2-. In some embodiments, R 2 is -CH2C(CH3)2CH2-. In some embodiments, R 2 is -CH2CH2C(CH3)2-. In some embodiments, R 2 is -CH(CH3)-O-CH2-. In some embodiments, R 2 is -C(CH3)2-O-CH2-. In some embodiments, R 2 is -CH2-O-CH(CH3)-. In some embodiments, R 2 is -CH2-O-C(CH3)2-. In some embodiments, R 2 is -CH2-S(O)-CH2-. In some embodiments, R 2 is -CH2-S(O)2-CH2-. In some embodiments, R 2 is -CH(CH3)-S-CH2-. In some embodiments, R 2 is -C(CH3)2-S-CH2-. In some embodiments, R 2 is -CH2-S-CH(CH3)-. In some embodiments, R 2 is -CH2-S-C(CH3)2-. In some embodiments, R 2 is -CH(CH3)-S(O)-CH2-. In some embodiments, R 2 is -C(CH3)2-S(O)-CH2-. In some embodiments, R 2 is -CH2-S(O)-CH(CH3)-. In some embodiments, R 2is -CH2-S(O)-C(CH3)2-. In some embodiments, R 2 is -CH(CH3)-S(O)2-CH2-. In some embodiments, R 2 is -C(CH3)2-S(O)2-CH2-. In some embodiments, R 2 is -CH2-S(O)2-CH(CH3)-. In some embodiments, R 2 is -CH2-S(O)2-C(CH3)2-. In some embodiments, R 2 is -CH2-NH-C(O)-. In some embodiments, R 2 is -C(O)-NH-CH2-. In some embodiments, R 2 is -C(O)-NH-CH(CH3)-. In some embodiments, R 2 It is –C(O)–NH–C(CH3)2–.

[0247] The following definitions apply to Formula III.

[0248] In some embodiments, the compound is a compound comprising a prostate specific membrane antigen (PSMA) targeting moiety of Formula III or a salt or solvate of Formula III:

[0249]

[0250] in:

[0251] R 0 is O or S;

[0252] R 1a is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -OPO3H2, -OSO3H, -B(OH)2 or

[0253] R 1b is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -B(OH)2 or

[0254] R 1c is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -B(OH)2 or

[0255] R 2is -CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-, -CH(CH3)-O-CH2-, -C (CH3)2-O-CH2-, -CH2-O-CH(CH3)-, -CH2-OC(CH3)2-, -CH2-S(O)-CH2-, -CH2-S(O)2-CH2-, -CH(CH3)-S-CH2-, -C(CH3)2-S-CH2-, -CH2-S-C H(CH3)-, -CH2-SC(CH3)2-, -CH(CH3)-S(O)-CH2-, -C(CH3)2-S(O)-CH2-, -CH2-S(O)-CH(CH3)-, -CH2-S(O)-C(CH3)2-, -CH(CH3)-S(O)2-C and

[0256] R 3 It's a connector.

[0257] In some embodiments, the PSMA targeting moiety of Formula III is a PSMA targeting moiety of Formula IIIa:

[0258]

[0259] Where R 1a , R 1b , R 1c , R 2 and R 3 As defined for Formula III. In some embodiments, the PSMA targeting moiety is a salt or solvate of Formula IIIa.

[0260] Connector (R 3 ) can be any linker. In some embodiments, R 3 It is a C1-C2- 20 alkylene, alkenylene or alkynylene, or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 20 In some embodiments, R 3 It is a C1-C2-20 Alkylene or alkenylene, or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 20 In some embodiments, R 3 It is a straight-chain or branched peptide linker.

[0261] In some embodiments, R 2 is -CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-, -CH( CH3)-O-CH2-, -C(CH3)2-O-CH2-, -CH2-O-CH(CH3)-, -CH2-OC(CH3)2-, -CH2-S(O)-CH2-, -CH2-S(O)2-CH2-, -CH(CH3)-S-C H2-, -C(CH3)2-S-CH2-, -CH2-S-CH(CH3)-, -CH2-SC(CH3)2-, -CH(CH3)-S(O)-CH2-, -C(CH3)2-S(O)-CH2-, -CH2-S(O)-CH( CH3)-, -CH2-S(O)-C(CH3)2-, -CH(CH3)-S(O)2-CH2-, -C(CH3)2-S(O)2-CH2-, -CH2-S(O)2-CH(CH3)- or -CH2-S(O)2-C(CH3) 2。

[0262] In some embodiments, R 2 is -CH(CH3)CH2CH2-. In some embodiments, R 2 is -CH2CH(CH3)CH2-. In some embodiments, R 2 is -CH2CH2CH(CH3)-. In some embodiments, R 2 is -C(CH3)2CH2CH2-. In some embodiments, R 2 is -CH2C(CH3)2CH2-. In some embodiments, R 2 is -CH2CH2C(CH3)2-. In some embodiments, R 2 is -CH(CH3)-O-CH2-. In some embodiments, R 2 is -C(CH3)2-O-CH2-. In some embodiments, R 2 is -CH2-O-CH(CH3)-. In some embodiments, R 2is -CH2-OC(CH3)2-. In some embodiments, R 2 is -CH2-S(O)-CH2-. In some embodiments, R 2 is -CH2-S(O)2-CH2-. In some embodiments, R 2 is -CH(CH3)-S-CH2-. In some embodiments, R 2 is -C(CH3)2-S-CH2-. In some embodiments, R 2 is -CH2-S-CH(CH3)-. In some embodiments, R 2 is -CH2-S-C(CH3)2-. In some embodiments, R 2 is -CH(CH3)-S(O)-CH2-. In some embodiments, R 2 is -C(CH3)2-S(O)-CH2-. In some embodiments, R 2 is -CH2-S(O)-CH(CH3)-. In some embodiments, R 2 is -CH2-S(O)-C(CH3)2-. In some embodiments, R 2 is -CH(CH3)-S(O)2-CH2-. In some embodiments, R 2 is -C(CH3)2-S(O)2-CH2-. In some embodiments, R 2 is -CH2-S(O)2-CH(CH3)-. In some embodiments, R 2 is -CH2-S(O)2-C(CH3)2-. In some embodiments, R 2 is -C(O)-NH-CH2-. In some embodiments, R 2 is -C(O)-NH-CH(CH3)-. In some embodiments, R 2 It is –C(O)–NH–C(CH3)2–.

[0263] In some embodiments, R 2 is –CH2CH(CH3)CH2–, where R 2 The second carbon in has the R-configuration.

[0264] In some embodiments, the compound further comprises one or more radiolabeling groups attached to the linker, which are independently selected from: a radiometal chelator optionally bound by a radiometal; an aryl or heteroaryl group substituted by a radiohalogen; a prosthetic group containing a trifluoroborate; or a prosthetic group containing a silicon-fluorine-acceptor moiety, a fluorophosphate, a fluorosulfate, or a sulfonyl fluoride. In some embodiments, the compound comprises a radiometal chelator. In some embodiments, the radiometal chelator is bound by a radiometal. In some embodiments, the compound comprises an aryl group substituted by a radiohalogen. In some embodiments, the compound comprises a prosthetic group containing a trifluoroborate. In some embodiments, the compound comprises a prosthetic group containing a silicon-fluorine-acceptor moiety. In some embodiments, the compound comprises a prosthetic group containing a fluorophosphate. In some embodiments, the compound comprises a prosthetic group containing a fluorosulfate. In some embodiments, the compound comprises a prosthetic group containing a sulfonyl fluoride. In some embodiments, the fluorine in the aforementioned groups is 18 F.

[0265] In some embodiments, the one or more radiolabeling groups include: a radiometal chelator, optionally bound by a radiometal; and a prosthetic group comprising a trifluoroborate, optionally wherein 1, 2, or 3 fluorines in the trifluoroborate are 18 F.

[0266] In some embodiments, the compound comprising the PSMA targeting moiety of Formula III is a compound of Formula II (or Formula IIa) or a salt or solvate of Formula II (or Formula IIa), wherein R 2are –CH(CH3)CH2CH2–, –CH2CH(CH3)CH2–, –CH2CH2CH(CH3)–, –C(CH3)2CH2CH2–, –CH2C(CH3)2CH2–, –CH2CH2C(CH3)2–, –CH(CH3)–O–CH2–, –C (CH3)2–O–CH2–, –CH2–O–CH(CH3)–, –CH2–O–C(CH3)2–, –CH2–S(O)–CH2–, –CH2–S(O)2–CH2–, –CH(CH3)–S–CH2–, –C(CH3)2–S–CH2–, –CH2–S– CH(CH3)–, –CH2–S–C(CH3)2–, –CH(CH3)–S(O)–CH2–, –C(CH3)2–S(O)–CH2–, –CH2–S(O)–CH(CH3)–, –CH2–S(O)–C(CH3)2–, –CH(CH3)–S(O)2 –CH2–, –C(CH3)2–S(O)2–CH2–, –CH2–S(O)2–CH(CH3)–, –CH2–S(O)2–C(CH3)2–, –C(O)–NH–CH2–, –C(O)–NH–CH(CH3)–, or –C(O)–NH–C(CH3)2–.

[0267] Unless otherwise indicated, the following definitions apply to any compound of Formula II / IIa (or salts / solvates thereof) and any compound comprising a PSMA targeting moiety of Formula III / IIIa (or salts / solvates thereof). Thus, the following definitions apply to compounds comprising a PSMA targeting moiety of Formula III / IIIa, including but not necessarily limited to when such compound is a compound of Formula II / IIa.

[0268] In some embodiments, R 0 is O. In other embodiments, R 0 It’s S.

[0269] In some embodiments, R 1a is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -OPO3H2, or -OSO3H. In some embodiments, R 2a is -CO2H, -SO2H, -SO3H, -PO2H or -PO3H2. In some embodiments, R 3a is -CO2H, -SO2H, -SO3H, -PO2H or -PO3H2. In some embodiments, R 1a is -CO2H. In some embodiments, R 1b is -CO2H. In some embodiments, R 1cis -CO2H. In some embodiments, R 1a and R 1b Each is -CO2H. In some embodiments, R 1a and R 1c Each is -CO2H. In some embodiments, R 1b and R 1c Each is -CO2H. In some embodiments, R 1a , R 1b and R 1c Each is -CO2H. In some embodiments, R 1a , R 1b and R 1c It is the aforementioned anion or metal salt.

[0270] In some embodiments, R 3 It is a C1-C2- 20 Alkylene or alkenylene, or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 20 heteroalkylene or heteroalkenylene.

[0271] In some embodiments, R 3 It is a straight-chain non-cyclic C3-C 15 In some embodiments, R 3 It is a straight-chain non-cyclic C3-C 15 Alkylene, wherein 1-5 carbons are replaced by N, S and / or O heteroatoms. In some embodiments, R 3 It is a straight chain non-cyclic saturated C3-C 10 alkylene, optionally substituted with 1-5 amino, amide, oxo, hydroxyl, thiol, methyl or ethyl groups. 3 Yes - (CH2) 3-15 -. In some embodiments, R 3 is -CH2-. In some embodiments, R 3 is -(CH2)2-. In some embodiments, R 3 is -(CH2)3-. In some embodiments, R 3 is -(CH2)4-. In some embodiments, R 3 is -(CH2)5-. In some embodiments, R 3 is -CH2-O-CH2-. In some embodiments, R 3 is -CH2-S-CH2-. In some embodiments, R 3 is -CH=CH-. In some embodiments, R 3is -CH2-C≡C-. In some embodiments, R 3 It is a straight chain C3-C5 alkenylene and / or alkynylene group.

[0272] In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 is -NHC(O)-. In some embodiments, R 4 is -C(O)NH-. In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 is -S(O)-. In some embodiments, R 4 is -S(O)2-. In some embodiments, R 4 is -C(O)-(NH)2-C(O)-. In some embodiments, R 4 is -OC(O)NH-. In some embodiments, R 4 is -NHC(O)C-. In some embodiments, R 4 is -NHC(O)NH-. In some embodiments, R 4 is -OC(S)NH. In some embodiments, R 4 is -NHC(S)O-. In some embodiments, R 4 is -NHC(S)NH-. In some embodiments, R 4 is -NHC(O)C(O)NH-. In some embodiments, R 4 In some embodiments, R 4 is -S-CH2-S-. In some embodiments, R 4 is -NH-NH-C(O)-. In some embodiments, R 4 is or -C(O)-NH-NH-.

[0273] In some embodiments, R 3 Yes - (CH2) 3-15 - and R 4 is -C(O)NH-. In some embodiments, R 3 Yes - (CH2) 3-5 - and R 4 is -C(O)NH-. In some embodiments, R 3 is -(CH2)4- and R 4 It is -C(O)NH-.

[0274] In some embodiments, R 5 Yes - (CH2) 0-3 CH(R 10 )(CH2) 0-3 -. In some embodiments, R 5 Yes -CH(R 10 )-. In some embodiments, R 5 It is -CH2CH(R 10 )-. In some embodiments, R 5 Yes -CH(R 10 )CH2-. In some embodiments, R 5 Yes -CH(R 10 )-.

[0275] In some embodiments, R 10 It is a C2-C3 straight chain or branched, cyclic or acyclic and / or aromatic or non-aromatic 19 alkyl, alkenyl or alkynyl; linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X3 having only 1 to 3 heteroatoms 19 heteroalkyl, heteroalkenyl or heteroalkynyl.

[0276] In some embodiments, R 10 Yes-CH2R 23 , where R 23 is an optionally substituted C4-C 16 An aromatic ring or a partially or fully aromatic fused ring system, wherein 0-3 carbons in the aromatic ring or the partially or fully aromatic fused ring system are replaced by N, S and / or O heteroatoms, and wherein the optional substitution is selected from OH, NH2, NO2, halogen, C1-C6 alkyl and / or C1-C6 alkoxy.

[0277] In some embodiments, R 10 yes

[0278] Optionally modified with one, more than one or a combination of: halogen, OMe, SMe, NH2, NO2, CN, OH or one or more additional endocyclic nitrogen atoms.

[0279] In some embodiments, R 10 Contains C6-C 16 Aryl or X6-X having 1-3 heteroatoms independently selected from N, S and / or O 16 In some embodiments, C6-C 16 Aryl is benzyl. In some embodiments, X6-X 16 Heteroaryl is benzyloxy or benzylthio.

[0280] In some embodiments, R 10 yes:

[0281] In some embodiments, R 10 yes In some embodiments, R 10 yes In some embodiments, R 10 yes In some embodiments, R 10 yes In some embodiments, R 10 yes In some embodiments, R 10 yes In some embodiments, R 10 yes In some embodiments, R 10 yes In some embodiments, R 10 yes In some embodiments, R 10 yes In some embodiments, R 10 yes In some embodiments, R 10 yes In some embodiments, R 10 yes In some embodiments, R 10 yes In some embodiments, R 10 yes In some embodiments, R 10 Yes. In some embodiments, R 10 yes In some embodiments, R 10 yes In some embodiments, R 10 yes: In some embodiments, R 10 yes

[0282] In some embodiments, R 5 Yes -CH(R 10 )-, where R 10 As defined in any of the above embodiments.

[0283] In some embodiments, R 5 Yes - (CH2) 0-3CH(R 10 )(CH2) 0-3 - and R 10 is -(CH2)5CH3. In some embodiments, R 5 Yes -CH(R 10 )-and R 10 is -(CH2)5CH3. In some embodiments, R 5 Yes - (CH2) 0-3 CH(R 10 )(CH2) 0-3 -.

[0284] In some embodiments, R 10 Yes-CH 2 -R 23 In some embodiments, R 23 is phenyl substituted by 1 or 2 iodo groups and optionally further substituted by 1 oxo group. 5 Yes - (CH2) 0-3 CH(R 10 )(CH2) 0-3 -, where R 10 Yes-CH2R 23 And R 23 is phenyl substituted by 1 or 2 iodo groups and optionally further substituted by 1 oxo group. 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes In some embodiments, R 23 yes

[0285] In some embodiments, at least one R 9 or R 5 yes In some embodiments, at least one R 9 or R 5 yes In some embodiments, at least one R 9 or R 5 yes

[0286] In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes

[0287] In some embodiments, R 6 is hydrogen. In some embodiments, R 6 In some embodiments, R 6 It is ethyl.

[0288] In some embodiments, (Xaa 1 ) 1-4 In some embodiments, (Xaa 1 ) 1-4 is a dipeptide in which each Xaa 1 Can be the same or different. In some embodiments, (Xaa 1 ) 1-4 is a tripeptide in which each Xaa 1 Can be the same, different or a combination thereof. In some embodiments, (Xaa 1 ) 1-4 It is composed of four amino acid residues linked by peptide bonds, each of which is Xaa 1 Can be the same, different or a combination thereof. In some embodiments, each Xaa 1 Independently selected from the proteinogenic amino acids and non-proteinogenic amino acids listed in Table 1, wherein each peptide backbone amino group is optionally methylated.

[0289] In some embodiments, at least one R 9 YesR 24 -R 25 -R 26 , where R 24 -R 25 -R 26 Independently selected from: -(CH2) 0-3 -; C3-C8 cycloalkylene, wherein 0-3 carbons are replaced by N, S or O heteroatoms, and optionally substituted by one or more OH, NH2, NO2, halogen, C1-C6 alkyl and / or C1-C6 alkoxy; and C4-C 16 Arylene, wherein 0-3 carbons are replaced by N, S or O heteroatoms, and optionally substituted by one or more OH, NH2, NO2, halogen, C1-C6 alkyl and / or C1-C6 alkoxy. In some embodiments, (Xaa 1 )1-4 Yes(Xaa 1 ) 0-3 NHR 27 C(O), where R 27 yes In some embodiments, at least one R 9 yes In some embodiments, at least one R 9 yes In some embodiments, at least one R 9 yes In some embodiments, at least one R 8 is hydrogen. In some embodiments, all R 8 In some embodiments, at least one Xaa 1 is a tranexamic acid residue. In some embodiments, (Xaa 1 ) 1-4 It is composed of a single tranexamic acid residue.

[0290] In some embodiments, R 3 is -(CH2)4- and -(Xaa 1 ) 1-4 N(R 6 )R 5 R 4 -yes Wherein, in an alternative embodiment, R 10 is any R defined above 10 In some embodiments, R 10 Yes-CH 2 -R 23 And R 23 is phenyl substituted by 1 or 2 iodo groups and optionally further substituted by 1 oxo group.

[0291] In some embodiments, R 3 is -(CH2)4- and -(Xaa 1 ) 1-4 N(R 6 )R 5 R 4 -yes Wherein, in an alternative embodiment, R 10 is any R defined above 10 In some embodiments, R 10 Yes-CH 2 -R 23 And R 23 is phenyl substituted by 1 or 2 iodo groups and optionally further substituted by 1 oxo group.

[0292] Unless otherwise indicated, the following definitions apply to any applicable compound of Formula I / Ia (or salts / solvates thereof), all compounds of Formula II / IIa (or salts / solvates thereof), and compounds comprising a PSMA targeting moiety of Formula III / IIIa (or salts / solvates thereof). Accordingly, the following definitions apply to compounds comprising a PSMA targeting moiety of Formula III / IIIa, including but not necessarily limited to when such compound is a compound of Formula II / IIa.

[0293] R 7 A radiolabeling group may be included, optionally separated by an amino acid or peptide linker. Thus, in some embodiments, R 7 YesR X -(Xaa 2 ) 0-4 -, where R X Bonded to N-terminal Xaa capable of forming an amide bond 2 N-terminal or Xaa 2 The amino acid group (e.g., the side chain of an α amino acid) can be X Xaa forming amide bond 2 An example of a side chain is an amino group. X Non-limiting examples of amino acid residues that form amides include Lys, Orn, Dab, Dap, Arg, homo-Arg, etc. In some embodiments, R X Bonded to N-terminal Xaa 2 In other embodiments, Xaa 2 does not exist.

[0294] In some embodiments, R 7 Two radiolabeling groups may be included, wherein the amino acid or peptide linker provides two attachment points for the radiolabeling groups. 7 yes For example, the first R X Can be bonded to N-terminal Xaa 2 The N-terminus and the second R X Can bond to Xaa 2 Alternatively, two R X The group can be bonded to different Xaa 2 Side chains or other functional groups.

[0295] R 7 Both a radiolabeling group and an albumin binding group may be included.

[0296] Therefore, in a case with a single R X In some embodiments of the group, R7 yes When (Xaa 2 ) 0-4 Yes(Xaa 2 ) 1-4 When R X Bonded to N-terminal Xaa capable of forming an amide bond 2 N-terminal or Xaa 2 The amino group (e.g., the side chain of an α-amino acid), and wherein (Xaa 3 ) 0-4 Yes(Xaa 3 ) 1-4 When (Xaa 3 ) 1-4 is oriented to form amide bonds with adjacent carbonyl and amino groups. X In other embodiments of the group, R 7 yes When (Xaa 2 ) 0-4 Yes(Xaa 2 ) 1-4 When R X Bonded to N-terminal Xaa capable of forming an amide bond 2 N-terminal or Xaa 2 The amino group (e.g., the side chain of an α-amino acid), and wherein (Xaa 3 ) 0-4 Yes(Xaa 3 ) 1-4 When (Xaa 3 ) 1-4 is oriented to form amide bonds with adjacent carbonyl and amino groups.

[0297] The albumin binding group R 28 Any albumin binding group may be used.

[0298] In some embodiments, the albumin binding group R 28 yes

[0299] In some embodiments, the albumin binding group R 28 yes

[0300] In some embodiments, the albumin binding group R 28 yes Where R 12 It is I, Br, F, Cl, H, OH, OCH3, NH2, NO2 or CH3.

[0301] In some embodiments, R 7yes When (Xaa 2 ) 0-4 Yes(Xaa 2 ) 1-4 When R X Bonded to N-terminal Xaa capable of forming an amide bond 2 N-terminal or Xaa 2 The amino group (such as the side chain of an α amino acid).

[0302] In other embodiments, R 7 yes When (Xaa 2 ) 0-4 Yes(Xaa 2 ) 1-4 When R X Bonded to N-terminal Xaa capable of forming an amide bond 2 N-terminal or Xaa 2 The amino group (such as the side chain of an α amino acid).

[0303] In other embodiments, R 7 yes When (Xaa 2 ) 0-4 Yes(Xaa 2 ) 1-4 When R X Bonded to N-terminal Xaa capable of forming an amide bond 2 N-terminal or Xaa 2 The amino group (such as the side chain of an α amino acid).

[0304] In some embodiments, R 11 In some embodiments, R 11 yes In some embodiments, R 11 yes In some embodiments, R 11 yes In some embodiments, R 11 yes In some embodiments, R 11 yes In some embodiments, R 11 yes In some embodiments, R 11 yes In some embodiments, R 11 yes In some embodiments, R 11 yes

[0305] In some embodiments, R 12 In some embodiments, R 12 In some embodiments, R 12 In some embodiments, R 12 is iodine. In some embodiments, R 12 In some embodiments, R 12 In some embodiments, R 12 is hydrogen. In some embodiments, R 12 is hydroxide. In some embodiments, R 12 is OCH3. In some embodiments, R 12 is NH2. In some embodiments, R 12 is NO2. In some embodiments, R 12 is CH3. In some embodiments, R 12 is para-CH3. In some embodiments, R 12 In some embodiments, R 12 In some embodiments, R 12 It is para-OCH3.

[0306] In some embodiments, Xaa 2 In some embodiments, (Xaa 2 ) 0-4 Is a single amino acid residue. In some embodiments, (Xaa 2 ) 0-4 is a dipeptide in which each Xaa 2 Can be the same or different. In some embodiments, (Xaa 2 ) 0-4 is a tripeptide in which each Xaa 2 Can be the same, different or a combination thereof. In some embodiments, (Xaa 2 ) 0-4 It is composed of four amino acid residues linked by peptide bonds, each of which is Xaa 2 Can be the same, different or a combination thereof. In some embodiments, each Xaa 2 is independently selected from the proteinogenic amino acids and non-proteinogenic amino acids listed in Table 1, wherein each peptide backbone amino group is optionally methylated. 2 ) 1-4 Each R in 13 is hydrogen. In some embodiments, (Xaa 2 ) 1-4 At least one R13 In some embodiments, (Xaa 2 ) 1-4 At least one R 14 is -(CH2)2[O(CH2)2] 1-6 -(For example, when Xaa 2 It is amino-dPEG TM 4-Acid or amino-dPEG TM 6-acid residue).

[0307] In some embodiments, Xaa 3 In some embodiments, (Xaa 3 ) 0-4 Is a single amino acid residue. In some embodiments, (Xaa 3 ) 0-4 is a dipeptide in which each Xaa 3 Can be the same or different. In some embodiments, (Xaa 3 ) 0-4 is a tripeptide in which each Xaa 3 Can be the same, different or a combination thereof. In some embodiments, (Xaa 3 ) 0-4 It is composed of four amino acid residues linked by peptide bonds, each of which is Xaa 3 Can be the same, different or a combination thereof. In some embodiments, each Xaa 3 is independently selected from the proteinogenic amino acids and non-proteinogenic amino acids listed in Table 1, wherein each peptide backbone amino group is optionally methylated. 3 ) 1-4 Each R in 13 is hydrogen. In some embodiments, (Xaa 3 ) 1-4 At least one R 13 In some embodiments, (Xaa 3 ) 1-4 At least one R 14 is -(CH2)2[O(CH2)2] 1-6 -(For example, when Xaa 3 It is amino-dPEG TM 4-Acid or amino-dPEG TM 6-acid residue).

[0308] In some embodiments, one or more R XA radiometal chelator optionally bound by a radiometal is included. The radiometal chelator can be any radiometal chelator suitable for binding to a radiometal and functionalized to attach to an amino group. Many suitable radiometal chelators are known, for example as summarized in Price and Orvig, Chem. Soc. Rev., 2014, 43, 260-290, which is incorporated by reference in its entirety. Non-limiting examples of radioisotope chelators include chelators selected from the group consisting of DOTA and derivatives; DOTAGA; NOTA; NODAGA; NODASA; CB-DO2A; 3p-C-DEPA; TCMC; DO3A; DTPA and DTPA analogs optionally selected from CHX-A"-DTPA and 1B4M-DTPA; TETA; NOPO; Me-3,2-HOPO; CB-TE1A1P; CB-TE2P; MM-TE2A; DM-TE2A; macrocyclic sarcophagus and macrocyclic sarcophagus optionally selected from SarAr, SarAr-NCS, diamSar, AmBaSar and BaBaSar. Cyclosarcophagus derivatives; TRAP; AAZTA; DATA and DATA derivatives; H2-macropa or its derivatives; H2dedpa, H4octapa, H4py4pa, H4Pypa, H2azapa, H5decapa and other picolinic acid derivatives; CP256; PCTA; C-NETA; C-NE3TA; HBED; SHBED; BCPA; CP256; YM103; deferoxamine (DFO) and DFO derivatives; and H6phospa. Exemplary non-limiting examples of radioisotope chelators and exemplary radioisotopes chelated by these chelators are shown in Table 2. In alternative embodiments, R X A radioisotope chelator selected from those listed above or in Table 2, or any other radioisotope chelator, may be included. One skilled in the art may substitute another chelator for any of the chelators listed herein.

[0309] Table 2: Exemplary chelators and exemplary isotopes that bind to the chelators

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316] In some embodiments, the radioisotope chelator is conjugated to a radioisotope. The conjugated radioisotope can be, but is not limited to 68 Ga, 61 Cu, 64 Cu, 67 Ga, 99m Tc, 111 In, 44 Sc, 86 Y. 89 Zr, 90 Nb, 177 Lu, 117m Sn, 165 2. 90 Y. 227 Th, 225 Ac, 213 Bi, 212 Bi, 211 As, 203 Pb, 212 Pb, 47 Sc, 166 Ho, 188 Re, 186 Re, 149 Pm, 159 Gd, 105 Rh, 109 Pd, 198 Au, 199 Au, 175 Yb, 142 Pr, 114m In et al. In some embodiments, the chelator is a chelator from Table 2 and the conjugated radioisotope is the radioisotope of the binding agent indicated in Table 2 as a chelator.

[0317] In some embodiments, the radioisotope chelator is not conjugated to a radioisotope.

[0318] In some embodiments, the chelating agent is: 177 Lu, 111 In, 213 Bi, 68 Ga, 67 Ga, 203 Pb, 212 Pb, 44 Sc, 47 Sc, 90 Y. 86 Y. 225 Ac, 117m Sn, 153 Sm,149 Tb, 161 Tb, 165 2. 213 Bi, 224 Ra, 212 Bi, 227 Th, 223 Ra, 64 Cu or 67 Cu-conjugated DOTA or its derivatives; and 225 Ac-conjugated H2-MACROPA; 227 Th-conjugated Me-3,2-HOPO; 225 Ac, 227 Th or 177 Lu-conjugated H4py4pa; 177 Lu-conjugated H4pypa; 68 Ga-conjugated NODAGA; with 111 In-conjugated DTPA; or 89 Zr-conjugated DFO.

[0319] In some embodiments, the chelating agent is TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid), SarAr (1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]-eicosane-1,8-diamine), NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid), TRAP (1,4,7-triazacyclononane-1,4,7-tris[methyl(2-carboxyethyl)phosphinic acid), HBED (N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]-eicosane-1,8-diamine), ,N0-bis(2-hydroxybenzyl)-ethylenediamine-N,N0-diacetic acid), 2,3-HOPO (3-hydroxypyridin-2-one), PCTA (3,6,9,15-tetraazabicyclo[9.3.1]-pentadecan-1(15),11,13-triene-3,6,9,-triacetic acid), DFO (deferoxamine), DTPA (diethylenetriaminepentaacetic acid), OCTAPA (N,N0-bis(6-carboxy-2-pyridylmethyl)-ethylenediamine-N,N0-diacetic acid) or another picolinic acid derivative.

[0320] One or more R X Can be included for use 99m Tc, 94m Tc, 186 Re or 188 Re radiolabeled chelators such as mercaptoacetyl, hydrazinonicotinamide, dimercaptosuccinic acid, 1,2-ethylenediylbis-L-cysteine ​​diethyl ester, methylenediphosphonate, hexamethylpropyleneamine oxime and hexa(methoxyisobutylisonitrile). In some embodiments, one or more RX The invention also includes a chelating agent, wherein the chelating agent is mercaptoacetyl, hydrazinonicotinamide, dimercaptosuccinic acid, 1,2-ethylenediylbis-L-cysteine ​​diethyl ester, methylenediphosphonate, hexamethylpropyleneamine oxime or hexa(methoxyisobutylisonitrile). In some of these embodiments, the chelating agent is bound by a radioactive isotope. In some such embodiments, the radioactive isotope is 99m Tc, 94m Tc, 186 Re or 188 Re.

[0321] One or more R X Can include Can be combined 18 F-aluminum fluoride ([ 18 F]AlF) chelating agent, such as 1,4,7-triazacyclononane-1,4-diacetate (NODA) and the like. In some embodiments, the chelating agent is NODA. In some embodiments, the chelating agent is [ 18 F]AlF combination.

[0322] One or more R X Can include Can be combined 72 As or 77 In some embodiments, the chelating agent is a trithiol chelate. In some embodiments, the chelating agent is a trithiol chelate. 72 As conjugation. In some embodiments, the chelating agent is 77 As conjugation.

[0323] One or more R X Can contain aryl groups substituted with radioactive isotopes. In some embodiments, one or more R X yes wherein A, B, C, D and E are independently C or N, and R 15 is a radioactive halogen. In some embodiments, one or more R X yes In some embodiments, one or more R X yes In some embodiments, one or more R X yes In some embodiments, one or more R X yes In some embodiments, one or more R X yes In some embodiments, one or more R X yes In some embodiments, one or more R X yes In some embodiments, one or more R X yes In some of these embodiments, R 15 Independently 211 At 131 I. 124 I. 123 I. 77 Br or 18 F. In some of these embodiments, R 15 yes 18 F.

[0324] In some embodiments, one or more R X May contain a trifluoroborate (BF3)-containing auxiliary group, capable of 18 F / 19 In such embodiments, one or more R X It can be R 16 R 17 BF3, where each R 16 Independently And R 18 does not exist, Each-R 17 BF3 can be independently selected from Table 3 (below), Table 4 (below) or One or a combination of those listed in 19 and R 20 is independently a C1-C5 straight or branched alkyl. For Tables 3 and 4, R in the pyridine substituted with -OR, -SR, -NR-, -NHR or -NR2 groups is a C1-C5 branched or straight alkyl. In some embodiments, one or more -R 17 BF3 is independently selected from one or a combination of those listed in Table 3. In some embodiments, one or more -R 17 BF3 is independently selected from one or a combination of those listed in Table 4. In some embodiments, one fluorine is 18 F. In some embodiments, all three fluorines are 19 F.

[0325] Table 3: Exemplary R 17 BF3 group.

[0326]

[0327]

[0328] Table 4: Exemplary R 17 BF3 group.

[0329]

[0330]

[0331] In some embodiments, R 17 BF3 can form

[0332]

[0333] Wherein R (when present) in the pyridine substituted by -OR, -SR, -NR-, -NHR or -NR2 is a branched or straight chain C1-C5 alkyl. In some embodiments, R is a branched or straight chain C1-C5 saturated alkyl. In some embodiments, R is methyl. In some embodiments, R is ethyl. In some embodiments, R is propyl. In some embodiments, R is isopropyl. In some embodiments, R is n-butyl. In some embodiments, one fluorine is 18 F. In some embodiments, all three fluorines are 19 F.

[0334] In some embodiments, R 17 BF3 can form

[0335]

[0336] Wherein R (when present) in the pyridine substituted by -OR, -SR, -NR- or -NR2 is a branched or straight chain C1-C5 alkyl. In some embodiments, R is a branched or straight chain C1-C5 saturated alkyl. In some embodiments, R is methyl. In some embodiments, R is ethyl. In some embodiments, R is propyl. In some embodiments, R is isopropyl. In some embodiments, R is n-butyl. In some embodiments, one or more -R 17 BF3 is In some embodiments, one fluorine is 18 F. In some embodiments, all three fluorines are 19 F.

[0337] In some embodiments, one or more -R 17 BF3 is In some embodiments, R 19 In some embodiments, R 19 In some embodiments, R19 In some embodiments, R 19 In some embodiments, R 19 In some embodiments, R 19 In some embodiments, R 19 In some embodiments, R 20 In some embodiments, R 20 In some embodiments, R 20 In some embodiments, R 20 In some embodiments, R 20 In some embodiments, R 20 In some embodiments, R 20 In some embodiments, R 19 and R 20 In some embodiments, one fluoro is 18 F. In some embodiments, all three fluorines are 19 F.

[0338] In some embodiments, one or more R X A prosthetic group containing a silicon-fluorine-acceptor moiety may be included. In some embodiments, the fluorine of the silicon-fluorine acceptor moiety is 18 F. The auxiliary group comprising the silicon-fluorine-acceptor moiety can be independently selected from one or a combination of the following: Where R 21 and R 22 are independently linear or branched, cyclic or acyclic and / or aromatic or non-aromatic C1-C 10 In some embodiments, R 21 and R 22 is independently selected from the group consisting of phenyl, tert-butyl, secondary propyl or methyl. In some embodiments, the auxiliary group is In some embodiments, the prosthetic group is In some embodiments, the prosthetic group is In some embodiments, the prosthetic group is

[0339] In some embodiments, one or more R X In some embodiments, one or more R X Contains a prosthetic group containing a fluorosulfate. In some embodiments, one or more R XA prosthetic group containing sulfonyl fluoride is included. Such prosthetic groups are well known and commercially available and are easily attached (e.g., via an amide linkage). In some embodiments, the fluorine atom in the fluorophosphate, fluorosulfate, or sulfonyl fluoride is 18 F. In some embodiments, the fluorine atom in the fluorophosphate, fluorosulfate, or sulfonyl fluoride is 19 F.

[0340] Certain doubly labeled compounds (i.e., when R 7 Contains two R X When the group has only a single radioactive atom. For example, but not limited to, one R X Groups can be 18 F mark and another R X A group may contain only 19 F, or another R X The group may include a chelator that does not chelate to a radioactive metal or chelates to a metal that is not a radioisotope. In another non-limiting example, one R X The group may contain an aryl group substituted with a radioisotope, and another R X A group may contain only 19 F, or another R X The group may include a chelator that does not chelate to a radioactive metal or chelates to a metal that is not a radioisotope. X The group may comprise a chelator conjugated to a radioisotope and another R X A group may contain only 19 F.

[0341] In some embodiments, R 7 Contains the first R X Group and second R X A group in which the first R X The group is a radiometal chelator optionally bound by a radiometal and the second R X The group is a trifluoroborate containing prosthetic group. In some embodiments, R 7 Contains the first R X Group and second R X A group in which the first R X The group is a radiometal chelator optionally bound by a radiometal and the second R X The group is a trifluoroborate-containing auxiliary group.

[0342] In certain embodiments, the compound is conjugated to a radioisotope for use in positron emission tomography (PET) or single photon emission computed tomography (SPECT) imaging of PSMA-expressing tumors, wherein the compound is conjugated to a radioisotope that is a positron emitter or a gamma emitter. Without limitation, the positron or gamma emitting radioisotope is 68 Ga, 67 Ga, 61 Cu, 64 Cu, 99m Tc, 110m In, 111 In, 44 Sc, 86 Y. 89 Zr, 90 Nb, 18 F. 131 I. 123 I. 124 I and 72 As.

[0343] In certain embodiments, the compound is conjugated to a radioisotope for use in treating PSMA-expressing tumors. This includes radioisotopes such as 165 2. 212 Bi, 211 At 166 Ho, 149 Pm, 159 Gd, 105 Rh, 109 Pd, 198 Au, 199 Au, 175 Yb, 142 Pr, 177 Lu, 111 In, 213 Bi, 203 Pb, 212 Pb, 44 Sc, 47 Sc, 90 Y. 225 Ac, 117m Sn, 153 Sm, 149 Tb, 161 Tb, 224 Ra, 227 Th, 223 Ra, 77 As, 64 Cu or 67 Cu.

[0344] The compound may be HTK03149 or a salt or solvate thereof, optionally conjugated to a radioactive metal. In some embodiments, the radioactive metal is 177 Lu, 111 In, 213 Bi, 68 Ga, 67 Ga, 203 Pb, 212 Pb, 44 Sc, 47 Sc, 90 Y. 86 Y. 225 Ac, 117m Sn, 153 Sm, 149 Tb, 161 Tb, 165 2. 224 Ra, 212 Bi, 227 Th, 223 Ra, 64 Cu or 67 Cu. In some embodiments, the radioactive metal is 68 Ga.

[0345] The compound may be HTK03169, HTK03161, HTK03177, HTK03187, HTK03153, HTK03170, HTK04053, HTK03189A, HTK03189B, HTK04018, HTK04033, HTK04040, HTK04036, HTK04037, HTK04041, HTK04028, HTK04048, HTK04050, HTK03162 or HTK04055, or a salt or solvate thereof, optionally conjugated to a radioactive metal. In some embodiments, the radioactive metal is 177 Lu, 111 In, 213 Bi, 68 Ga, 67 Ga, 203 Pb, 212 Pb, 44 Sc, 47 Sc, 90 Y. 86 Y. 225 Ac, 117m Sn, 153 Sm, 149 Tb, 161 Tb, 165 2. 224 Ra, 212Bi, 227 Th, 223 Ra, 64 Cu or 67 Cu. In some embodiments, the radioactive metal is 68 Ga. In some embodiments, the radiometal is 177 Lu.

[0346] When the radiolabeled group comprises or is conjugated to a diagnostic radioisotope, certain embodiments of the compound are disclosed for use in preparing a radiolabeled tracer for imaging PSMA-expressing tissue in a subject. Also disclosed is a method for imaging PSMA-expressing tissue in a subject, wherein the method comprises: administering to the subject a composition comprising a compound of certain embodiments and a pharmaceutically acceptable excipient; and imaging the subject's tissue, for example, using PET or SPECT. When the tissue is a diseased tissue (e.g., a PSMA-expressing cancer), a PSMA-targeted therapy may be selected to treat the subject.

[0347] When the radiolabeled group comprises a therapeutic radioisotope, certain embodiments of the compound (or its pharmaceutical composition) are disclosed for use in treating a PSMA-expressing condition or disease (e.g., cancer, etc.) in a subject. Thus, provided is the use of the compound in the preparation of a medicament for treating a PSMA-expressing condition or disease in a subject. Also provided is a method of treating a PSMA-expressing disease in a subject, wherein the method comprises: administering to the subject a composition comprising the compound and a pharmaceutically acceptable excipient. For example, but not limited to, the disease may be a PSMA-expressing cancer.

[0348] PSMA expression has been detected in various cancers (e.g., Rowe et al., 2015, Annals of Nuclear Medicine 29:877-882; Sathekge et al., 2015, Eur J Nucl Med Mol Imaging 42:1482–1483; Verburg et al., 2015, Eur J Nucl Med Mol Imaging 42:1622–1623; and Pyka et al., J Nucl Med 2015 Nov 19 jnumed.115.164442). Thus, without limitation, the PSMA-expressing cancer may be prostate cancer, kidney cancer, breast cancer, thyroid cancer, gastric cancer, colorectal cancer, bladder cancer, pancreatic cancer, lung cancer, liver cancer, brain tumors, melanoma, neuroendocrine tumors, ovarian cancer, or sarcoma. In some embodiments, the cancer is prostate cancer.

[0349] Compounds containing retro-inverted peptide linkers

[0350] It is well known to those skilled in the art that the concept of retro-inversion peptide design can be used to further change the joint constructs defined for the above various compounds. Without compromising a given stereoisomer and not necessarily subject to a given stereoisomer constraint, the use of the retro-inversion method will require a preferred stereochemical configuration at certain stereoatoms that are reversed, provided that the polarity of one or more linking groups (e.g., N-terminal and C-terminal) including the stereoatoms in question has been reversed in the design of the retro-inversion peptide fragment. It is also well known that the amide linkage in the peptide joint can be replaced by an alternative linkage and in some cases extended by another group of atoms, such as CH2 or C=O at a given amino acid. Therefore, it will be obvious to replace such joints defined above (or elsewhere herein, e.g., in the examples) with a joint (wherein the polarity of the amino acid is reversed and / or wherein the amide linkage is replaced by an alternative linkage (wherein the overall position and 3D conformation of the joint is retained)). This principle is demonstrated in the non-limiting examples of the following embodiments to illustrate how a molecular part with the same or similar functional group is replaced by an retro-inversion counterpart, as will be readily understood by those skilled in the art of peptide chemistry:

[0351]

[0352] Therefore, also disclosed are compounds of formula IV or formula V as defined below.

[0353] A compound is disclosed, wherein the compound has Formula IV or is a salt or solvate of Formula IV:

[0354]

[0355] in:

[0356] R 0 is S or O;

[0357] R 1a is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -OPO3H2, -OSO3H, -B(OH)2 or

[0358] R 1b is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -B(OH)2 or

[0359] R 1c is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -B(OH)2 or

[0360] R 2is -CH2-, -CH(OH)-, -CHF-, -CF2-, -CH(CH3)-, -C(CH3)2-, -CH2CH(OH)-, -CH2CHF-, -CHFCH2-, -CF2CH2-, -CH2CF2-, -CH(OH)CH2-, -CH (CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-, -CH2CH(OH)CH2-, -CH2CHFCH2-, -(CH2)2CH(OH)-, -(CH2)2CHF-, -(CH2)3- , -CH2OCH2-, -CH2SCH2-, -CHFCH2CH2-, -CH(OH)CH2CH2-, -CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2- , -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-, -CH(CH3)-O-CH2-, -C(CH3)2-O-CH2-, -CH2-O-CH(CH3)-, -CH2-OC(CH3)2-, -CH2-S(O)-CH2-, -CH2-S(O)2-CH2-, -CH(CH3)-S-CH2-, -C(CH3)2-S-CH2-, -CH2-S-CH(CH3)-, -CH2-SC(CH3)2-, -CH(CH3)-S(O)-, -CH2-, -C(CH3)2-S( O)-CH2-, -CH2-S(O)-CH(CH3)-, -CH2-S(O)-C(CH3)2-, -CH(CH3)-S(O)2-CH2-, -C(CH3)2-S(O)2-CH2-, -CH2-S(O)2-CH(CH3)-, -CH2- S(O)2-C(CH3)2-, -CH2-NH-C(O)-, -C(O)-NH-CH2-, -C(O)-NH-CH(CH3)-, -C(O)-NH-C(CH3)2-, -CH2SeCH2-, -CH(COOH)-, -CH2CH(COOH)-, -CH2CH(COOH)CH2-, -CH2CH2CH(COOH)-, -CH=CH-, -CH=CHCH2-, –C≡CCH2-, -HC[CH2]CH- or -HC[CH2]CHCH2-, wherein HC[CH2]CH represents a cyclopropyl ring;

[0361] R 3 It is a C1-C2- 20Alkylene or alkenylene, or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 20 heteroalkylene or heteroalkenylene;

[0362] R 4 Is -O-, -S-, -Se-, -S(O)-, -S(O)2-, -NHC(O)-, -C(O)NH-, -C(O)-(NH)2-C(O)-, -OC(O)NH-, -NHC(O)O-, -NHC(O)NH-, -OC(S)NH-, -NHC(S)O-, -NHC(S)NH-, -NHC(O)C(O)NH-, -SS-, -S-CH2-S-, -NH-NH-C(O)-, -C(O)-NH-NH-,

[0363] R 5 It is a C1-C2- 30 Alkylene, alkenylene or alkynylene, or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 30 heteroalkylene, heteroalkenylene, or heteroalkynylene;

[0364] R 6 is hydrogen or methyl or ethyl;

[0365] XA 1 It is a compound having the formula -N(R 8 )R 9 C(O)-amino acids, where each R 8 are independently hydrogen or methyl, and wherein each R 9 are independently: linear or branched, cyclic or acyclic and / or aromatic or non-aromatic C1-C 20 Alkylene, alkenylene or alkynylene; or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 20 heteroalkylene, heteroalkenylene, or heteroalkynylene;

[0366] At least one R 9 or R 5 Yes - (CH2) 0-3 CH(R 10 )(CH2) 0-3 -, where R 10 yes:

[0367] Straight or branched, cyclic or acyclic and / or aromatic or non-aromatic C2-C 19Alkyl, alkenyl or alkynyl; linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X3 having only 1 to 3 heteroatoms 19 heteroalkyl, heteroalkenyl or heteroalkynyl;

[0368] -CH2R 23 , where R 23 is an optionally substituted C4-C 16 an aromatic ring or a partially or fully aromatic fused ring system, wherein 0-3 carbons in the aromatic ring or the partially or fully aromatic fused ring system are replaced by N, S and / or O heteroatoms, and wherein the optional substituents are selected from OH, NH2, NO2, halogen, C1-C6 alkyl and / or C1-C6 alkoxy; or

[0369] Selected from:

[0370] optionally modified with one, more than one, or a combination of: halogen, OMe, SMe, NH2, NO2, CN, OH, or another endocyclic nitrogen atom;

[0371] R 7 YesR X -(Xaa 2 ) 0-4 -、

[0372] R 28 It is an albumin binder;

[0373] XA 2 and Xaa 3 , when present, is independently -N(R 13 )R 14 C(O)-, where each R 13 are independently hydrogen or methyl, and wherein each R 14 are independently: linear or branched, cyclic or acyclic and / or aromatic or non-aromatic C1-C 20 Alkylene, alkenylene or alkynylene; or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 20 heteroalkylene, heteroalkenylene, or heteroalkynylene; and

[0374] Each R X is a radiolabeling group independently selected from: a radiometal chelator optionally bound to a metal; an aryl or heteroaryl group substituted with a radioisotope; a prosthetic group containing a trifluoroborate; or a prosthetic group containing a silicon-fluorine-acceptor moiety, a fluorophosphate, a fluorosulfate or a sulfonyl fluoride;

[0375] And where R7 -(Xaa 1 ) 1-4 -N(R 6 )-R 5 -R 4 -R 3 Any amide linkage within or any combination thereof is optionally replaced by one or a combination selected from the group consisting of: -O-, -S-, -Se-, -S(O)-, -S(O)2-, -NHC(O)-, -C(O)NH-, -C(O)-, -(NH)2-C(O)-, -OC(O)NH-, -NHC(O)O-, -NHC(O)NH-, -OC(S)NH-, -NHC(S)O -, -NHC(S)NH-, -NHC(O)C(O)NH-, -SS-, -S-CH2-S-, -NH-NH-C(O)-, and -C(O)-NH-NH-.

[0376] In various embodiments of the compound of Formula IV or a salt or solvate of Formula IV, for the variable R 0 , R 1a , R 1b , R 1c , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 Alternatively, the definition of any variable defined in the definitions of the preceding variables may be any such definition defined for Formula II.

[0377] In some embodiments of the compound of Formula IV or a salt or solvate of Formula IV, -N(R 6 )-R 5 -R 4 -yes

[0378] wherein X═CH or N, and Y═NH, S or O, and wherein any of these triaryl / heteroaryl groups is optionally modified by one, more than one or a combination of: halogen, OMe, SMe, NH 2 , NO 2 , CN, OH or one or more additional endocyclic nitrogen atoms.

[0379] Also disclosed is a compound, wherein the compound has Formula V or is a salt or solvate of Formula V:

[0380]

[0381] in:

[0382] R0 is S or O;

[0383] R 1a is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -OPO3H2, -OSO3H, -B(OH)2 or

[0384] R 1b is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -B(OH)2 or

[0385] R 1c is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -B(OH)2 or

[0386] R 2is -CH2-, -CH(OH)-, -CHF-, -CF2-, -CH(CH3)-, -C(CH3)2-, -CH2CH(OH)-, -CH2CHF-, -CHFCH2-, -CF2CH2-, -CH2CF2-, -CH(OH)CH2-, -CH (CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-, -CH2CH(OH)CH2-, -CH2CHFCH2-, -(CH2)2CH(OH)-, -(CH2)2CHF-, -(CH2)3- , -CH2OCH2-, -CH2SCH2-, -CHFCH2CH2-, -CH(OH)CH2CH2-, -CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2- , -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-, -CH(CH3)-O-CH2-, -C(CH3)2-O-CH2-, -CH2-O-CH(CH3)-, -CH2-OC(CH3)2-, -CH2-S(O)-CH2-, -CH2-S(O)2-CH2-, -CH(CH3)-S-CH2-, -C(CH3)2-S-CH2-, -CH2-S-CH(CH3)-, -CH2-SC(CH3)2-, -CH(CH3)-S(O)-, -CH2-, -C(CH3)2-S( O)-CH2-, -CH2-S(O)-CH(CH3)-, -CH2-S(O)-C(CH3)2-, -CH(CH3)-S(O)2-CH2-, -C(CH3)2-S(O)2-CH2-, -CH2-S(O)2-CH(CH3)-, -CH2- S(O)2-C(CH3)2-, -CH2-NH-C(O)-, -C(O)-NH-CH2-, -C(O)-NH-CH(CH3)-, -C(O)-NH-C(CH3)2-, -CH2SeCH2-, -CH(COOH)-, -CH2CH(COOH)-, -CH2CH(COOH)CH2-, -CH2CH2CH(COOH)-, -CH=CH-, -CH=CHCH2-, –C≡CCH2-, -HC[CH2]CH- or -HC[CH2]CHCH2-, wherein HC[CH2]CH represents a cyclopropyl ring;

[0387] R 3 It is a C1-C2- 20Alkylene or alkenylene, or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 20 heteroalkylene or heteroalkenylene;

[0388] R 4 is -O-, -S-, -Se-, -S(O)-, -S(O)2-, -NHC(O)-, -C(O)NH-, -C(O)-(NH)2-C(O)-, -OC(O)NH-, -NHC(O)O-, -NHC(O)NH-, -OC(S)NH-, -NHC(S)O-, -NHC(S)NH-, -NHC(O)C(O)NH-, -SS-, -S-CH2-S-, -NH-NH-C(O)-, -C(O)-NH-NH-,

[0389] R 5 It is a C1-C2- 30 Alkylene, alkenylene or alkynylene, or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 30 heteroalkylene, heteroalkenylene, or heteroalkynylene;

[0390] R 6 is optionally a carbonyl, phosphoryl or sulfonyl group, which is 1 or alternatively: -NHC(O)-, -(NH)2-C(O)-, -C(O)-(NH)2-C(O)-, -OC(O)-, -OC(S)-, -NHC(S)-, -NHC(O)C(O)-, -NH-NH-C(O)-, to attach Xaa 1 Alpha nitrogen in.

[0391] XA 1 It is a compound having the formula -N(R 8 )R 9 C(O)-amino acids, where each R 8 are independently hydrogen or methyl, and wherein each R 9 are independently: linear or branched, cyclic or acyclic and / or aromatic or non-aromatic C1-C 20 Alkylene, alkenylene or alkynylene; or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 20 heteroalkylene, heteroalkenylene, or heteroalkynylene;

[0392] At least one R 9 or R 5Yes - (CH2) 0-3 CH(R 10 )(CH2) 0-3 -, where R 10 yes:

[0393] Straight or branched, cyclic or acyclic and / or aromatic or non-aromatic C2-C 19 Alkyl, alkenyl or alkynyl; linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X3 having only 1 to 3 heteroatoms 19 heteroalkyl, heteroalkenyl or heteroalkynyl;

[0394] -CH2R 23 , where R 23 is an optionally substituted C4-C 16 an aromatic ring or a partially or fully aromatic fused ring system, wherein 0-3 carbons in the aromatic ring or the partially or fully aromatic fused ring system are replaced by N, S and / or O heteroatoms, and wherein the optional substituents are selected from OH, NH2, NO2, halogen, C1-C6 alkyl and / or C1-C6 alkoxy; or

[0395] Selected from:

[0396] optionally modified with one, more than one, or a combination of: halogen, OMe, SMe, NH2, NO2, CN, OH, or another endocyclic nitrogen atom;

[0397] R 7 YesR X -(Xaa 2 ) 0-4 -、

[0398] R 28 It is an albumin binder;

[0399] XA 2 and Xaa 3 , when present, is independently -N(R 13 )R 14 C(O)-, where each R 13 are independently hydrogen or methyl, and wherein each R 14 are independently: linear or branched, cyclic or acyclic and / or aromatic or non-aromatic C1-C 20 Alkylene, alkenylene or alkynylene; or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 20 heteroalkylene, heteroalkenylene, or heteroalkynylene; and

[0400] Each RX is a radiolabeling group independently selected from: a radiometal chelator optionally bound to a metal; an aryl or heteroaryl group substituted with a radioisotope; a prosthetic group containing a trifluoroborate; or a prosthetic group containing a silicon-fluorine-acceptor moiety, a fluorophosphate, a fluorosulfate or a sulfonyl fluoride.

[0401] In various embodiments of the compound of Formula V or a salt or solvate of Formula V, for the variable R 0 , R 1a , R 1b , R 1c , R 2 , R 3 , R 4 , R 5 or in the case of the aforementioned variables or the variable R 6 or R 7 The definition of any variable defined in the definition of may be any such definition defined for Formula II.

[0402] Compounds provided herein are incorporated with peptides, which can be synthesized by any of the various methods established in the art. This includes but is not limited to liquid and solid phase peptide synthesis using methods employing 9-fluorenylmethoxycarbonyl (Fmoc) and / or tert-butyloxycarbonyl (Boc) chemistry, and / or other synthetic pathways.

[0403] Solid phase peptide synthesis methods and techniques are established in the art. For example, peptides can be synthesized by incorporating the target amino acid residues one at a time. In such a method, peptide synthesis is usually initiated by attaching the C-terminal amino acid of the target peptide to a suitable resin. Prior to this, the reactive side chain and α-amino of amino acid were protected by suitable protecting groups to avoid reaction, and only α-carboxyl groups were allowed to react with functional groups such as amino, hydroxyl or haloalkyl on a solid support. After the C-terminal amino acid is coupled to the support, the protecting groups on the side chain and / or α-amino of amino acid are selectively removed, thereby allowing the next target amino acid to be coupled. Repeat this process until the desired peptide is fully synthesized, at which point the peptide can be cut from the support and purified. A non-limiting example of an instrument for solid phase peptide synthesis is an AapptecEndeavor 90 peptide synthesizer.

[0404] To allow coupling of additional amino acids, the Fmoc protecting group can be removed from the amino acid on the solid support, for example under mild alkaline conditions, such as piperidine in DMF (20%-50% v / v). The amino acid to be added must also have been activated for coupling (e.g. at the alpha carboxylate). Non-limiting examples of activating agents include, but are not limited to, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), benzotriazol-1-yl-oxy-tris(pyrrolidinyl)phosphonium hexafluorophosphate (PyBOP). Racemization is minimized by using triazoles, such as 1-hydroxy-benzotriazole (HOBt) and 1-hydroxy-7-aza-benzotriazole (HOAt). Coupling can be performed in the presence of a suitable base such as N,N-diisopropylethylamine (DIPEA / DIEA) or the like. For long peptides or if necessary, peptide synthesis and ligation can be used.

[0405] In addition to forming typical peptide bonds to extend the peptide, the peptide can be extended in a branched manner by attachment to side chain functional groups (e.g., carboxylic acid or amino groups): side chain to side chain; or side chain to backbone amino or carboxylate. Coupling to amino acid side chains can be performed by any known method and can be performed on or off the resin. Non-limiting examples include: the formation of amides between amino acid side chains containing carboxyl groups (e.g., Asp, D-Asp, Glu, D-Glu, etc.) and amino acid side chains containing amino groups (e.g., Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, etc.) or the N-terminus of a peptide; the formation of amides between amino acid side chains containing amino groups (e.g., Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, etc.) and amino acid side chains containing carboxyl groups (e.g., Asp, D-Asp, Glu, D-Glu, etc.) or the C-terminus of a peptide; and the formation of 1,2,3-triazoles between amino acid side chains containing azide groups (e.g., Lys(N3), D-Lys(N3), etc.) and alkynyl groups (e.g., Pra, D-Pra, etc.) via click chemistry. Prior to amide bond formation, the protecting groups on the appropriate functional groups must be selectively removed, whereas the reaction between alkynes and azides to form 1,2,3-triazoles via a click reaction does not require selective deprotection. Non-limiting examples of selectively removable protecting groups include 2-phenylisopropyl ester (O-2-PhiPr) (e.g., on Asp / Glu) and 4-methyltrityl (Mtt), allyloxycarbonyl (alloc), 1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl (Dde), and 1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl (ivDde) ​​(e.g., on Lys / Orn / Dab / Dap). O-2-PhiPr and Mtt protecting groups can be selectively deprotected under mild acidic conditions, such as 2.5% trifluoroacetic acid (TFA) in DCM. The Alloc protecting group can be selectively deprotected using tetrakis(triphenylphosphine)palladium(0) and phenylsilane in DCM. The Dde and ivDde protecting groups can be selectively deprotected using 2%-5% hydrazine in DMF. The deprotected side chains of Asp / Glu (L-type or D-type) and Lys / Orn / Dab / Dap (L-type or D-type) can then be coupled, for example, by using the above-mentioned coupling reaction conditions.

[0406] The peptide backbone amide can be N-methylated (i.e., α-aminomethylated). This can be achieved by directly using Fmoc-N-methylated amino acids during peptide synthesis. Alternatively, N-methylation can be performed under Mitsunobu conditions. First, a solution of 4-nitrobenzenesulfonyl chloride (Ns-Cl) and 2,4,6-trimethylpyridine (collidine) in NMP is used to protect the free primary amine group. N-methylation can then be accomplished in the presence of triphenylphosphine, diisopropyl azodicarboxylate (DIAD), and methanol. Subsequently, N-deprotection can be performed using mercaptoethanol and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in NMP. In order to couple the protected amino acid to the N-methylated α-amino group, HATU, HOAt, and DIEA can be used.

[0407] PSMA binding moieties (e.g., Lys-ureido-Aad, etc.) can be constructed on the solid phase via the formation of a ureido linkage between the amino groups of two amino acids. This can be accomplished by attaching an Fmoc protected amino acid (e.g., Fmoc-Lys(ivDde)-OH) to Wang resin using a standard activation / coupling strategy (e.g., Fmoc protected amino acid (4 equiv.), HATU (4 equiv.), and N,N-diisopropylethylamine (7 equiv.) in N,N-dimethylformamide). The Fmoc protecting group is then removed by 20% piperidine in N,N-dimethylformamide. To form the ureido linkage, the free amino group of the solid phase attached amino acid is brought into contact with the second 个 The amino acid is reacted, the carboxylate group of the latter is protected by a tert-butyl group and the amino group thereof is activated and converted to an isocyanate group (-N=C=O). The activation and conversion of the amino group to an isocyanate group can be achieved by reacting the amino group with phosgene or triphosgene. After the urea linkage is formed, the side chain functional group of the amino acid (e.g., ivDde on Lys) can be removed, and a linker, an albumin binding motif, and / or a radiolabeling group (e.g., a radiometal chelator, etc.) can then be coupled to the PSMA binding moiety.

[0408] Thioether (-S-) and ether (-O-) linkages (e.g. for R 4) can be achieved on the solid phase or in the solution phase. For example, the formation of thioether (-S-) linkages can be achieved by coupling between thiol-containing compounds (such as thiol groups on the side chain of cysteine) and halogenated alkyls (such as 3-(Fmoc-amino) bromopropane, etc.) in the presence of a base (such as N,N-diisopropylethylamine, etc.) in an appropriate solvent (such as N,N-dimethylformamide, etc.). The formation of ether (-O-) linkages can be achieved via the Mitsunobu reaction between alcohols (such as hydroxyl groups on the side chains of serine or threonine) and phenolic groups (such as the side chain of tyrosine) in the presence of triphenylphosphine and diisopropyl azodicarboxylate (DIAD) in an aprotic solvent (such as 1,4-dioxane, etc.). If the reaction is carried out in the solution phase, the reactants used are preferably in an equimolar ratio (1 to 1), and the desired product can be purified by flash column chromatography or high performance liquid chromatography (HPLC). If the reaction is carried out on a solid phase, meaning that one reactant is already attached to the solid phase, the other reactant is typically used in excess (≥ 3 equivalents of the reactant attached to the solid phase). After the reaction, the excess unreacted reactants and reagents can be removed by washing the solid phase (resin) sequentially with a combination of solvents such as N,N-dimethylformamide, methanol, and dichloromethane.

[0409] The non-peptide moiety (e.g., a radiolabeling group, an albumin binding group, and / or a linker) can be coupled to the peptide N-terminus when the peptide is attached to a solid support. This is easy when the non-peptide moiety comprises an activated carboxylate (and a protected group if necessary) so that the coupling can be performed on the resin. For example, but not limited to, bifunctional chelators such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) tri(tert-butyl ester) can be activated in the presence of N-hydroxysuccinimide (NHS) and N,N'-dicyclohexylcarbodiimide (DCC) to couple to the peptide. Alternatively, the non-peptide moiety can be incorporated into the compound via a copper-catalyzed click reaction under liquid or solid phase conditions. Copper-catalyzed click reactions are well established in the art. For example, 2-azidoacetic acid is first activated by NHS and DCC and then coupled to the peptide. Then, the alkyne-containing non-peptide moiety can be in water and organic solvents such as acetonitrile (ACN) and DMF in Cu. 2+ and sodium ascorbate were clicked into azide-containing peptides.

[0410] The synthesis of radiometal chelators is well known and many are commercially available (e.g. from Sigma-Aldrich TM / Milipore Sigma TMetc.). The conjugation scheme of radioactive metals to chelators is also well known (see, for example, Example 1 below). The synthesis of the silicon-fluorine-acceptor moiety can be accomplished according to previously reported procedures (e.g., Bernard-Gauthier et al. Biomed Res Int. 2014 2014:454503; Kostikov et al. Nature Protocols 2012 7:1956–1963; Kostikov et al. Bioconjug Chem. 2012 18:23:106-114; each of which is incorporated by reference in its entirety). The synthesis or acquisition of radioisotope-substituted aromatic groups is equally easy.

[0411] R on PSMA-targeted compounds 16 R 17 The synthesis of the BF3 component can be accomplished according to previously reported procedures (Liu et al. Angew Chem Int Ed 2014 53: 11876-11880; Liu et al. J Nucl Med 2015 55: 1499-1505; Liu et al. Nat Protoc 2015 10: 1423-1432; Kuo et al. J Nucl Med, in press, doi: 10.2967 / jnumed.118.216598; each of which is incorporated by reference in its entirety). Generally, the BF3-containing motif can be coupled to the linker via click chemistry by forming a 1,2,3-triazole ring between the BF3-containing azide (or alkynyl) and the alkynyl (or azide) on the linker, or by forming an amide linkage between the BF3-containing carboxylate and the amino group on the linker. To prepare azides, alkynes or carboxylates containing BF3, first prepare azides, alkynes or carboxylates containing borate, then convert the borate to BF3 in a mixture of HCl, DMF and KHF2. For alkyl BF3, azides, alkynes or carboxylates containing borate can be prepared by coupling an alkyl halide containing borate (such as iodomethylboronic acid pinacol ester) with an azide, alkynes or carboxylates containing amino groups (such as N, N-dimethylpropargylamine). For aryl BF3, borate can be prepared using aryl halides (iodine or bromide) and bis(pinacol) diboron via Suzuki coupling.

[0412] PSMA-targeting compounds containing BF3 18 F- 19 F isotope exchange reaction 18F-fluorination can be achieved according to previously published procedures (Liu et al. Nat Protoc 201510:1423-1432, incorporated by reference in its entirety). Typically, about 100 nmol of the BF3-containing compound was dissolved in a mixture of 15 μl of pyridazine-HCl buffer (pH=2.0-2.5, 1 M), 15 μl of DMF, and 1 μl of 7.5 mM KHF2 aqueous solution. 18 F-fluoride solution (in saline, 60 μl) is added to the reaction mixture and the resulting solution is heated at 80° C. for 20 minutes. At the end of the reaction, the desired product can be purified by solid phase extraction or by reverse phase high performance liquid chromatography (HPLC) using a mixture of water and acetonitrile as the mobile phase.

[0413] When the peptide is fully synthesized on a solid support, the desired peptide can be cut from the solid support using suitable reagents such as TFA, triisopropylsilane (TIS) and water. Side chain protecting groups such as Boc, pentamethyldihydrobenzofuran-5-sulfonyl (Pbf), trityl (Trt) and tert-butyl (tBu) are removed (i.e., deprotected) at the same time. The crude peptide can be precipitated and collected from the solution by adding cold ether and then centrifuging. The purification and characterization of the peptide can be performed based on the size, charge and polarity of the peptide by standard separation techniques such as high performance liquid chromatography (HPLC). The identity of the purified peptide can be confirmed by mass spectrometry or other similar methods.

[0414] Synthesis scheme of HTK03149 and its 68 The conjugation of Ga is depicted in Figure 2 and are further explained in detail in Example 1 below. Examples of general synthetic schemes for other compounds are shown in Figure 3 and Figure 4 The synthesis and testing of exemplary compounds HTK03041, HTK03169, HTK03161, HTK03177, HTK03187, HTK03153, HTK03170, HTK04053, HTK03189 (A and B), HTK04018, HTK04033, HTK04040, HTK04036, HTK04037, HTK04041, HTK04028, HTK04048, HTK04050, HTK03162 and HTK04055 are described in Example 2.

[0415] The present invention will be further illustrated in the following examples.

[0416] Example 1: HTK03149

[0417] General approach

[0418] All chemicals and solvents were obtained from commercial sources and used without further purification. The PSMA targeting peptide was synthesized using a solid phase method on an AAPPTec (Louisville, KY) Endeavor 90 peptide synthesizer. Peptide purification was performed on an Agilent 1260 Infinity II preparative system equipped with a 1260 Infinity II preparative binary pump, a 1260 Infinity variable wavelength detector (set to 220 nm) and a 1290 Infinity II preparative open-bed fraction collector. The HPLC column used was a preparative column (Gemini, NX-C18, 5μ, 50×30 mm) purchased from Phenomenex. The collected HPLC eluate containing the desired peptide was lyophilized using a Labconco (Kansas City, MO) FreeZone 4.5 Plus freeze dryer. Mass analysis was performed using an AB SCIEX (Framingham, MA) 4000QTRAP mass spectrometer system with an ESI ion source. C18 Sep-Pak solid phase extraction column (1cm 3 , 50 mg) was obtained from Waters (Milford, MA). 68 Ga was eluted from an iThemba Labs (Somerset West, South Africa) generator. -25R / W dose calibrator measurement 68 The radioactivity of the peptides was labeled with Ga, and the radioactivity in mouse tissues collected from the biodistribution studies was counted using a Perkin Elmer (Waltham, MA) Wizard2 2480 automated gamma counter.

[0419] Synthesis of HTK03149

[0420] The structures of HTK03041 and HTK03149 are shown below, differing only in that the former has a Glu residue in the PSMA binding moiety (Lys-ureido-Glu), whereas the latter has an Aad in the PSMA binding moiety (Lys-ureido-Aad) and thus has a side chain that is one carbon longer:

[0421]

[0422] like Figure 2As shown, the peptidomimetic PSMA targeting Lys-ureido-Aad moiety was synthesized by solid phase peptide chemistry. Fmoc-Lys(ivDde)-Wang resin (0.05 mmol, 0.58 mmol / g loading) was suspended in DMF for 30 minutes. Fmoc was then removed by treating the resin with 20% piperidine in DMF (3×8 minutes). To generate the isocyanate of the 2-aminoadipoyl moiety, a solution of L-2-aminoadipic acid (Aad) di-tert-butyl ester hydrochloride (154.9 mg, 0.5 mmol, 10 equivalents relative to the resin) and diisopropylethylamine (287.4 μL, 1.65 mmol, DIEA) in CH2Cl2 (5 mL) was cooled to -78°C in a dry ice / acetone bath. Triphosgene (49.0 mg, 0.165 mmol) was dissolved in CH2Cl2 (5 mL), and the resulting solution was added dropwise to the reaction at -78°C. The reaction was then allowed to warm to room temperature and stirred for 30 minutes to give an isocyanate solution of the 2-aminoadipoyl moiety. 87.1 μL of DIEA (0.5 mmol) was then added before adding to the lysine immobilized resin and reacting for 16 h. After washing the resin with DMF, the ivDde protecting group was removed (5×5 min) with 2% hydrazine in DMF. Fmoc-Ala(9-Anth)-OH was then coupled to the side chain of Lys using Fmoc-protected amino acids (4 equiv.), HATU (4 equiv.) and N,N-diisopropylethylamine (7 equiv.). Extension was then continued by adding Fmoc-tranexamic acid and finally DOTA-tri(tert-butyl) ester (2-(4,7,10-tri(2-(tert-butyloxy)-2-oxoethyl)-1,4,7,10)-tetraazacyclododec-1-yl)acetic acid.

[0423] The peptide was then deprotected and simultaneously cleaved from the resin by treatment with 95 / 5 trifluoroacetic acid (TFA) / triisopropylsilane (TIS) at room temperature for 2 h. After filtration, the peptide was precipitated by adding cold ether to the TFA solution. The crude peptide was purified by HPLC using a preparative column. The eluate containing the desired peptide was collected, pooled and lyophilized. The preparative HPLC conditions were 24% acetonitrile in water containing 0.1% TFA and a flow rate of 30 mL / min. The retention time was 6.9 minutes. The yield of HTK03149 was 21.4%. ESI-MS: HTK03149 C 54 H 75 N9O 16 [M+H] + Calculated value 1106.5410; [M+H] + The measured value is 1106.0954.

[0424] Synthesis of Ga-HTK03149

[0425] To prepare Ga-HTK03149, a solution of HTK03149 was incubated with GaCl3 (5 equivalents) in NaOAc buffer (0.1 M, 500 μL, pH 4.2) at 80°C for 15 minutes. The reaction mixture was then purified by HPLC using a semi-preparative column, and the HPLC eluate containing the desired peptide was collected, pooled and lyophilized. The HPLC conditions were 24% acetonitrile in water containing 0.1% TFA, and the flow rate was 30 mL / min. The retention time was 10.9 minutes. The yield of Ga-HTK03149 was 90.3%. ESI-MS: Ga-HTK03149C 54 H 74 N9O 16 [M+H] of Ga + Calculated value 1173.4509; [M+H] + The measured value is 1173.5450.

[0426] Cell culture

[0427] LNCaP cell line is obtained from ATCC (LNCaP clone FGC, CRL-1740). It is established from the metastatic site of the left supraclavicular lymph node of human prostate adenocarcinoma. Cells are cultured in a humidified incubator containing 5% CO2 at 37°C in the PRMI 1640 culture medium supplemented with 10% FBS, penicillin (100U / mL) and streptomycin (100 μg / mL). Then the cells grown to 80%-90% confluence are washed with sterile phosphate buffered saline (1 × PBS pH 7.4) and collected by trypsinization. The collected cell concentration is counted with Hausser Scientific (Horsham, PA) hemocytometer.

[0428] PET / CT imaging and biodistribution

[0429] Imaging and biodistribution experiments were performed using NODSCID 1L2RγKO male mice. Mice were anesthetized by inhalation of 2% isoflurane in oxygen and implanted subcutaneously behind the left shoulder with 1 × 10 7 When tumors grew to 5-8 mm in diameter within 5-6 weeks, mice were imaged or used for biodistribution studies.

[0430] PET imaging experiments were performed using a Siemens Inveon micro-PET / CT scanner. Each tumor-bearing mouse was injected with 6-8MBq of Ga-68 labeled tracer through the tail vein under anesthesia (2% isoflurane in oxygen). The mice were allowed to recover and move freely in their cages. After 50 minutes, the mice were sedated again by inhaling 2% isoflurane in oxygen and placed in the scanner. After segmentation to reconstruct the PET image, a 10-Min CT scan was first performed for positioning and attenuation correction. Then, a 10-min static PET imaging was performed to determine the uptake in the tumor and other organs. The mice were kept warm by a heating pad during the collection process. For biodistribution studies, mice were injected with radioactive tracers as described above. Mice were anesthetized by inhalation of 2% isoflurane and euthanized by inhalation of CO2. Blood was immediately drawn from the heart, and the target organs / tissues were collected. The collected organs / tissues were weighed and counted using a Perkin Elmer (Waltham, MA) Wizard2 2480γ counter. The uptake in each organ / tissue was normalized to the injected dose using a standard curve and expressed as the percentage of injected dose per gram of tissue (%ID / g). Figure 5 Intravenous injection is shown 68 Images obtained 1 and 3 hours after Ga-HTK03149. Images show very high tumor accumulation (solid arrows) with minimal kidney accumulation (dashed arrows) and very low activity in other organs.

[0431] Tables 5A and 5B show the biodistribution data of HTK03149 at 1 hour and 3 hours after injection, and Table 6 shows the biodistribution data of HTK03041 at 1 hour after injection.

[0432] Table 5A: 1 h after injection, 68 Biodistribution data and tumor-to-background contrast of Ga-labeled HTK03149 in mice bearing PSMA-expressing LNCaP cancer xenografts.

[0433]

[0434] Table 5B: 3h after injection, 68 Biodistribution data and tumor-to-background contrast of Ga-labeled HTK03149 in mice bearing PSMA-expressing LNCAP cancer xenografts.

[0435]

[0436] Table 6: 1 h after injection, 68Biodistribution data and tumor-to-background contrast of Ga-labeled HTK03041 in mice bearing PSMA-expressing LNCAP cancer xenografts.

[0437]

[0438]

[0439] Comparison of Tables 5A and 5B (HTK03149) with Table 6 (HTK03041) thus demonstrates that the longer side chain of the Lys-ureido-Aad PSMA targeting moiety compared to Lys-ureido-Glu significantly reduces the uptake of HTK03149 compared to HTK03041 in the kidney and salivary glands without sacrificing tumor to background contrast. Modification of the Glu residue thus results in improved imaging and therapeutic agents for PSMA expressing diseases / conditions.

[0440] Example 2: HTK03041, HTK03169, HTK03161, HTK03177, HTK03187, HTK03153, HTK03170, HTK04053, HTK03189 (A and B), HTK04018, HTK04033, HTK04040, HTK04036, HTK04037, HTK04041, HTK04028, HTK04048, HTK04050, HTK03162, and HTK04055

[0441] General approach

[0442] PSMA targeting peptides were synthesized using a solid phase method on an AAPPTec (Louisville, KY) Endeavor 90 peptide synthesizer. Purification and quality control of cold and radiolabeled peptides were performed on the following systems: (1) Agilent HPLC system equipped with a 1200 quaternary pump, a 1200 UV absorbance detector (set at 220 nm), and a Bioscan (Washington, DC) NaI scintillation detector. The operation of the Agilent HPLC system was controlled using Agilent ChemStation software. The HPLC columns used were semi-preparative columns (Luna C18, 5μ, 250×10 mm) and analytical columns (Luna C18, 5μ, 250×4.6 mm) purchased from Phenomenex (Torrance, CA); or (2) an Agilent 1260 Infinity II preparative system equipped with a 1260 Infinity II preparative binary pump, a 1260 Infinity variable wavelength detector (set at 220 nm) and a 1290 Infinity II preparative open-bed fraction collector. The HPLC columns used were preparative columns (Gemini, NX-C18, 5μ, 50×30 mm) purchased from Phenomenex. The collected HPLC eluate containing the desired peptide was lyophilized using a Labconco (Kansas City, MO) FreeZone 4.5 Plus freeze dryer. Mass analysis was performed using an AB SCIEX (Framingham, MA) 4000QTRAP mass spectrometer system with an ESI ion source. C18 Sep-Pak solid phase extraction column (1cm 3 , 50 mg) was obtained from Waters (Milford, MA). Capintec (Ramsey, NJ) was used -25R / W dose calibrator measurement 68 The radioactivity of the peptides was Ga-labeled, and radioactivity was counted in mouse tissues collected from biodistribution studies using a Perkin Elmer (Waltham, MA) Wizard2 2480 automated gamma counter.

[0443] The structures of HTK03041, HTK03149, HTK03169, HTK03161, HTK03177, HTK03187, HTK03153, HTK03170, HTK04053, HTK03189A, HTK03189B, HTK04018, HTK04033, HTK04040, HTK04036, HTK04037, HTK04041, HTK04028, HTK04048, HTK04050, HTK03162 and HTK04055 are Figure 6 Shown in.

[0444] Synthesis of HTK03169 and HTK04053

[0445] The peptidomimetic PSMA targeting Aad-urea-lysine moiety was synthesized by solid phase peptide chemistry. Fmoc-Lys(ivDde)-Wang resin (0.10 mmol, 0.58 mmol / g loading) was suspended in DMF for 30 minutes. Fmoc was then removed by treating the resin with 20% piperidine in DMF (3×8 minutes). To generate the isocyanate of the 2-aminoadipoyl moiety, a solution of L-2-aminoadipic acid (Aad) di-tert-butyl ester hydrochloride (154.9 mg, 0.5 mmol, 5 equivalents relative to the resin) and diisopropylethylamine (287.4 μL, 1.65 mmol, DIEA) in CH2Cl2 (5 mL) was cooled to -78°C in a dry ice / acetone bath. Triphosgene (49.0 mg, 0.165 mmol) was dissolved in CH2Cl2 (5 mL), and the resulting solution was added dropwise to the reaction at -78°C. The reaction was then allowed to warm to room temperature and stirred for 30 minutes to obtain an isocyanate solution of the 2-aminoadipoyl moiety. 87.1 μL DIEA (0.5 mmol) was then added and then added to the lysine fixed resin and reacted for 16 h. After washing the resin with DMF, the ivDde protecting group was removed (5×5 minutes) with 2% hydrazine in DMF. Fmoc-2-naphthylalanine (for HTK03169) or Fmoc-3-iodo-L-phenylalanine (for HTK04053) was then coupled to the side chain of Lys using Fmoc-protected amino acids (4 equivalents), HATU (4 equivalents) and DIEA (7 equivalents). Afterwards, extension was continued by adding Fmoc-tranexamic acid and finally DOTA-tri(tert-butyl)ester (2-(4,7,10-tri(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10)-tetraazacyclododec-1-yl)acetic acid.

[0446] The peptide was then deprotected and simultaneously cleaved from the resin by treatment with 95 / 5 trifluoroacetic acid (TFA) / triisopropylsilane (TIS) at room temperature for 2 h. After filtration, the peptide was precipitated by adding cold ether to the TFA solution. The crude peptide was purified by HPLC using a preparative column or a semi-preparative column. The eluate containing the desired peptide was collected and lyophilized. For HTK03169, the preparative HPLC conditions were 20% acetonitrile in water containing 0.1% TFA and the flow rate was 30 mL / min. The retention time was 9.0 minutes. The yield was 29.6%. ESI-MS: HTK03169 C 50 H 73 N9O 16 [M+H] + Calculated value 1056.5254; [M+H] + Found 1056.5647. For HTK04053, the semi-preparative HPLC conditions were 24% acetonitrile in water containing 0.1% TFA, and the flow rate was 4.5 mL / min. The retention time was 11.9 minutes. The yield was 47.6%. ESI-MS: HTK04053 C 46 H 70 N9O 16 I's [M+H] + Calculated value 1132.4063; [M+H] + The measured value is 1132.5523.

[0447] Synthesis of HTK03041, HTK03161, HTK03177, HTK03187, HTK03189 (A and B), HTK04018, HTK04033 and HTK04040

[0448] Peptidomimetic PSMA targeting Asp- (for HTK03161), Glu- (for HTK03041), S-carboxymethylcysteine- (for HTK03177) and O-carboxymethylserine- (for HTK03187), racemic 2-aminopimelate- (for HTK03189A and B), 3- (carboxymethyl)sulfonyl-L-alanine- (for HTK04018), (4R)-4-fluoro-Glu- (for HTK04040) ureido-lysine moieties were synthesized by solid phase peptide chemistry. Fmoc-Lys(ivDde)-Wang resin (0.1 mmol, 0.58 mmol / g loading) was suspended in DMF for 30 min. Fmoc was then removed by treating the resin with 20% piperidine in DMF (3×8 min). In order to produce isocyanate derivatives, di-tert-butyl L-aspartate hydrochloride (140.9 mg, 0.5 mmol, 5 equivalents to the resin), di-tert-butyl L-glutamate hydrochloride (147.9 mg, 0.5 mmol, 5 equivalents to the resin), di-tert-butyl S-carboxymethylcysteine ​​hydrochloride (163.9 mg, 0.5 mmol, 5 equivalents to the resin), di-tert-butyl O-carboxymethylserine hydrochloride (155.9 mg, 0.5 mmol, 5 equivalents to the resin), di-tert-butyl 2-aminopimelate hydrochloride (161.9 mg, 0.5 mmol, 5 equivalents to the resin) were added. A solution of (4R)-4-fluoro-L-glutamic acid di-tert-butyl ester hydrochloride (156.6 mg, 0.5 mmol, 5 equiv., relative to the resin), 3-(carboxymethyl)sulfonyl-L-alanine di-tert-butyl ester (179.9 mg, 0.5 mmol, 5 equiv., relative to the resin), (4R)-4-fluoro-L-glutamic acid di-tert-butyl ester hydrochloride (156.6 mg, 0.5 mmol, 5 equiv., relative to the resin) or (4S)-4-fluoro-L-glutamic acid di-tert-butyl ester hydrochloride (156.6 mg, 0.5 mmol, 5 equiv., relative to the resin) and DIEA (287.4 μL, 1.65 mmol, DIEA) in CHCl (5 mL) was cooled to -78°C in a dry ice / acetone bath. Triphosgene (49.0 mg, 0.165 mmol) was dissolved in CHCl (5 mL) and the resulting solution was added dropwise to the reaction at -78°C. The reaction was then allowed to warm to room temperature and stirred for 30 minutes to give a solution of the derivative. Then 87.1 μL DIEA (0.5 mmol) was added, and then added to the lysine fixed resin and reacted for 16 h. After washing the resin with DMF, the ivDde protecting group was removed (5×5 minutes) with 2% hydrazine in DMF. Then Fmoc-Ala(9-Anth)-OH was coupled to the side chain of Lys using Fmoc protected amino acids (4 equivalents), HATU (4 equivalents) and DIEA (7 equivalents). Afterwards, the extension was continued by adding Fmoc tranexamic acid and finally DOTA-tri(tert-butyl) ester.

[0449] The peptide was then deprotected and simultaneously cleaved from the resin by treatment with 95 / 5 trifluoroacetic acid (TFA) / triisopropylsilane (TIS) at room temperature for 2 h. After filtration, the peptide was precipitated by adding cold ether to the TFA solution. The crude peptide was purified by HPLC using a preparative column or a semi-preparative column. The eluate containing the desired peptide was collected and lyophilized. For HTK03161, the preparative HPLC conditions were 23% acetonitrile in water containing 0.1% TFA and the flow rate was 30 mL / min. The retention time was 7.9 minutes. The yield was 17.2%. ESI-MS: HTK03161 C 52 H 72 N9O 16 [M+H] + Calculated value 1078.5097; [M+H] + Found 1078.4720. For HTK03041, the semi-preparative HPLC conditions were 31% acetonitrile in water containing 0.1% TFA, and the flow rate was 4.5 mL / min. The retention time was 7.2 minutes. The yield was 27%. ESI-MS: HTK03161 C 53 H 74 N9O 16 [M+H] + Calculated value 1092.5; [M+H] + Found 1092.6. For HTK03177, the preparative HPLC conditions were 24% acetonitrile in water containing 0.1% TFA, and the flow rate was 30 mL / min. The retention time was 8.2 minutes. The yield was 34.0%. ESI-MS: HTK03177 C 53 H 73 N9O 16 S's [M+H] + Calculated value 1124.4974; [M+H] + Found 1124.4980. For HTK03187, the semi-preparative HPLC conditions were 28% acetonitrile in water containing 0.1% TFA, and the flow rate was 4.5 mL / min. The retention time was 10.4 minutes. The yield was 30.3%. ESI-MS: HTK03187C 53 H 73 N9O 17 [M+H] + Calculated value 1108.5203; [M+H] +Found 1108.5101. For HTK03189, the semi-preparative HPLC conditions were 28% acetonitrile in water containing 0.1% TFA, and the flow rate was 4.5 mL / min. The retention time of HTK03189A was 13.9 minutes, and the yield was 19.7%. The retention time of HTK03189B was 15.5 minutes, and the yield was 15.6%. ESI-MS: HTK03189 C 55 H 77 N9O 16 [M+H] + Calculated value 1120.5567; [M+H] + Found 1120.5865 (for HTK03189A) and 1120.5118 (for HTK03189B). For HTK04018, the semi-preparative HPLC conditions were 30% acetonitrile in water containing 0.1% TFA, and the flow rate was 4.5 mL / min. The retention time was 9.2 minutes. ESI-MS: HTK04018 C 53 H 73 N9O 18 S's [M+H] + Calculated value 1156.4873; [M+H] + Found 1156.3678. For HTK04033, the preparative HPLC conditions were 23% acetonitrile in water containing 0.1% TFA, and the flow rate was 30 mL / min. The retention time was 8.5 minutes. The yield was 45.7%. ESI-MS: HTK04033C 53 H 72 N9O 16 F's [M+H] + Calculated value 1110.5159; [M+H] + Found 1110.3887. For HTK04040, the preparative HPLC conditions were 23% acetonitrile in water containing 0.1% TFA, and the flow rate was 30 mL / min. The retention time was 9.4 minutes. The yield was 33.3%. ESI-MS: HTK04040 C 53 H 72 N9O 16 F's [M+H] + Calculated value 1110.5159; [M+H] + The measured value is 1110.0578.

[0450] Synthesis of HTK04036, HTK04037 and HTK04041

[0451] The peptidomimetic PSMA targeting Aad-urea-lysine moiety was synthesized by solid phase peptide chemistry. Fmoc-Lys(ivDde)-Wang resin (0.10 mmol, 0.58 mmol / g loading) was suspended in DMF for 30 minutes. Fmoc was then removed by treating the resin with 20% piperidine in DMF (3×8 minutes). To generate the isocyanate of the 2-aminoadipoyl moiety, a solution of L-2-aminoadipic acid (Aad) di-tert-butyl ester hydrochloride (154.9 mg, 0.5 mmol, 5 equivalents relative to the resin) and DIEA (287.4 μL, 1.65 mmol) in CH2Cl2 (5 mL) was cooled to -78°C in a dry ice / acetone bath. Triphosgene (49.0 mg, 0.165 mmol) was dissolved in CH2Cl2 (5 mL), and the resulting solution was added dropwise to the reaction at -78°C. The reaction was then allowed to warm to room temperature and stirred for 30 minutes to give an isocyanate solution of the 2-aminoadipoyl moiety. 87.1 μL of DIEA (0.5 mmol) was then added before adding to the lysine immobilized resin and reacting for 16 h. After washing the resin with DMF, the ivDde protecting group was removed (5×5 min) with 2% hydrazine in DMF. Fmoc-Ala(9-Anth)-OH was then coupled to the side chain of Lys using Fmoc protected amino acids (4 equiv.), HATU (4 equiv.) and DIEA (7 equiv.). Extension was then continued by adding Fmoc-4-aminomethyl-phenylacetic acid (for HTK04036), Fmoc-3-aminomethyl-phenylacetic acid (for HTK04037) or Fmoc-4-aminobenzoic acid (for HTK04041) and finally DOTA-tri(tert-butyl) ester.

[0452] The peptide was then deprotected and simultaneously cleaved from the resin by treatment with 95 / 5 TFA / TIS for 2 h at room temperature. After filtration, the peptide was precipitated by adding cold ether to the TFA solution. The crude peptide was purified by HPLC using a preparative column or a semi-preparative column. The eluate containing the desired peptide was collected and lyophilized. For HTK04036, the preparative HPLC conditions were 23% acetonitrile in water containing 0.1% TFA and the flow rate was 30 mL / min. The retention time was 9.7 minutes. The yield was 28.2%. ESI-MS: HTK04036C 55 H 71 N9O 16 [M+H] + Calculated value 1114.5097; [M+H] +Found 1114.3070. For HTK04037, the preparative HPLC conditions were 23% acetonitrile in water containing 0.1% TFA, and the flow rate was 30 mL / min. The retention time was 11.6 minutes. The yield was 27.0%. ESI-MS: HTK04037 C 55 H 71 N9O 16 [M+H] + Calculated value 1114.5097; [M+H] + Found 1114.3629. For HTK04041, the semi-preparative HPLC conditions were 23% acetonitrile in water containing 0.1% TFA, and the flow rate was 4.5 mL / min. The retention time was 10.8 minutes. The yield was 12.8%. ESI-MS: HTK04041 C 53 H 67 N9O 16 [M+H] + Calculated value 1086.4784; [M+H] + The measured value is 1086.4066.

[0453] Synthesis of HTK03153 and HTK03170

[0454] The peptidomimetic PSMA targeting Aad-urea-lysine moiety was synthesized by solid phase peptide chemistry. Fmoc-Lys(ivDde)-Wang resin (0.10 mmol, 0.58 mmol / g loading) was suspended in DMF for 30 minutes. Fmoc was then removed by treating the resin with 20% piperidine in DMF (3×8 minutes). To generate the isocyanate of the 2-aminoadipoyl moiety, a solution of L-2-aminoadipic acid (Aad) di-tert-butyl ester hydrochloride (154.9 mg, 0.5 mmol, 5 equivalents relative to the resin) and DIEA (287.4 μL, 1.65 mmol) in CH2Cl2 (5 mL) was cooled to -78°C in a dry ice / acetone bath. Triphosgene (49.0 mg, 0.165 mmol) was dissolved in CH2Cl2 (5 mL), and the resulting solution was added dropwise to the reaction at -78°C. The reaction was then allowed to warm to room temperature and stirred for 30 minutes to give an isocyanate solution of the 2-aminoadipoyl moiety. 87.1 μL of DIEA (0.5 mmol) was then added before adding to the lysine immobilized resin and reacting for 16 h. After washing the resin with DMF, the ivDde protecting group was removed (5×5 min) with 2% hydrazine in DMF. Fmoc-Ala(9-Anth)-OH was then coupled to the side chain of Lys using Fmoc-based chemistry, followed by Fmoc-tranexamic acid, Fmoc-Lys(ivDde)-OH, and Fmoc-Gly-OH. All couplings were performed in DMF using Fmoc-protected amino acids (4 equivalents), HATU (4 equivalents), and DIEA (7 equivalents). Afterwards, the extension was continued using Fmoc-based chemistry by adding 4-(p-chlorophenyl)butyric acid (for HTK03153) or 4-(p-methoxyphenyl)butyric acid (for HTK03170) coupled to the same peptide-bound resin. After removal of the ivDde protecting group with 2% hydrazine in DMF (5×5 min), DOTA-tri(tert-butyl) ester was coupled to the side chain of Lys to give the precursor.

[0455] The peptide was then deprotected and simultaneously cleaved from the resin by treatment with 95 / 5 TFA / TIS at room temperature for 2 h. After filtration, the peptide was precipitated by adding cold ether to the TFA solution. The crude peptide was purified by HPLC using a preparative or semi-preparative column. The eluate containing the desired peptide was collected and lyophilized. For HTK03153, the preparative HPLC conditions were 32% acetonitrile in water containing 0.1% TFA and the flow rate was 30 mL / min. The retention time was 7.9 minutes. ESI-MS: HTK03153 C 72 H 99 N 12 O 19 [M+H] of Cl +Calculated value 1471.6916; [M+H] + Found 1471.1257. For HTK03170, the semi-preparative HPLC conditions were 34% acetonitrile in water containing 0.1% TFA, and the flow rate was 4.5 mL / min. The retention time was 13.1 minutes. ESI-MS: HTK03170C 73 H 102 N 12 O 20 [M+2H] 2+ Calculated value 734.3745; [M+2H] 2+ The measured value is 734.5822.

[0456] Synthesis of HTK04028, HTK04048 and HTK04050

[0457] The synthetic procedures for constructing the core structures of HTK04028, HTK04048 and HTK04050 are the same as those for constructing the core structures of HTK03187, HTK03177 and HTK04033, respectively, as described above. After Fmoc-tranexamic acid, Fmoc-Lys(ivDde)-OH, Fmoc-Gly-OH and 4-(p-methoxyphenyl)butyric acid are continued to be extended using Fmoc-based chemistry. All couplings are carried out in DMF using Fmoc-protected amino acids (4 equivalents), HATU (4 equivalents) and DIEA (7 equivalents). After removing the ivDde protecting group with 2% hydrazine in DMF (5×5 minutes), DOTA-tri(tert-butyl) ester is coupled to the side chain of Lys to obtain the precursor.

[0458] The peptide was then deprotected and simultaneously cleaved from the resin by treatment with 95 / 5 TFA / TIS for 2 h at room temperature. After filtration, the peptide was precipitated by adding cold ether to the TFA solution. The crude peptide was purified by HPLC using a preparative column or a semi-preparative column. The eluate containing the desired peptide was collected and lyophilized. For HTK04028, the preparative HPLC conditions were 28% acetonitrile in water containing 0.1% TFA and the flow rate was 30 mL / min. The retention time was 14.8 minutes. The yield was 21.4%. ESI-MS: HTK04028C 72 H 100 N 12 O 21 [M+H] + Calculated value 1469.7204; [M+H] +Found 1469.7000. For HTK04048, the semi-preparative HPLC conditions were 35% acetonitrile in water containing 0.1% TFA, and the flow rate was 4.5 mL / min. The retention time was 11.7 minutes. The yield was 53.4%. ESI-MS: HTK04048 C 72 H 100 N 12 O 20 S's [M+H] + Calculated value 1485.6976; [M+H] + Found 1485.9910. For HTK04050, the semi-preparative HPLC conditions were 35% acetonitrile in water containing 0.1% TFA, and the flow rate was 4.5 mL / min. The retention time was 11.4 minutes. The yield was 17.5%. ESI-MS: HTK04050C 72 H 99 N 12 O 20 F's [M+H] + Calculated value 1471.7161; [M+H] + The measured value is 1471.9511.

[0459] Synthesis of Non-Radioactive Ga Complex Standards

[0460] To prepare non-radioactive Ga complexed standards, a solution of each precursor was incubated with GaCl3 (5 equivalents) in NaOAc buffer (0.1 M, 500 μL, pH 4.2) at 80°C for 15 minutes. The reaction mixture was then purified by HPLC using a preparative or semi-preparative column, and the HPLC eluate containing the desired peptide was collected, pooled and lyophilized. For Ga-HTK03041, the semi-preparative HPLC conditions were 31% acetonitrile in water containing 0.1% TFA at a flow rate of 4.5 mL / min. The retention time was 9.3 minutes. The yield was 89%. ESI-MS: Ga-HTK03041 C 53 H 72 N9O 16 [M+H] of Ga + Calculated value 1159.4; [M+H] + Found 1159.4. For Ga-HTK03161, semi-preparative HPLC conditions were 29% acetonitrile in water containing 0.1% TFA, flow rate was 4.5 mL / min. Retention time was 11.3 minutes. Yield was 37.4%. ESI-MS: Ga-HTK03161 C 52 H 69 N9O 16 [M+H] of Ga + Calculated value 1145.4196; [M+H]+ Found 1146.1355. For Ga-HTK03169, the semi-preparative HPLC conditions were 25% acetonitrile in water containing 0.1% TFA, and the flow rate was 4.5 mL / min. The retention time was 14.1 minutes. The yield was 55.0%. ESI-MS: Ga-HTK03169C 50 H 70 N9O 16 [M+H] of Ga + Calculated value 1122.4275; [M+H] + Found 1122.3041. For Ga-HTK03177, the semi-preparative HPLC conditions were 32% acetonitrile in water containing 0.1% TFA, and the flow rate was 4.5 mL / min. The retention time was 7.8 minutes. The yield was 55.9%. ESI-MS: Ga-HTK03177 C 53 H 70 N9O 16 SGa's [M+H] + Calculated value 1190.3995; [M+H] + Found 1190.3061. For Ga-HTK03187, semi-preparative HPLC conditions were 29% acetonitrile in water containing 0.1% TFA, flow rate was 4.5 mL / min. Retention time was 13.3 minutes. Yield was 52.8%. ESI-MS: Ga-HTK03187C 53 H 70 N9O 17 [M+H] of Ga + Calculated value 1174.4224; [M+H] +Found 1174.3425. For Ga-HTK03189A, the semi-preparative HPLC conditions were 30% acetonitrile in water containing 0.1% TFA, and the flow rate was 4.5 mL / min. The retention time was 13.0 minutes. The yield was 52.6%. ESI-MS: [M+H]+ calculated for Ga-HTK03189A C55H74N9O16Ga 1186.4588; [M+H]+ found 1186.4164. For Ga-HTK03189B, the semi-preparative HPLC conditions were 30% acetonitrile in water containing 0.1% TFA, and the flow rate was 4.5 mL / min. The retention time was 13.9 minutes. The yield was 42.1%. ESI-MS: [M+H]+ Calculated for Ga-HTK03189BC55H74N9O16Ga 1186.4588; [M+H]+ Found 1186.3279. For Ga-HTK04033, the semi-preparative HPLC conditions were 29% acetonitrile in water with 0.1% TFA, and the flow rate was 4.5 mL / min. The retention time was 13.3 minutes. The yield was 59.5%. ESI-MS: [M+H]+ Calculated for Ga-HTK04033 C53H70N9O16FGa 1177.4259; [M+H]+ Found 1178.4800. For Ga-HTK04036, the semi-preparative HPLC conditions were 29% acetonitrile in water with 0.1% TFA, and the flow rate was 4.5 mL / min. The retention time was 13.1 minutes. The yield was 61.3%. ESI-MS: [M+H]+ Calculated for Ga-HTK04036C55H69N9O16Ga 1181.4196; [M+H]+ Found 1181.4720. For Ga-HTK04037, the semi-preparative HPLC conditions were 29% acetonitrile in water with 0.1% TFA, and the flow rate was 4.5 mL / min. The retention time was 15.6 minutes. The yield was 54.2%. ESI-MS: [M+H]+ Calculated for Ga-HTK04037 C55H69N9O16Ga 1181.4196; [M+H]+ Found 1180.5278. For Ga-HTK04040, the semi-preparative HPLC conditions were 30% acetonitrile in water with 0.1% TFA, and the flow rate was 4.5 mL / min. The retention time was 10.2 minutes. The yield was 46.5%. ESI-MS: [M+H]+ calculated for Ga-HTK04040 C53H70N9O16FGa 1177.4259; [M+H]+ found 1176.7043. For Ga-HTK04041, the semi-preparative HPLC conditions were 29% acetonitrile in water containing 0.1% TFA, and the flow rate was 4.5 mL / min. The retention time was 14.4 minutes. The yield was 55.2%.ESI-MS: [M+H]+ Calculated for Ga-HTK04041C53H65N9O16Ga 1153.3883; [M+H]+ Found 1153.5379. For Ga-HTK04053, the semi-preparative HPLC conditions were 25% acetonitrile in water containing 0.1% TFA, and the flow rate was 4.5 mL / min. The retention time was 12.4 minutes. The yield was 74.7%. ESI-MS: [M+H]+ Calculated for Ga-HTK04053 C46H68N9O16Ga 1199.3163; [M+H]+ Found 1199.5712.

[0461] Synthesis of Ga-68 Labeled Compounds

[0462] A total of 4 mL of 0.1 M HCl was used to 68 Ga]GaCl3 eluted from the iThemba Labs generator. 68 The Ga]GaCl3 solution was added to 2 mL of concentrated HCl. The radioactive mixture was then added to a DGA resin column and washed with 3 mL of 5M HCl. The column was then air dried and washed with 0.5 mL of water. 68 Ga]GaCl3 (0.10–0.50 Gbq) was eluted into a vial containing a solution of unlabeled precursor (25 μg) in 0.7 mL HEPES buffer (2M, pH 5.3). The reaction mixture was heated in a microwave oven (Danby; DMW7700WDB) at power setting 2 for 1 minute. The mixture was purified by semi-preparative HPLC column and quality controlled by analytical HPLC under co-injection of unlabeled standards. Radiochemical yield (attenuation correction)>50% and radiochemical purity>95%.

[0463] Synthesis of Lu complex standards

[0464] To prepare non-radioactive Lu complex standards of HTK03149, HTK03153, HTK03170, HTK04028, HTK04048 and HTK04050, the precursor solution was incubated with LuCl3 (5 equivalents) in NaOAc buffer (0.1M, 500μL, pH 4.2) at 90°C for 30 minutes. The reaction mixture was then purified by HPLC using a semi-preparative column, and the HPLC eluate containing the desired peptide was collected, pooled and lyophilized. For Lu-HTK03149, the HPLC conditions were 29% acetonitrile in water containing 0.1% TFA and the flow rate was 4.5mL / min. The retention time was 8.4 minutes. The yield of Lu-HTK03149 was 91.3%. ESI-MS: Lu-HTK03149C 54 H 74N9O 16 Lu's [M+H] + Calculated value 1173.4509; [M+H] + Found 1173.5450. For Lu-HTK03153, the HPLC conditions were 39% acetonitrile in water containing 0.1% TFA, and the flow rate was 4.5 mL / min. The retention time was 8.1 minutes. The yield of Lu-HTK03153 was 62.5%. ESI-MS: Lu-HTK03153 C 72 H 96 N 12 O 19 ClLu[M+H] + Calculated value 1643.6089; [M+H] + Found 1643.9000. For Lu-HTK03170, the HPLC conditions were 34% acetonitrile in water containing 0.1% TFA, and the flow rate was 4.5 mL / min. The retention time was 15.4 minutes. The yield of Lu-HTK03170 was 94.7%. ESI-MS: Lu-HTK03170C 73 H 99 N 12 O 20 Lu's [M+H] + Calculated value 1639.6585; [M+H] + Found 1639.6933. For Lu-HTK04028, the HPLC conditions were 35% acetonitrile in water containing 0.1% TFA, and the flow rate was 4.5 mL / min. The retention time was 11.5 minutes. The yield of Lu-HTK04028 was 29.4%. ESI-MS: Lu-HTK04028 C 72 H 97 N 12 O 21 Lu's [M+H] + Calculated value 1641.6377; [M+H] + Found 1641.7775. For Lu-HTK04048, the HPLC conditions were 35% acetonitrile in water containing 0.1% TFA, and the flow rate was 4.5 mL / min. The retention time was 13.9 minutes. The yield of Lu-HTK04048 was 70.2%. ESI-MS: Lu-HTK04048C 72 H 97 N 12 O 20 SLu's [M+H] + Calculated value 1657.6149; [M+H] +Found 1657.8672. For Lu-HTK04050, the HPLC conditions were 35% acetonitrile in water containing 0.1% TFA, and the flow rate was 4.5 mL / min. The retention time was 13.2 minutes. The yield of Lu-HTK04050 was 44.9%. ESI-MS: Lu-HTK04050 C 72 H 96 N 12 O 20 FLu's [M+H] + Calculated value 1643.6334; [M+H] + The measured value is 1644.7152.

[0465] Synthesis of Lu-177 Labeled Compounds

[0466] [ 177 Lu]LuCl3 was purchased from ITM Isotopen Technologien Munchen AG. [ 177 Lu]LuCl3 (100–1000 MBq) was added to a solution of unlabeled precursor (25 μg) in 0.5 mL of NaOAc buffer (0.1 M, pH 4.5). The reaction mixture was incubated at 100 °C for 15 minutes. The mixture was purified by semi-preparative HPLC column and quality controlled by analytical HPLC column under co-injection of unlabeled standards. Radiochemical yield (attenuation correction) >50% and radiochemical purity >95%.

[0467] Synthesis of HTK03162 and HTK04055

[0468] The intermediates HTK03156 and HTK04039 containing diazide for synthesizing HTK03162 and HTK04055 respectively are synthesized by solid phase method. The synthetic procedure of the preparation of the core structure of HTK03156 and HTK04039 is the same as that of HTK03149 (for HTK03156) and HTK03187 (for HTK04039). After coupling Fmoc-tranexamic acid, continue to extend by adding Fmoc-Lys (Fmoc)-OH. Coupling is carried out in DMF using amino acids (4 equivalents), HATU (4 equivalents) and DIEA (7 equivalents) protected by Fmoc. After removing the group protected by Fmoc, Fmoc-Aad (OtBu)-OH is coupled to both the side chain and N-terminal of Lys. The coupling was carried out in DMF using Fmoc protected amino acids (5 equiv.), HATU (5 equiv.) and DIEA (9 equiv.). 2-Azidoacetic acid (5 equiv.) was coupled to the N-terminus with DIEA (5 equiv.) and N-hydroxysuccinimide (6 equiv.) to give a diazide-containing intermediate. At the end, the peptide was deprotected and simultaneously cleaved from the resin by treatment with 95 / 5 TFA / TIS for 2 h at room temperature. After filtration, the peptide was precipitated by adding cold ether to the TFA solution. The crude peptide was purified by HPLC using a preparative column. The eluate containing the desired peptide was collected, pooled and lyophilized. For HTK03156, the preparative HPLC conditions were 34% acetonitrile in water containing 0.1% TFA at a flow rate of 30 mL / min. The retention time was 4.8 minutes and the yield of the precursor was 39%. ESI-MS: C 60 H 82 N 15 O 18 [M+H] + Calculated value 1300.5962; [M+H] + Found 1300.6369. For HTK04039, the preparative HPLC conditions were 31% acetonitrile in water containing 0.1% TFA, and the flow rate was 30 mL / min. The retention time was 8.0 min, and the yield of the precursor was 5.8%. ESI-MS: C 59 H 79 N 15 O 19 [M+H] + Calculated value 1302.5755; [M+H] + The measured value is 1302.6022.

[0469] To synthesize HTK03162, the diazide-containing intermediate HTK03156 (7.4 mg, 5.7 μmol), N-propargyl-N,N-dimethylammoniomethyl-trifluoroborate (4.7 mg, 28.5 μmol, 5 equivalents) were dissolved in 300 μL acetonitrile, and the solution was adjusted to alkaline conditions (pH about 8) by 1M K2CO3. A solution of 1M CuSO4 (28.5 μL, 5 equivalents) and 1M sodium ascorbate (57 μL, 10 equivalents) were then added, and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was purified by HPLC using a semi-preparative column, eluting with 36% acetonitrile in water containing 0.1% TFA at a flow rate of 4.5 mL / min. The retention time was 8.0 min, and the yield of HTK03162 was 70.7%. ESI-MS: C 72 H 104 B2F6N 17 O 18 [M+H] + Calculated value 1630.7836; [M+H] + The measured value is 1630.8000.

[0470] To synthesize HTK04055, the diazide-containing intermediate HTK04039 (2.0 mg, 1.5 μmol), N-propargyl-N,N-dimethylammoniomethyl-trifluoroborate (1.24 mg, 7.5 μmol, 5 equivalents) were dissolved in 300 μL acetonitrile, and the solution was adjusted to alkaline conditions (pH about 8) by 1M K2CO3. A solution of 1M CuSO4 (7.5 μL, 5 equivalents) and 1M sodium ascorbate (15 μL, 10 equivalents) was then added, and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was purified by HPLC using a semi-preparative column, eluting with 33% acetonitrile in water containing 0.1% TFA at a flow rate of 4.5 mL / min. The retention time was 11.6 min, and the yield of HTK04055 was 55.9%. ESI-MS: C 71 H 101 B2F6N 17 O 19 [M+H] + Calculated value 1632.7628; [M+H] + The measured value is 1632.6622.

[0471] Synthesis of F-18 labeled compounds

[0472] The H2 was bombarded with 18-MeV protons (Advanced Cyclotron Systems Inc. 18O, and then captured on an anion exchange resin column (preactivated with saline and washed with DI water) to obtain [ 18 F] fluoride. The [ 18 F] fluoride. Unlabeled trifluoroborate precursor HTK03162 or HTK04055 (100 nmol) was suspended in DMF (15 μL). The eluted [ 18 F] Fluoride (30-100 GBq) was added to the reaction vessel containing HTK03162 or HTK04055 solution. The vial was heated on a heating block at 80 ° C for 20 minutes and quenched after adding 1 mL of water. The mixture was purified by semi-preparative HPLC column and quality controlled via an analytical HPLC column under co-injection of unlabeled standards. Radiochemical yield (attenuation correction)>10% and radiochemical purity>95%.

[0473] Cell culture

[0474] LNCaP cell line is obtained from ATCC (LNCaP clone FGC, CRL-1740). It is established from the metastatic site of the left supraclavicular lymph node of human prostate adenocarcinoma. The cells are cultured in a humidified incubator containing 5% CO2 at 37°C in PRMI 1640 culture medium supplemented with 10% FBS, penicillin (100U / mL) and streptomycin (100μg / mL). The cells grown to 80%-90% confluence are then washed with sterile phosphate buffered saline (1×PBS pH 7.4) and collected by trypsinization. The collected cell concentration is counted with Hausser Scientific (Horsham, PA) hemocytometer.

[0475] PET / CT, SPECT / CT imaging and biodistribution studies

[0476] Imaging and biodistribution experiments were performed using NODSCID 1L2RγKO male mice. Mice were anesthetized by inhalation of 2% isoflurane in oxygen and implanted subcutaneously behind the left shoulder with 1 × 10 7 When tumors grew to 5-8 mm in diameter within 5-6 weeks, mice were imaged or used for biodistribution studies.

[0477] PET imaging experiments were performed using Siemens Inveon micro-PET / CT scanners. Each tumor-bearing mouse was injected with 6-8MBq of Ga-68 or F-18 labeled tracers by tail vein under anesthesia (2% isoflurane in oxygen). Mice were allowed to recover and move freely in their cages. After 50 minutes, mice were sedated again by inhaling 2% isoflurane in oxygen and placed in the scanner. After segmentation to reconstruct PET images, 10-Min CT scans were first performed to locate and attenuate correction. Then, 10-min static PET imaging was performed to determine the uptake in tumors and other organs.

[0478] SPECT / CT imaging experiments were performed using a MILabs (Utrecht, the Netherlands) U-SPECT-II / CT scanner. Each tumor-bearing mouse was injected with approximately 37 MBq of 177 Lu labeled tracer. Allow mice to recover and move freely in their cages, and image 1, 4, 24, 72 and 120 hours after injection. At each time point, mice were sedated again and placed in the scanner. First, a 5-min CT scan was performed as an anatomical reference at a voltage set at 60kV and a current set at 615μA, and then a 60-min static emission scan was performed in list mode using an ultra-high resolution multi-pinhole rat-mouse (1mm pinhole size) collimator. Data were reconstructed using U-SPECT II software with a window width of 20% on three energy windows. The light peak window was centered at 208keV, and the lower scattering window and upper scattering window were centered at 170keV and 255keV, respectively. Reconstruction parameters used maximum likelihood expectation maximization (3 iterations), pixel-based ordered subset expectation maximization (16 subsets) and a 0.5mm post-processing filter (Gaussian blur). Image attenuation was corrected to injection time in PMOD (PMOD Technologies, Switzerland) and then converted to DICOM in Inveon Research Workplace (Siemens Medical Solutions USA, Inc.) for qualitative visualization.

[0479] For biodistribution studies, mice were injected with the radiotracer as described above. 68 Ga study: 1h; for 177Lu study: 1, 4, 24, 72 or 120h), mice were anesthetized by inhalation of 2% isoflurane and euthanized by inhalation of CO2. Blood was immediately drawn from the heart and the target organs / tissues were collected. The collected organs / tissues were weighed and counted using a Perkin Elmer (Waltham, MA) Wizard2 2480 gamma counter. The uptake in each organ / tissue was normalized to the injected dose using a standard curve and expressed as a percentage of the injected dose per gram of tissue (% ID / g).

[0480] The results of Example 2 are shown in Tables 7A, 7B and 8-13 below. Figure 7-Figure 13 Shown in.

[0481] Table 7A: 68 Biodistribution data and tumor-to-background contrast of Ga-labeled HTK03149, HTK03161, HTK03169, HTK3177, HTK03187, HTK03189A, and HTK03189B in mice bearing PSMA-expressing LNCaP cancer xenografts.

[0482]

[0483]

[0484] Table 7B: 68 Biodistribution data and tumor-to-background contrast of Ga-labeled HTK04033, HTK04040, HTK04036, HTK04037, HTK04041, and HTK04053 in mice bearing PSMA-expressing LNCaP cancer xenografts.

[0485]

[0486]

[0487] Table 8: 177 Biodistribution data and tumor-to-background contrast of Lu-labeled HTK03149 in mice bearing PSMA-expressing LNCaP cancer xenografts.

[0488]

[0489]

[0490] Table 9: 177 Biodistribution data and tumor-to-background contrast of Lu-labeled HTK03153 in mice bearing PSMA-expressing LNCaP cancer xenografts.

[0491]

[0492] Table 10: 177 Biodistribution data and tumor-to-background contrast of Lu-labeled HTK03170 in mice bearing PSMA-expressing LNCaP cancer xenografts.

[0493]

[0494]

[0495] Table 11: 177 Biodistribution data and tumor-to-background contrast of Lu-labeled HTK04028 in mice bearing PSMA-expressing LNCaP cancer xenografts.

[0496]

[0497]

[0498] Table 12: 177 Biodistribution data of Lu-labeled HTK04048 in mice bearing PSMA-expressing LNCaP cancer xenografts and tumor vs. background comparison.

[0499]

[0500] Table 13: 18 F-labeled biodistribution data and tumor-to-background contrast of HTK03162 and HTK04055 in mice bearing PSMA-expressing LNCaP cancer xenografts.

[0501]

[0502] Example 1 demonstrates that modification of the Glu side chain in the Lys-ureido-Glu PSMA targeting moiety in compounds of Formula I, II, and III (e.g., by extending the Glu side chain) can significantly reduce tracer uptake in the kidney and salivary glands without sacrificing tumor to background contrast in the radiolabeled tracer (comparing HTK03041 to HTK03149). The results in Example 2 further demonstrate that modification of the Glu side chain provides improved imaging and therapeutic agents for PSMA expressing diseases / conditions. Specifically, it is noted that compounds of Formula I, II, or III (wherein R 2The results in Example 2 further demonstrate that substitution of R with butylene (-CH2-CH2-CH2-CH2-) or its derivatives for R 2 This resulted in poor uptake by PSMA-expressing tumors (see compounds HTK03189A and HTK03189B), indicating that binding to PSMA was severely impaired.

[0503] Example 2 further shows that compounds of formula I, II and III (wherein R 2 is a derivative of ethylene (-CH2-CH2-)) can lead to reduced uptake in the kidneys and salivary glands while maintaining binding to PSMA-expressing tumors, such as when R 2 is substituted ethylene or other ethylene derivatives. For example, when R 2 When it is -CH2-CHF- (HTK04033 and HTK04040), the results show that the compounds of the present invention can still bind PSMA well and have much less kidney and salivary gland uptake. It is worth noting that although HTK04040 (S isomer) has a relatively high kidney uptake (76% ID / g), it is still much lower than the kidney uptake of HTK03041 lacking the fluorine substituent (170% ID / g). Therefore, these results show that small substituents (such as F, CH3, OH) do not eliminate PSMA binding.

[0504] Results further showed that conjugation of an albumin binder further enhanced tumor uptake, resulting in increased tumor-to-kidney and tumor-to-salivary gland uptake rates, especially at later time points.

[0505] The present invention has been described with respect to one or more embodiments. However, it will be apparent to those skilled in the art that various changes and modifications may be made without departing from the scope of the invention as defined in the following claims. Therefore, the scope of the present invention should not be limited to the preferred embodiments set forth in the above examples, but should be given the broadest interpretation consistent with the entire description.

[0506] The contents of U.S. Provisional Application No. 63 / 006,643, filed on April 7, 2020, and U.S. Provisional Application No. 62 / 865,088, filed on June 21, 2019, are incorporated herein by reference in their entirety. If there may be any inconsistency between the definitions therein, the definitions herein in the above paragraph shall prevail.

Claims

1. A compound, wherein the compound has formula II or is a salt or solvate of formula II: in: R 0 is O or S; R 1a is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -OPO3H2, -OSO3H, -B(OH)2 or R 1b It is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H 2、 -B(OH)2 or R 1c It is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H 2、 -B(OH)2 or R 2 is -CH2-, -CH(OH)-, -CHF-, -CF2-, -CH(CH3)-, -C(CH3)2-, -CH2CH(OH)-, -CH2CHF-, -CHFCH2-, -CF2CH2-, -CH2CF2-, -CH(OH)CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-, -CH2CH(OH)CH2-, -CH2CHFCH2-, -(CH2)2CH(OH)-, -(CH2)2CHF-, -(CH2)3-, -CH2OCH2-, -CH2SCH2-, -CHFCH2CH2-, -CH(OH)CH2CH2-, -CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-, -CH(CH3)-O-CH2-, -C(CH3)2-O-CH2-, -CH2-O-CH(CH3)-, -CH2-O-C(CH3)2-, -CH2-S(O)-CH2-, -CH2-S(O)2-CH2-, -CH(CH3)-S-CH2-, -C(CH3)2-S-CH2-, -CH2-S-CH(CH3)-, -CH2-S-C(CH3)2-, -CH(CH3)-S(O)-CH2-, -C(CH3)2-S(O)-CH2-, -CH2-S(O)-CH(CH3)-, -CH2-S(O)-C(CH3)2-, -CH(CH3)-S(O)2-CH2-, -C(CH3)2-S(O)2-CH2-, -CH2-S(O)2-CH(CH3)-, -CH2-S(O)2-C(CH3)2-, -CH2-NH-C(O)-, -C(O)-NH-CH2-, -C(O)-NH-CH(CH3)- or -C(O)-NH-C(CH3)2-; R 3 It is a C1-C2- 20 alkylene, alkenylene or alkynylene, or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 20 heteroalkylene, heteroalkenylene, or heteroalkynylene; R 4 is -O-, -S-, -Se-, -S(O)-, -S(O)2-, -NHC(O)-, -C(O)NH-, -C(O)-(NH)2-C(O)-, -OC(O)NH, -NHC(O)O-, -NHC(O)NH-, -OC(S)NH, -NHC(S)O-, -NHC(S)NH-, -NHC(O)C(O)NH-, -S-S-, -S-CH2-S-, -NH-NH-C(O)-, -C(O)-NH-NH; R 5 It is a C1-C2- 30 Alkylene, alkenylene or alkynylene, or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 30 heteroalkylene, heteroalkenylene, or heteroalkynylene; R 6 is hydrogen or methyl or ethyl; XA 1 It is a compound having the formula -N(R 8 )R 9 C(O)-amino acids, where each R 8 are independently hydrogen or methyl, and wherein each R 9 are independently: linear or branched, cyclic or acyclic and / or aromatic or non-aromatic C1-C 20 Alkylene, alkenylene or alkynylene; or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 20 heteroalkylene, heteroalkenylene, or heteroalkynylene; At least one R 9 or R 5 Yes - (CH2) 0-3 CH(R 10 )(CH2) 0-3 -, where R 10 yes: Straight or branched, cyclic or acyclic and / or aromatic or non-aromatic C2-C 19 Alkyl, alkenyl or alkynyl; linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X3 having only 1 to 3 heteroatoms 19 heteroalkyl, heteroalkenyl or heteroalkynyl; -CH2R 23 , where R 23 is an optionally substituted C4-C 16 an aromatic ring or a partially or fully aromatic fused ring system, wherein 0-3 carbons in the aromatic ring or the partially or fully aromatic fused ring system are replaced by N, S and / or O heteroatoms, and wherein the optional substituents are selected from OH, NH2, NO2, halogen, C1-C6 alkyl and / or C1-C6 alkoxy; or Selected from: optionally modified with one, more than one, or a combination of: halogen, OMe, SMe, NH2, NO2, CN, OH, or another endocyclic nitrogen atom; R 7 YesR X -(Xaa 2 ) 0-4 -、 R 28 It is an albumin binder; XA 2 and Xaa 3 , when present, is independently -N(R 13 )R 14 C(O)-, where each R 13 are independently hydrogen or methyl, and wherein each R 14 are independently: linear or branched, cyclic or acyclic and / or aromatic or non-aromatic C1-C 20 Alkylene, alkenylene or alkynylene; or linear or branched, cyclic or acyclic and / or aromatic or non-aromatic X2-X 20 heteroalkylene, heteroalkenylene, or heteroalkynylene; and Each R X is a radiolabeling group independently selected from the following: a radiometal chelator optionally bound by a radiometal; an aryl or heteroaryl group substituted with a radiohalogen; a prosthetic group containing a trifluoroborate; a prosthetic group containing a silicon-fluorine-acceptor moiety; or a prosthetic group containing a fluorophosphate, a fluorosulfate, a sulfonyl fluoride or a combination thereof.

2. The compound of claim 1, wherein R 0 It's O.

3. The compound according to claim 1 or 2, wherein: R 1a Is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, OPO3H2, OSO3H; R 2a is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2; and R 3a They are -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2.

4. The compound according to claim 1 or 2, wherein R 1a , R 1b and R 1c Each of them is -CO2H.

5. The compound according to any one of claims 1 to 4, wherein R 2 is –CH2–, –CHOH–, –CHF–, –CH2CHOH–, –CH2CHF–, –CH2CHOHCH2–, –CH2CHFCH2–, –(CH2)2CHOH–, –(CH2)2CHF–, –(CH2)3–, –CH2OCH2–, or –CH2SCH2–.

6. The compound according to any one of claims 1 to 4, wherein R 2 are –CH2–, –CH(OH)–, –CHF–, –CF2–, –CH(CH3)–, –C(CH3)2–, –CH2CH(OH)–, –CH2CHF–, –CHFCH2–, –CF2CH2–, –CH2 CF2–, –CH(OH)CH2–, –CH(CH3)CH2–, –CH2CH(CH3)–, –C(CH3)2CH2–, –CH2C(CH3)2–, –CH2CH(OH)CH2–, –CH2CHF CH2–, –(CH2)2CH(OH)–, –(CH2)2CHF–, –(CH2)3–, –CH2OCH2–, –CH2SCH2–, –CHFCH2CH2–, –CH(OH)CH2CH2–, –CH (CH3)CH2CH2–, –CH2CH(CH3)CH2–, –CH2CH2CH(CH3)–, –C(CH3)2CH2CH2–, –CH2C(CH3)2CH2–, –CH2CH2C(CH3)2– , –CH(CH3)–O–CH2–, –C(CH3)2–O–CH2–, –CH2–O–CH(CH3)–, –CH2–O–C(CH3)2–, –CH2–S(O)–CH2–, –CH2–S(O)2– CH2–, –CH(CH3)–S–CH2–, –C(CH3)2–S–CH2–, –CH2–S–CH(CH3)–, –CH2–S–C(CH3)2–, –CH(CH3)–S(O)–CH2–, –C(C H3)2–S(O)–CH2–, –CH2–S(O)–CH(CH3)–, –CH2–S(O)–C(CH3)2–, –CH(CH3)–S(O)2–CH2–, –C(CH3)2–S(O)2–CH2 –, –CH2–S(O)2–CH(CH3)–, –CH2–S(O)2–C(CH3)2–, –C(O)–NH–CH2–, –C(O)–NH–CH(CH3)–, or –C(O)–NH–C(CH3)2–.

7. A compound as claimed in any one of claims 1 to 4, wherein R 2 It is -(CH2)3-.

8. A compound as claimed in any one of claims 1 to 4, wherein R 2 are –CH2CH(OH)CH2–, –CH2CHFCH2–, –(CH2)2CH(OH)–, –(CH2)2CHF–, –(CH2)3–, –CH2OCH2–, –CH2SCH2–, –CHFCH2CH2–, –CH(OH)CH2CH2–, –CH(CH3)CH2CH2–, –CH2CH(CH3)CH2–, –CH 2CH2CH(CH3)–, –C(CH3)2CH2CH2–, –CH2C(CH3)2CH2–, –CH2CH2C(CH3)2–, –CH(CH3)–O–C H2–, –C(CH3)2–O–CH2–, –CH2–O–CH(CH3)–, –CH2–O–C(CH3)2–, –CH2–S(O)–CH2–, –CH2–S( O)2–CH2–, –CH(CH3)–S–CH2–, –C(CH3)2–S–CH2–, –CH2–S–CH(CH3)–, –CH2–S–C(CH3)2–, –CH(CH3)–S(O)–CH2–, –C(CH3)2–S(O)–CH2–, –CH2–S(O)–CH(CH3)–, –CH2–S(O)–C(CH3) 2–, –CH(CH3)–S(O)2–CH2–, –C(CH3)2–S(O)2–CH2–, –CH2–S(O)2–CH(CH3)–, –CH2–S(O)2 –C(CH3)2–, –CH2–NH–C(O)–, –C(O)–NH–CH2–, –C(O)–NH–CH(CH3)–, or –C(O)–NH–C(CH3)2–.

9. The compound of claim 8, wherein R 2 It is -CH2-O-CH2- or -CH2-S-CH2-.

10. The compound of any one of claims 1 to 4, wherein R 2 are –CH2–, –CH(OH)–, –CHF–, –CF2–, –CH(CH3)–, –C(CH3)2–, –CHFCH2–, –CF2CH2–, –CH(OH)CH2–, –CH(CH3)CH2–, –C(CH3)2CH2–, –(CH2)2CH(OH)–, –(CH2)2CHF–, –(CH2)3–, –CH2OCH2–, –CH2SCH 2–, –CHFCH2CH2–, –CH(OH)CH2CH2–, –CH(CH3)CH2CH2–, –CH2CH2CH(CH3)–, –C(CH3)2CH2CH2–, – CH2CH2C(CH3)2–, –CH(CH3)–O–CH2–, –C(CH3)2–O–CH2–, –CH2–O–CH(CH3)–, –CH2–O–C(CH3)2–, –CH2–S(O)–CH2–, –CH2–S(O)2–CH2–, –CH(CH3)–S–CH2–, –C(CH3)2–S–CH2–, –CH2–S–CH(CH3)– , –CH2–S–C(CH3)2–, –CH(CH3)–S(O)–CH2–, –C(CH3)2–S(O)–CH2–, –CH2–S(O)–CH(CH3)–, –CH2– S(O)–C(CH3)2–, –CH(CH3)–S(O)2–CH2–, –C(CH3)2–S(O)2–CH2–, –CH2–S(O)2–CH(CH3)–, –CH2– S(O)2–C(CH3)2–, –CH2–NH–C(O)–, –C(O)–NH–CH2–, –C(O)–NH–CH(CH3)–, or –C(O)–NH–C(CH3)2–.

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