Radiolabeled compounds targeting prostate-specific membrane antigen

Abstract

To provide novel radiolabeled compounds targeting PSMA, particularly compounds with low accumulation in salivary glands and / or kidneys.SOLUTION: Provided is a compound comprising a prostate-specific membrane antigen (PSMA)-targeting moiety of the following formula or of a salt or a solvate thereof. R0 is O or S. 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. R3 is a linker. When the PSMA-targeting moiety is linked to a radiolabeling group, the compound may be used as an imaging agent or therapeutic agent for PSMA-expressing diseases / conditions.SELECTED DRAWING: None

Description

[Technical field]

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

[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 prostate metastases. Due to the pathological expression patterns of PSMA, various radiolabeled constructs that target PSMA have been designed and evaluated for imaging PSMA-expressing tissues and / or treating diseases or conditions characterized by PSMA expression.

[0003] 18 F-DCFBC, 18 F-DCFPyL, 68 Ga-PSMA-HBED-CC, 68 Ga-PSMA-617, 68 Ga-PSMA I and T (see FIG. 1), as well as the lysine-urea-glutamate (Lys-ureido-Glu) derivative, were used as α-emitters ( 225 Ac) or β-ray emitting nuclei ( 177 Lu or 90 A number of radiolabeled Lys-ureido-Glu derivatives have been developed to target PSMA, including versions labeled with Lys-ureido-Glu (e.g., Y).

[0004] In clinical trials, 177 Lu and 225PSMA-617 radiolabeled with therapeutic radionuclides such as Ac has shown promise as an effective systemic treatment for metastatic castration-resistant prostate cancer (mCRPC). However, dry mouth (xerostomia), taste changes, and adverse renal events are common side effects of this treatment due to high accumulation of the radiotracer in the salivary glands and kidneys (Hofman et al.,2018 The Lancet 16(6):825-833; Rathke et al.2019 Eur J Nucl Med Mol Imaging46(1):139-147; Sathekge et al.2019 Eur J Nucl Med Mol Imaging 46(1):129-138). Thus, accumulation of radiotracers in the kidneys and salivary glands is a limiting factor that reduces the maximum cumulative administered radioactivity dose that can be safely administered to patients, limiting the potential therapeutic efficacy of Lys-Urea-Glu-based radiopharmaceuticals (Violet et al. 2019 J Nucl Med. 60(4):517-523). Thus, there is a need for novel radiolabeled compounds that target PSMA, particularly those that exhibit low accumulation in the salivary glands and / or kidneys.

[0005] No admission is necessarily intended, nor should be construed, that any of the preceding information constitutes prior art against the present invention. Summary of the Invention

[0006] Various embodiments disclosed herein relate to a compound having formula I, or a salt or solvate of formula I: [ka] During the ceremony, n is 0 or 1, R 1a , R 1b and R 1c each is independently -CO2H, -SO2H, -SO3H, -SO4H, -PO2H, -PO3H, or -PO4H; When n is 0, R 2 is -CH2-, -CHOH-, -CHF-, -CH2CHOH-, -CH2CHF-, -CH2CHOHCH2-, -CH2CHFCH2-, -(CH2)2CHOH-, -(CH2)2CHF-, -(CH2)3-, -CH2OCH2- or -CH2SCH2-, When n is 1, R 2 is -CH2-, -CHOH-, -CHF-, -CH2CHOH-, -CH2CHF- or -(CH2)2-, R 3 is a linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 20 Alkylenyl or alkenylenyl, or X-X which is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 20 heteroalkylenyl or heteroalkenylenyl, R 4 -O-, -S-, -NHC(O)-, -C(O)NH-, [ka] and R 5 is a linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 30 X-X is alkylenyl, alkenylenyl or alkynylenyl, or is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 30 heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; R 6 is hydrogen or methyl, Xaa 1 is -N(R 8 )R 9 C(O)-, where each R 8 is independently hydrogen or methyl; 9 are independently straight or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 20Alkylenyl, alkenylenyl or alkynylenyl, or X-X which is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 20 heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; At least one R 9 or R 5 teeth, [ka] and At least one R 9 or R 5 is -(CH2) 0-3 CH(R 10 )(CH2) 0-3 -, wherein R 10 is a linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C2-C 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; R 7 is R X -(Xaa 2 ) 0-4 -, [ka] and R 11 does not exist or [ka] and R 12 is I, Br, F, Cl, H, OH, OCH3, NH2, NO2 or CH3, Xaa 2 When present, -N(R 13 )R 14 C(O)—, where each R 13is independently hydrogen or methyl; 14 are independently straight or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 20 Alkylenyl, alkenylenyl or alkynylenyl, or X-X which is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 20 heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; Each R X is independently a radiolabeling group selected from a radiometal chelator optionally bound to a radiometal, a radioisotope-substituted aryl, a prosthetic group containing a trifluoroborate, and a prosthetic group containing a silicon-fluorine-acceptor moiety.

[0007] Various embodiments disclosed herein relate to a compound having formula II, or a salt or solvate of formula II: [ka] During the ceremony, R 0 is O or S, R 1a is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, OPO3H2, OSO3H, -B(OH)2 or [ka] and R 1b are -CO2H, -SO2H, -SO3H, -PO2H, -PO3H 2、 -B(OH)2 or [ka] and R 1c are -CO2H, -SO2H, -SO3H, -PO2H, -PO3H 2、 -B(OH)2 or [ka] and R 2 -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)C H2CH2-, -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(CH 3)-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(C H3)-, -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 is a linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 20 Alkylenyl, alkenylenyl or alkynylenyl, or X-X which is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 20 heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; R4 -O-, -S-, -Se-, -S(O)-, -S(O)2-, -NHC(O)-, -C(O)NH-, [ka] -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, R 5 is a linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 30 X-X is alkylenyl, alkenylenyl or alkynylenyl, or is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 30 heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; R 6 is hydrogen, methyl or ethyl, Xaa 1 is -N(R 8 )R 9 C(O)-, where each R 8 is independently hydrogen or methyl; 9 are independently straight or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 20 Alkylenyl, alkenylenyl or alkynylenyl, or X-X which is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 20 heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; At least one R 9 or R 5 is -(CH2) 0-3 CH(R 10 )(CH2) 0-3 -, wherein R 10 teeth, Straight or branched chain, cyclic or acyclic, and / or aromatic or non-aromatic C2-C 19 X-X is alkyl, alkenyl or alkynyl, linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic, with only 1 to 3 heteroatoms; 19 heteroalkyl, heteroalkenyl or heteroalkynyl, -CH2R 23 (That R 23 is an optionally substituted C4-C 16 an aromatic ring system, a partially aromatic fused ring system or a fully aromatic fused ring system in which 0-3 carbons are replaced by heteroatoms N, S and / or O, the optional substituents being selected from OH, NH2, NO2, halogen, C1-C6 alkyl and / or C1-C6 alkoxy groups; or [ka] (optionally modified with one, two or more, or a combination of halogen, OMe, SMe, NH2, NO2, CN, OH or additional nitrogen atoms in the ring); R 7 is R X -(Xaa 2 ) 0-4 -, [ka] and R 28 is an albumin binder, Xaa 2 and Xaa 3 When present, each independently represents -N(R 13 )R 14 C(O)—, where each R 13 is independently hydrogen or methyl; 14 are independently straight or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 20Alkylenyl, alkenylenyl or alkynylenyl, or X-X which is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 20 heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; Each R X is independently a radiolabeling group selected from a radiometal chelator optionally having a radiometal bound thereto, an aryl or heteroaryl substituted with a radioactive halogen, a prosthetic group comprising a trifluoroborate, a prosthetic group comprising a silicon-fluorine-acceptor moiety, or a prosthetic group comprising a fluorophosphate, a fluorosulfate, a sulfonyl fluoride, or combinations thereof.

[0008] In some embodiments of the compound, salt, or solvate of Formula II, R 0 is O, R 1a , R 1b and R 1c each is independently -CO2H, -SO2H, -SO3H, -SO4H, -PO2H, -PO3H, or -PO4H; R 2-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)C H2CH2-, -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(CH 3)-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(C H3)-, -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 is a linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 20 Alkylenyl or alkenylenyl, or X-X which is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 20 heteroalkylenyl or heteroalkenylenyl, R 4-O-, -S-, -S(O)-, -S(O)2-, -NHC(O)-, -C(O)NH-, [ka] and R 5 is a linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 30 X-X is alkylenyl, alkenylenyl or alkynylenyl, or is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 30 heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; R 6 is hydrogen or methyl, Xaa 1 is -N(R 8 )R 9 C(O)-, where each R 8 is independently hydrogen or methyl; 9 are independently straight or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 20 Alkylenyl, alkenylenyl or alkynylenyl, or X-X which is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 20 heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; At least one R 9 or R 5 is -(CH2) 0-3 CH(R 10 )(CH2) 0-3 -, wherein R 10 is a linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C2-C 19 X-X is alkyl, alkenyl or alkynyl, linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic, with only 1 to 3 heteroatoms; 19 Heteroalkyl, heteroalkenyl, or heteroalkynyl, or -CHR23 (That R 23 is an optionally substituted C4-C 16 an aromatic ring system, a partially aromatic fused ring system, or a fully aromatic fused ring system, in which 0-3 carbons are replaced by heteroatoms N, S and / or O, and the optional substituents are selected from OH, NH2, NO2, halogen, C1-C6 alkyl and / or C1-C6 alkoxy groups; R 7 is R X -(Xaa 2 ) 0-4 -, [ka] and R 11 does not exist or [ka] and R 12 is I, Br, F, Cl, H, OH, OCH3, NH2, NO2 or CH3, Xaa 2 When present, -N(R 13 )R 14 C(O)—, where each R 13 is independently hydrogen or methyl; 14 are independently straight or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 20 Alkylenyl, alkenylenyl or alkynylenyl, or X-X which is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 20 heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; Each R Xis independently a radiolabeling group selected from a radiometal chelator optionally bound to a radiometal, a radioisotope-substituted aryl, a prosthetic group containing a trifluoroborate, and a prosthetic group containing a silicon-fluorine-acceptor moiety.

[0009] Various embodiments disclosed herein relate to compounds that include a prostate-specific membrane antigen (PSMA) targeting moiety of formula III, or a salt or solvate of formula III: [ka] During the ceremony, R 0 is O or S, R 1a is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, OPO3H2, OSO3H, -B(OH)2 or [ka] and R 1b are -CO2H, -SO2H, -SO3H, -PO2H, -PO3H 2、 -B(OH)2 or [ka] and R 1c is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -B(OH)2 or [ka] and 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-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-, -C(O)-NH-CH2-, -C(O)-NH-CH(CH3)- or -C(O)-NH-C(CH3)2-, R 3 is the linker.

[0010] In some embodiments of the compound, salt, or solvate of Formula III, R 0 is O, R 1a , R 1b and R 1c each is independently -CO2H, -SO2H, -SO3H, -SO4H, -PO2H, -PO3H, or -PO4H; R 2-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(CH 3)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)-, -C(O)-NH-C(CH3)2-, -CH2CH(COOH)CH2- or -CH2CH2CH(COOH)-, R 3 is the linker.

[0011] Various embodiments disclosed herein relate to a compound having formula IV, or a salt or solvate of formula IV: [ka] During the ceremony, R 0 is S or O, R 1a is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -OPO3H2, -OSO3H, -B(OH)2 or [ka] and R 1b is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -B(OH)2 or [ka] and R 1c is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -B(OH)2 or [ka] and R 2-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-, -C H2C(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(C H3)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-, in which HC[CH2]CH represents a cyclopropyl ring; R 3 is a linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 20Alkylenyl or alkenylenyl, or X-X which is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 20 heteroalkylenyl or heteroalkenylenyl, R 4 -O-, -S-, -Se-, -S(O)-, -S(O)2-, -NHC(O)-, -C(O)NH-, [ka] -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-, [ka] and R 5 is a linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 30 X-X is alkylenyl, alkenylenyl or alkynylenyl, or is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 30 heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; R 6 is hydrogen, methyl or ethyl, Xaa 1 is -N(R 8 )R 9 C(O)-, where each R 8 is independently hydrogen or methyl; 9 are independently straight or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 20 Alkylenyl, alkenylenyl or alkynylenyl, or X-X which is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 20heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; At least one R 9 or R 5 is -(CH2) 0-3 CH(R 10 )(CH2) 0-3 -, wherein R 10 teeth, Straight or branched chain, cyclic or acyclic, and / or aromatic or non-aromatic C2-C 19 X-X is alkyl, alkenyl or alkynyl, linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic, with only 1 to 3 heteroatoms; 19 heteroalkyl, heteroalkenyl or heteroalkynyl, -CH2R 23 (That R 23 is an optionally substituted C4-C 16 an aromatic ring system, a partially aromatic fused ring system or a fully aromatic fused ring system in which 0-3 carbons are replaced by heteroatoms N, S and / or O, the optional substituents being selected from OH, NH2, NO2, halogen, C1-C6 alkyl and / or C1-C6 alkoxy groups; or [ka] (optionally modified with one, two or more, or a combination of halogen, OMe, SMe, NH2, NO2, CN, OH or additional nitrogen atoms in the ring); R 7 is R X -(Xaa 2 ) 0-4 -, [ka] and R 28 is an albumin binder, Xaa 2 and Xaa3 When present, each independently represents -N(R 13 )R 14 C(O)—, where each R 13 is independently hydrogen or methyl; 14 are independently straight or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 20 Alkylenyl, alkenylenyl or alkynylenyl, or X-X which is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 20 heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; Each R X is independently a radiolabeling group selected from an optionally metal-bound radiometal chelator, a radioisotope-substituted aryl or heteroaryl, a trifluoroborate-containing prosthetic group, or a silicon-fluorine-acceptor moiety, a fluorophosphate, a fluorosulfate, or a sulfonyl fluoride-containing prosthetic group; R 7 -(Xaa 1 ) 1-4 -N(R 6 )-R 5 -R 4 -R 3 Any one or any combination of the amide bonds in the formula (I) may be selected from the group consisting of -O-, -S-, -Se-, -S(O)-, -S(O)2-, -NHC(O)-, -C(O)NH-, [ka] It is replaced by one or a combination selected from the group consisting of -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-.

[0012] Various embodiments disclosed herein relate to a compound having formula V, or a salt or solvate of formula V: [ka] During the ceremony, R 0 is S or O, R 1a is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -OPO3H2, -OSO3H, -B(OH)2 or [ka] and R 1b is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -B(OH)2 or [ka] and R 1c is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -B(OH)2 or [ka] and R 2-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-, -C H2C(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(C H3)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-, in which HC[CH2]CH represents a cyclopropyl ring; R 3 is a linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 20Alkylenyl or alkenylenyl, or X-X which is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 20 heteroalkylenyl or heteroalkenylenyl, R 4 -O-, -S-, -Se-, -S(O)-, -S(O)2-, -NHC(O)-, -C(O)NH-, [ka] -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-, [ka] and R 5 is a linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 30 X-X is alkylenyl, alkenylenyl or alkynylenyl, or is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 30 heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; R 6 is optional, Xaa 1 a carbonyl group which results in an amide bond, a phosphoryl group which results in a phosphoramidate / phosphonamidate bond, or a sulfonyl group which results in a sulfonamide bond, or 1 -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)-, Xaa 1 is -N(R 8 )R 9C(O)-, where each R 8 is independently hydrogen or methyl; 9 are independently straight or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 20 Alkylenyl, alkenylenyl or alkynylenyl, or X-X which is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 20 heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; At least one R 9 or R 5 is -(CH2) 0-3 CH(R 10 )(CH2) 0-3 -, wherein R 10 teeth, Straight or branched chain, cyclic or acyclic, and / or aromatic or non-aromatic C2-C 19 X-X is alkyl, alkenyl or alkynyl, linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic, with only 1 to 3 heteroatoms; 19 heteroalkyl, heteroalkenyl or heteroalkynyl, -CH2R 23 (That R 23 is an optionally substituted C4-C 16 an aromatic ring system, a partially aromatic fused ring system or a fully aromatic fused ring system in which 0-3 carbons are replaced by heteroatoms N, S and / or O, the optional substituents being selected from OH, NH2, NO2, halogen, C1-C6 alkyl and / or C1-C6 alkoxy groups; or [ka] (optionally modified with one, two or more, or a combination of halogen, OMe, SMe, NH2, NO2, CN, OH or additional nitrogen atoms in the ring); R7 is R X -(Xaa 2 ) 0-4 -, [ka] and R 28 is an albumin binder, Xaa 2 and Xaa 3 When present, each independently represents -N(R 13 )R 14 C(O)—, where each R 13 is independently hydrogen or methyl; 14 are independently straight or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 20 Alkylenyl, alkenylenyl or alkynylenyl, or X-X which is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 20 heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; Each R X is independently a radiolabeling group selected from an optionally metal-bound radiometal chelator, a radioisotope-substituted aryl or heteroaryl, a trifluoroborate-containing prosthetic group, or a silicon-fluorine-acceptor moiety, a fluorophosphate, a fluorosulfate, or a sulfonyl fluoride-containing prosthetic group.

[0013] Various embodiments may be used to image PSMA-expressing tissues in a subject.Various embodiments may be used to treat a condition or disease in a subject that expresses PSMA.

[0014] The features of the present invention will become apparent from the following description taken in conjunction with the accompanying drawings. [Brief description of the drawings]

[0015] [Figure 1]1 shows examples of prior art PSMA-targeted compounds for imaging prostate cancer. [Diagram 2] 1 shows a synthesis scheme for HTK03149 using a solid-phase approach. [Diagram 3] 1 shows a general synthesis scheme for several example compounds incorporating the PSMA binding moiety Lys-ureido-Aad. [Figure 4] A general synthesis scheme for an example compound having two BF3 labeling groups is shown. [Diagram 5] Shown are reconstructed 68Ga-labeled PET images of mice injected with 68Ga-HTK03149. Images were acquired 1 and 3 hours after intravenous injection of 68Ga-HTK03149 in immunodeficient mice bearing LNCaP xenografts. Solid arrows indicate extensive tumor uptake. Dotted arrows indicate minimal kidney uptake. [Figure 6] 1 shows the chemical structures of compounds HTK03041, HTK03149, HTK03169, HTK03161, HTK03177, HTK03187, HTK03153, HTK03170, HTK03189A, HTK03189B, HTK04033, HTK04036, HTK04037, HTK04040, HTK04041, HTK04053, HTK03162, and HTK04055. [Figure 7] Maximum intensity projection PET / CT images of 68Ga-HTK03041, 68Ga-HTK03149, 68Ga-HTK03161, 68Ga-HTK03169, 68Ga-HTK03177, 68Ga-HTK03187, 68Ga-HTK03189A, 68Ga-HTK03189B, 68Ga-HTK04033, 68Ga-HTK04036, 68Ga-HTK04037, 68Ga-HTK04040, 68Ga-HTK04041 and 68Ga-HTK04053 acquired 1 hour after injection. [Figure 8]Maximum projection SPECT / CT images of 177Lu-HTK03149 acquired 1 hour, 4 hours, 24 hours, 72 hours, and 120 hours after injection are shown (t: tumor, k: kidney, b: bladder). [Figure 9] Maximum projection SPECT / CT images of 177Lu-HTK03153 acquired 1 hour, 4 hours, 24 hours, 72 hours, and 120 hours after injection are shown (t: tumor, k: kidney, b: bladder). [Figure 10] Maximum intensity projection SPECT / CT images of 177Lu-HTK03170 acquired 1 hour, 4 hours, 24 hours, 72 hours, and 120 hours after injection are shown (t: tumor, k: kidney, b: bladder). [Figure 11] Maximum intensity projection SPECT / CT images of 177Lu-HTK04028 acquired 1 hour, 4 hours, 24 hours, 72 hours, and 120 hours after injection are shown (t: tumor, k: kidney, b: bladder). [Figure 12] Maximum projection SPECT / CT images of 177Lu-HTK04048 acquired 1, 4, 24, 72 and 120 hours after injection are shown (t: tumor, k: kidney, b: bladder). [Figure 13] Maximum intensity projection PET / CT images of 18F-HTK03162 and 18F-HTK04055 acquired 1 and 2 hours after injection are shown (t: tumor, k: kidney, b: bladder). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] As used herein, the terms "comprising," "having," "including," and "containing," as well as grammatical variations thereof, are inclusive or open ended and do not exclude additional elements and / or method steps not listed, even if a feature / component defined as part of an element and / or method step consists or consists essentially of the stated feature(s) / component(s). The term "consisting essentially of," when used herein in the context of a compound, composition, use, or method, indicates that additional elements and / or method steps may be present, but that these additions do not materially affect the manner in which the compound, composition, method, or use as listed functions. The term "consisting of," when used herein in the context of 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 including certain elements and / or steps may, in certain embodiments, consist essentially of those elements and / or steps, or in other embodiments, consist of those elements and / or steps, whether or not those embodiments are specifically mentioned. A compound, composition, use or method described herein as including certain elements and / or steps may, in certain embodiments, consist essentially of those elements and / or steps, or in other embodiments, consist of those elements and / or steps, whether or not those embodiments are specifically mentioned.

[0017] Reference to an element with the indefinite article "a" does not exclude the presence of more than one of that element, unless the context clearly requires that there be only one or one of that element. The singular forms "a," "an," and "the" include plural references unless the context clearly indicates otherwise. The use of the words "a" or "an," when used in conjunction with the term "comprising," may mean "one," but is also compatible with the meanings of "one or more," "at least one," and "one or more."

[0018] In this disclosure, when numerical ranges are recited by endpoints, they include all numbers within that range, including all whole numbers, all integers, and all intervening fractions, where appropriate (e.g., 1 to 5 may include 1, 1.5, 2, 2.75, 3, 3.80, 4, and 5, etc.).

[0019] Unless otherwise specified, the terms "certain embodiment," "various embodiments," "embodiments," and similar terms include the particular feature or features described for that embodiment, either alone or in combination with any other embodiment or embodiment described herein, whether or not that other embodiment is referred to directly or indirectly, and whether or not the feature or embodiment is described in the context of a method, product, method of use, composition, compound, etc.

[0020] As used herein, the terms "treat," "treatment," "therapeutic," and the like include amelioration of symptoms, reducing the progression of disease, improving prognosis, and reducing recurrence.

[0021] As used herein, the term "diagnostic agent" includes "imaging agent." Thus, a "diagnostic radiometal" includes a radiometal suitable for use as an imaging agent.

[0022] The term "subject" refers to an animal (e.g., a mammal or a non-mammal). The subject may be a human or a non-human primate. The subject may be a laboratory mammal (e.g., a mouse, a rat, a rabbit, a hamster, etc.). The subject may be a farm 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.

[0023] The compounds disclosed herein may also include their free base forms, salts or pharma- ceutically acceptable salts.Unless otherwise specified, 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 expressly set forth herein.

[0024] The compounds disclosed herein may be shown to have one or more charged groups, may be shown to have ionic groups in an uncharged (e.g., protonated) state, or may be shown without specifying a formal charge. As will be apparent to those skilled in the art, the ionization state of a particular group (e.g., but not limited to, CO2H, PO3H2, SO2H, SO3H, SO4H, OPO3H2, etc.) in a compound will depend, among other things, on the pKa of the group and the pH at which it is located. For example, but not limited to, carboxylic acid groups (i.e., COOH) are generally found to be deprotonated (and negatively charged) at neutral and at most physiological pH values, unless the protonation state is stabilized. Similarly, OSO3H (i.e., SO4H), SO2H, SO3H, OPO3H2 (i.e., PO4H2), and PO3H groups will generally be deprotonated (and negatively charged) at neutral and physiological pH values.

[0025] As used herein, the terms "salt" and "solvate" have their usual meaning in chemistry. Thus, when the compounds of the present invention are salts or solvates, they are associated with appropriate counterions. Methods for preparing salts or exchanging counterions are well known in the art. Generally, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of an appropriate base (e.g., but not limited to, hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg, or K), or by reacting the free base forms of these compounds with a stoichiometric amount of an appropriate acid. Such reactions are generally carried out in water or an organic solvent, or a mixture of the two. Counterions can be changed, for example, by ion exchange techniques such as ion exchange chromatography. All zwitterions, salts, solvates, and counterions are intended, unless a particular form is specifically indicated.

[0026] In certain embodiments, the salt or counterion may be pharma- ceutically acceptable for administration to a subject.More broadly, for any pharmaceutical composition disclosed herein, non-limiting examples of suitable excipients include any suitable buffer, stabilizer, salt, antioxidant, complexing agent, isotonicity agent, cryoprotectant, dry protection agent, suspending agent, emulsifying agent, antimicrobial agent, preservative, chelating agent, binder, surfactant, wetting agent, non-aqueous vehicle such as fixed oil, or polymer for slow or controlled 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 editors. Lippincott Williams & Wilkins Philadelphia) (each of which is incorporated by reference in its entirety).

[0027] As used herein, the expression "Xy-Xz" (where y and z are integers. For example, X1-X 15 , X1-X 30 , X1-X100 etc.) refers to the number of carbons in a compound, R group or substituent (in the case of alkyl (whether saturated or unsaturated) or aryl), or refers to the number of carbons and heteroatoms in a compound, R group or substituent (in the case of heteroalkyl (whether saturated or unsaturated) or heteroaryl). The heteroatoms may include any, some or all of the 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. Alternatively, the alkyl and aryl may be expressed as "Cy-Cz" (where y and z are integers, e.g., C3-C4). 15 It may be referred to using the terms ", " etc.

[0028] Unless expressly specified otherwise, the terms "alkyl" and "heteroalkyl" respectively include (1) saturated and unsaturated alkyls (including partially unsaturated alkyls) (e.g., alkenyl and alkynyl), (2) straight or branched chain, (3) acyclic or cyclic (aromatic or non-aromatic), where cyclic may include polycyclic (fused rings, non-fused polycyclics, or combinations thereof), and (4) unsubstituted or substituted, any reasonable combination. For example, an alkyl or heteroalkyl (i.e., "alkyl / heteroalkyl") may be saturated, branched and cyclic, unsaturated, branched and cyclic, or straight and unsaturated, or any other reasonable combination of any of the above, according to the knowledge of one of ordinary skill in the art. If not specified, the size of the alkyl / heteroalkyl is that size that would be deemed reasonable by one of ordinary skill in the art. For example, but not limited to, if not specified, the size of the alkyl group may be determined according to the common general knowledge of a person skilled in the art to 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, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 11 , 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, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or more in length.Furthermore, if not specified, the size of a heteroalkyl may be determined according to the common general knowledge of a person skilled in the art to 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, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 109, 108, 109, 110, 111, 112, 113, 114, 115 6, 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, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or more than 100 amino acids in length. In conjunction with the expressions "alkyl, alkenyl, or alkynyl" and similar expressions, "alkyl" is to be understood as a saturated alkyl. Similarly, in conjunction with the expressions "heteroalkyl, heteroalkenyl, or heteroalkynyl" and similar expressions, "heteroalkyl" is to be understood as a saturated heteroalkyl.

[0029] As used herein, in the context of alkyl / heteroalkyl groups of a compound, the term "straight-chain" can be used as commonly understood by those skilled in the art and generally refers to a chemical entity that contains a backbone or main chain that is not divided into two or more continuous chains. Non-limiting examples of straight-chain alkyls include methyl, ethyl, n-propyl, and n-butyl.

[0030] As used herein, the term "branched" can be used as commonly understood by those skilled in the art and generally refers to a chemical entity that includes a backbone or main chain that branches into two or more continuous chains. The portion of the backbone or main chain that branches in two or more directions can be linear, cyclic, or any combination thereof. Non-limiting examples of branched alkyl groups include tert-butyl and isopropyl.

[0031] The term "alkylenyl" refers to the divalent analog of an alkyl group. In the context of the expressions "alkylenyl, alkenylenyl or alkynylenyl", "alkylenyl or alkenylenyl" and similar expressions, "alkylenyl" is to be understood as a saturated alkylenyl. The term "heteroalkylenyl" refers to the divalent analog of a heteroalkyl group. In the context of the expressions "heteroalkylenyl, heteroalkenylenyl or heteroalkynylenyl", "heteroalkylenyl or heteroalkenylenyl" and similar expressions, "heteroalkylenyl" is to be understood as a saturated heteroalkylenyl.

[0032] As used herein, the term "saturated" when referring to a chemical entity may be used as commonly understood by one of ordinary skill in the art and generally refers to a chemical entity that contains only single bonds and may include linear, branched and / or cyclic groups. 20Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, i-pentyl, sec-pentyl, t-pentyl, n-hexyl, i-hexyl, 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, and 2-ethylbutyl. , 1,3-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, sec-hexyl, t-hexyl, n-heptyl, i-heptyl, sec-heptyl, t-heptyl, n-octyl, i-octyl, sec-octyl, t-octyl, n-nonyl, i-nonyl, sec-nonyl, t-nonyl, n-decyl, i-decyl, sec-decyl, t-decyl, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, cyclooctanyl, cyclononanyl, cyclodecanyl, and the like. Thus, unless otherwise specified, C1-C 20 Alkylenyl includes, but is not limited to, all the divalent analogs of the saturated alkyl groups listed above.

[0033] As used herein, the term "unsaturated" when referring to a chemical entity may be used as commonly understood by one of ordinary skill in the art and generally refers to a chemical entity that contains at least one double or triple bond and may include straight-chain, branched-chain 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. Thus, unless otherwise specified, C1-C 20 Alkenylenyl includes, but is not limited to, all the divalent analogs of the alkenyl groups listed above. C2-C20 Non-limiting examples of alkynyl groups may include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, and the like. Thus, unless otherwise specified, C1-C 20 Alkynylenyl includes, but is not limited to, all divalent analogs of the alkynyl groups listed above. Unless otherwise indicated, includes, but is not limited to, saturated C-C alkyl groups as defined above. 20 Alkyl groups, C2-C 20 Alkenyl groups and C2-C 20 All alkynyl groups are represented as X1-X 20 Unless otherwise indicated, the term "alkyl" includes, but is not limited to, saturated C-C alkyl groups as defined above. 20 Alkylenyl groups, C2-C 20 Alkenyl groups and C2-C 20 All alkynylenyl groups are represented as X1-X 20 The term "alkylenyl" includes the above-mentioned groups.

[0034] Including, but not limited to, "X1-X 20 The term "heteroalkyl" includes any saturated C-C alkyl group as defined above. 20 Alkyl groups, C2-C 20 Alkenyl groups and C2-C 20 Each of the alkynyl groups is intended to include groups in which one or more of the carbon atoms is independently replaced by a heteroatom. 20 The term "heteroalkylenyl" includes any saturated C-C alkyl group as defined above. 20 Alkylenyl groups, C2-C 20 Alkenyl groups and C2-C 20Each of the alkynylenyl groups includes groups in which one or more of its carbon atoms are independently replaced by heteroatoms.Those skilled in the art will understand that different combinations of different heteroatoms can be used.Non-limiting examples of non-aromatic heterocyclic groups include aziridinyl, azetidinyl, diazetidinyl, pyrrolidinyl, pyrrolinyl, piperidinyl, piperazinyl, imidazolinyl, pyrazolidinyl, imidazolidinyl, phthalimidyl, succinimidyl, oxiranyl, tetrahydropyranyl, oxetanyl, dioxanyl, thietanyl, thiepinyl, morpholinyl, oxathiolanyl, etc.

[0035] Unless further specified, "aryl" groups include both aromatic monocyclic 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, quinolinyl, isoquinolinyl, acridinyl, indolyl, isoindolyl, indolizinyl, purinyl, carbazolyl, indazolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, phenanthridinyl, phenazinyl, phenanthrolinyl, perimidinyl, furyl, dibenzofuryl, xanthenyl, benzofuryl, thiophenyl, thianthrenyl, benzothiophenyl, phosphorinyl, phosphinolinyl, phosphindolyl, thiazolyl, oxazolyl, isoxazolyl, and the like.

[0036] 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 a chemical group is replaced with a different chemical group.Unless otherwise specified, a substituted alkyl is an alkyl in which one or more hydrogen atoms are independently replaced with non-hydrogen atoms.For example, chloromethyl is a non-limiting example of a substituted alkyl, more specifically an example of a substituted methyl.Aminoethyl is another non-limiting example of a substituted alkyl, more specifically an example of a substituted ethyl.Unless otherwise specified, a substituted compound or group (e.g., alkyl, heteroalkyl, aryl, heteroaryl, etc.) may be substituted with any chemical group that is reasonable for those skilled in the art. For example, but not limited to, a hydrogen bonded to a carbon atom or a heteroatom (e.g., N) may be substituted with a halide (e.g., F, I, Br, Cl), an amine, an amide, an oxo, a hydroxyl, a thiol, a phosphate, a phosphonate, a sulfate, SOH, SOH, an alkyl, a heteroalkyl, an aryl, a heteroaryl, a ketone, a carboxaldehyde, a carboxylate, a carboxamide, a nitrile, a monohalomethyl, a dihalomethyl, or a trihalomethyl.

[0037] As used herein, the term "unsubstituted" is used as is commonly understood by those of ordinary skill in the art. Non-limiting examples of unsubstituted alkyl include methyl, ethyl, tert-butyl, pentyl, etc. The term "optionally substituted" is used synonymously with the term "unsubstituted or substituted."

[0038] In the structures depicted herein, hydrogen may or may not be shown. In some embodiments, hydrogen (whether shown or implied) is replaced by protium (i.e. 1 H), deuterium (i.e. 2 H), or 1 H and 2 H may be in combination. 1 H 2Methods for exchanging with H are well known in the art. For solvent exchangeable hydrogen, 1 H 2 Exchange with H is easily accomplished in the presence of a suitable deuterium source without any catalyst. The use of acids, bases or metal catalysts in combination with elevated temperature and pressure conditions can facilitate the exchange of non-exchangeable hydrogen atoms, generally resulting in the exchange of all hydrogen atoms in the molecule. 1 H, 2 It is replaced by H.

[0039] The term "Xaa" refers to an amino acid residue in a peptide chain or otherwise an amino acid that is part of a compound. An amino acid has both an amino group and a carboxylic acid group, either or both of which can be used for covalent attachment. Upon attachment to the remainder of the compound of the invention, the amino and / or carboxylic acid group may be converted to an amide or other structure, for example, the carboxylic acid group of a first amino acid is converted to an amide when attached to the amino group of a second amino acid (i.e., a peptide bond). Thus, Xaa can be represented by -N(R a )R b C(O)-, where R a and R b is an R group. awill typically be hydrogen or methyl. The amino acid residues of the peptide may contain typical peptide (amide) bonds and may further contain a bond between a side chain functional group and a side chain or main chain functional group of another amino acid. For example, the side chain carboxylate of one amino acid residue (e.g., Asp, Glu, etc.) in a peptide may be bonded to the amine of another amino acid residue (e.g., Dap, Dab, Orn, Lys) in the peptide. Further details are provided below. Unless otherwise indicated, "Xaa" may be any amino acid, including proteinogenic and non-proteinogenic amino acids.Non-limiting examples of non-proteinogenic amino acids are shown in Table 1 and include D-amino acids (including, but not limited to, the D-form of any 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-triazol-4-yl)-L-alanine, 1,2,4-triazol-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-aminovaleric acid, 6-aminohexanoic acid, 7-aminoheptanoic acid, 8-aminooctanoic acid, 9-aminononanoic acid, 10-aminodecanoic acid, 2-aminooctanoic acid, 2-amino-3-(amino)-(2-amino-1 ... 2-amino-3-(anthracen-2-yl)propanoic acid, 2-amino-3-(anthracen-9-yl)propanoic acid, 2-amino-3-(pyren-1-yl)propanoic 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-diaminopropargylglycine (Hpg), Aminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab), azidolysine (Lys(N3)), azido-ornithine (Orn(N3)), 2-amino-4-azidobutanoic 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. When not specified as an L-amino acid or a D-amino acid, it is understood that the amino acid includes both L-amino acids and D-amino acids.

[0040] [Table 1]

[0041] R of formula (e.g., Formula I) 4 , R 6 , R 7 , R 9 and R 11 In the definition of [ka] The symbol R is intended to define the R group on the other side of the wavy line without changing the definition of the structure on one side of the line. When an R group is attached to more than one moiety (e.g., R 11 ), any atoms shown outside the dashed lines are intended to clarify the orientation of the R group; that is, only the atoms between the two dashed lines constitute the definition of the R group. When no atoms are shown outside the dashed lines, or when a chemical group is shown without dashed lines but has bonds to multiple moieties (e.g., -C(O)NH-), the chemical group is intended to be ordered from left to right and oriented according to the formula to which the group pertains (e.g., -R a -R b -R c -, where R is defined as -C(O)NH- b When inserted into the formula, -R a -C(O)NH-R c -R a -NHC(O)-R c - does not mean.

[0042] In various embodiments, disclosed are compounds of Formula I (defined below), Formula II (defined below), Formula IV (defined below) or Formula V (defined below), or compounds comprising a PSMA targeting moiety of Formula III (defined below), including salts or solvates thereof.

[0043] The following definitions apply to compounds of formula I (and their salts / solvates).

[0044] In some embodiments, the compound of the invention is a compound of formula I, or a salt or solvate of formula I: [ka] During the ceremony, n is 0 or 1, R 1a , R 1b and R 1c each is independently -CO2H, -SO2H, -SO3H, -SO4H, -PO2H, -PO3H, or -PO4H; When n is 0, R 2 is -CH2-, -CHOH-, -CHF-, -CH2CHOH-, -CH2CHF-, -CH2CHOHCH2-, -CH2CHFCH2-, -(CH2)2CHOH-, -(CH2)2CHF-, -(CH2)3-, -CH2OCH2- or -CH2SCH2-, When n is 1, R 2 is -CH2-, -CHOH-, -CHF-, -CH2CHOH-, -CH2CHF- or -(CH2)2-, R 3 is a linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 20 Alkylenyl or alkenylenyl, or X-X which is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 20 heteroalkylenyl or heteroalkenylenyl, R 4 -O-, -S-, -NHC(O)-, -C(O)NH-, [ka] and R 5 is a linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 30X-X is alkylenyl, alkenylenyl or alkynylenyl, or is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 30 heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; R 6 is hydrogen or methyl, Xaa 1 is -N(R 8 )R 9 C(O)-, where each R 8 is independently hydrogen or methyl; 9 are independently straight or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 20 Alkylenyl, alkenylenyl or alkynylenyl, or X-X which is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 20 heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; At least one R 9 or R 5 teeth, [ka] and At least one R 9 or R 5 is -(CH2) 0-3 CH(R 10 )(CH2) 0-3 -, wherein R 10 is a linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C2-C 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; R 7 is R X -(Xaa 2 )0-4 -, [ka] and R 11 does not exist or [ka] and R 12 is I, Br, F, Cl, H, OH, OCH3, NH2, NO2 or CH3, Xaa 2 When present, -N(R 13 )R 14 C(O)—, where each R 13 is independently hydrogen or methyl; 14 are independently straight or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 20 Alkylenyl, alkenylenyl or alkynylenyl, or X-X which is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 20 heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; Each R X is independently a radiolabeling group selected from a radiometal chelator optionally bound to a radiometal, an aryl substituted with a radioisotope, a prosthetic group containing a trifluoroborate, and a prosthetic group containing a silicon-fluorine-acceptor moiety.

[0045] In some embodiments, the compound is a salt or solvate of Formula I.

[0046] In some embodiments, the compound of formula I is a compound of formula Ia: [ka] In the formula, R 1a , R 1b , R 1c , R 2 , R 3, R 4 , R 5 , R 6 , Xaa 1 and R 7 is as defined in formula I. In some embodiments, the compound is a salt or solvate of formula Ia.

[0047] In some embodiments, n is 0. In some embodiments, n is 1.

[0048] In some embodiments, R 1a is -COH. In some embodiments, R 1b is -COH. In some embodiments, R 1c is -COH. In some embodiments, R 1a and R 1b Each is -COH. In some embodiments, R 1a and R 1c Each is -COH. In some embodiments, R 1b and R 1c Each is -COH. In some embodiments, R 1a , R 1b and R 1c are -CO2H, respectively.

[0049] In some embodiments, R 2 is -CH2OCH2- or -CH2SCH2-.

[0050] In some embodiments, n is 0 and R 2 In some embodiments, n is 0 and R 2 In some embodiments, n is 0 and R 2 In some embodiments, n is 0 and R 2 In some embodiments, n is 0 and R 2 In some embodiments, n is 0 and R 2In some embodiments, n is 0 and R 2 In some embodiments, n is 0 and R 2 In some embodiments, n is 0 and R 2 In some embodiments, n is 0 and R 2 In some embodiments, n is 0 and R 2 In some embodiments, n is 0 and R 2 is -CH2SCH2-.

[0051] In some embodiments, n is 1 and R 2 In some embodiments, n is 1 and R 2 In some embodiments, n is 1 and R 2 In some embodiments, n is 1 and R 2 In some embodiments, n is 1 and R 2 In some embodiments, n is 1 and R 2 is -(CH2)2-.

[0052] In some embodiments, n is 0 and R 1a is -COH, R 2 In some embodiments, n is 0 and R 1a is -COH, R 2 In some embodiments, n is 0 and R 1a is -COH, R 1b is -COH, R 1c is -COH, R 2 In some embodiments, n is 0 and R 1a is -COH, R 2is -CH2-.

[0053] In some embodiments, R 3 is a straight chain acyclic C3-C 15 In some embodiments, R 3 is a straight-chain acyclic C3-C cyclic ring having 1 to 5 heteroatoms N, S and / or O. 15 In some embodiments, R 3 is a linear, acyclic, saturated C3-C alkyl group optionally substituted with 1 to 5 amine, amide, oxo, hydroxyl, thiol, methyl or ethyl groups. 10 In some embodiments, R 3 is -(CH2) 3-15 In some embodiments, R 3 is -CH-. 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 -CH-O-CH-. In some embodiments, R 3 is -CH2-S-CH2-.

[0054] In some embodiments, R 4 In some embodiments, R 4 is -S-. In some embodiments, R 4 is -NHC(O)-. In some embodiments, R 4 is -C(O)NH-. In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] It is.

[0055] In some embodiments, R 3 is -(CH2) 3-15 - and R 4 is -C(O)NH-. In some embodiments, R 3 is -(CH2) 3-5 - and R 4 is -C(O)NH-. In some embodiments, R 3 is -(CH2)4-, R 4 is -C(O)NH-.

[0056] In some embodiments, R 5 is -(CH2) 0-3 CH(R 10 )(CH2) 0-3 In some embodiments, R 5 is -CH(R 10 In some embodiments, R 5 is -CHCH(R 10 In some embodiments, R 5 is -CH(R 10 )CH-. In some embodiments, R 5 is -CH(R 10 )-.

[0057] In some embodiments, R 10 is C6-C 16 aryl or X6-X having 1 to 3 heteroatoms independently selected from N, S and / or O; 16 In some embodiments, the C6-C 16 Aryl is benzyl. In some embodiments, the X-X 16 Heteroaryl is benzyloxyl or benzylthio. In some embodiments, R 10 teeth, [ka] In some embodiments, R 10 teeth, [ka] In some embodiments, R 10 teeth, [ka] In some embodiments, R 10 teeth, [ka] It is.

[0058] In some embodiments, R 5 is -CH(R 10 )-, where R 10 is as defined in any of the above embodiments.

[0059] In some embodiments, R 5 is -(CH2) 0-3 CH(R 10 )(CH2) 0-3 - and R 10 is -(CH2)5CH3. In some embodiments, R 5 is -CH(R 10 )- and R 10 is -(CH2)5CH3.

[0060] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] It is.

[0061] In some embodiments, R6 is hydrogen. In some embodiments, R 6 is methyl.

[0062] In some embodiments, (Xaa 1 ) 1-4 consists of a single amino acid residue. 1 ) 1-4 is a dipeptide, wherein each Xaa 1 may be the same or different. In some embodiments, (Xaa 1 ) 1-4 is a tripeptide, wherein each Xaa 1 may be the same, different, or a combination of amino acid residues. 1 ) 1-4 consists of four amino acid residues linked by peptide bonds, where each Xaa 1 may be the same, different, or a combination of amino acid residues. 1 are independently selected from proteinogenic and non-proteinogenic amino acids listed in Table 1, and each amino group of the peptide backbone is optionally methylated. In some embodiments, at least one R 9 teeth, [ka] In some embodiments, at least one R 9 teeth, [ka] In some embodiments, at least one R 8 is hydrogen. In some embodiments, all R 8 is hydrogen. In some embodiments, at least one Xaa 1 is a tranexamic acid residue. In some embodiments, (Xaa 1 )1-4 consists of a single tranexamic acid residue.

[0063] In some embodiments, R 3 is -(CH2)4-, and -(Xaa 1 ) 1-4 N(R 6 )R 5 R 4 -teeth, [ka] It is.

[0064] In some embodiments, R 3 is -(CH2)4-, and -(Xaa 1 ) 1-4 N(R 6 )R 5 R 4 -teeth, [ka] It is.

[0065] The following definitions apply to compounds of formula II (and salts / solvates thereof).

[0066] In some embodiments, the compound of the invention is a compound of formula II, or a salt or solvate of formula II: [ka] During the ceremony, R 0 is O or S, R 1a is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -OPO3H2, -OSO3H, -B(OH)2 or [ka] and R 1b is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -B(OH)2 or [Chemical formula] and is R 1c is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -B(OH)2 or [Chemical formula] and is 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- and R 3 is a linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 20 Alkylenyl, alkenylenyl or alkynylenyl, or X-X which is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 20 heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; R 4 -O-, -S-, -Se-, -S(O)-, -S(O)2-, -NHC(O)-, -C(O)NH-, [ka] -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, R 5 is a linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 30 X-X is alkylenyl, alkenylenyl or alkynylenyl, or is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 30 heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; R 6 is hydrogen, methyl or ethyl, Xaa 1 is -N(R 8 )R 9 C(O)-, where each R 8 is independently hydrogen or methyl; 9 are independently straight or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 20 Alkylenyl, alkenylenyl or alkynylenyl, or X-X which is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic;20 heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; At least one R 9 or R 5 is -(CH2) 0-3 CH(R 10 )(CH2) 0-3 -, wherein R 10 teeth, Straight or branched chain, cyclic or acyclic, and / or aromatic or non-aromatic C2-C 19 X-X is alkyl, alkenyl or alkynyl, linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic, with only 1 to 3 heteroatoms; 19 heteroalkyl, heteroalkenyl or heteroalkynyl, -CH2R 23 (That R 23 is an optionally substituted C4-C 16 an aromatic ring system, a partially aromatic fused ring system or a fully aromatic fused ring system in which 0-3 carbons are replaced by heteroatoms N, S and / or O, the optional substituents being selected from OH, NH2, NO2, halogen, C1-C6 alkyl and / or C1-C6 alkoxy groups; or [ka] (optionally modified with one, two or more, or a combination of halogen, OMe, SMe, NH, NO, CN, OH, or one or more additional ring nitrogen atoms); R 7 is R X -(Xaa 2 ) 0-4 -, [ka] and R 28 is an albumin binder, Xaa 2and Xaa 3 When present, each independently represents -N(R 13 )R 14 C(O)—, where each R 13 is independently hydrogen or methyl; 14 are independently straight or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 20 Alkylenyl, alkenylenyl or alkynylenyl, or X-X which is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 20 heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; Each R X is independently a radiolabeling group selected from a radiometal chelator optionally having a radiometal bound thereto, an aryl or heteroaryl substituted with a radioactive halogen, a prosthetic group comprising a trifluoroborate, a prosthetic group comprising a silicon-fluorine-acceptor moiety, or a prosthetic group comprising a fluorophosphate, a fluorosulfate, a sulfonyl fluoride, or combinations thereof.

[0067] In some embodiments, the compound of formula II is a compound of formula IIa: [ka] In the formula, R 1a , R 1b , R 1c , R 2 , R 3 , R 4 , R 5 , R 6 , Xaa 1 and R 7 is as defined in formula II. In some embodiments, the compound of the invention is a salt or solvate of formula IIa.

[0068] In some embodiments, R 2 is -CH-. In some embodiments, R 2 is -CH(OH)-. In some embodiments, R2 In some embodiments, R 2 In some embodiments, R 2 is -CH(CH3)-. In some embodiments, R 2 is -C(CH3)2-.

[0069] In some embodiments, R 2 is -CHCH(OH)-. In some embodiments, R 2 is -CHCHF-. In some embodiments, R 2 is -CHFCH-. In some embodiments, R 2 is -CFCH-. In some embodiments, R 2 is -CHCF-. In some embodiments, R 2 is -CH(OH)CH-. In some embodiments, R 2 is -CH(CH)CH-. In some embodiments, R 2 is -CHCH(CH)-. In some embodiments, R 2 is -C(CH3)2CH2-. In some embodiments, R 2 is -CH2C(CH3)2-.

[0070] 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-.

[0071] In some embodiments, R 2-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-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-, -CH2CH(COOH)CH2-, or -CH2CH2CH(COOH)-. In some embodiments, R 2 is -CH2OCH2- or -CH2SCH2-.

[0072] In some embodiments, R 2is -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-, -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(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-.

[0073] In some embodiments, R 2-(CH2)2CHF-, -(CH2)3-, -CH2OCH2-, -CH2SCH2-, -CHFCH2CH2-, -CH(OH)CH2CH2-, -CH(CH3)CH2CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2CH2 C(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-, -C(O)-NH-CH2-, -C(O)-NH-CH(CH3)- or -C(O)-NH-C(CH3)2-.

[0074] In some embodiments, R 2 is -CH2CH(OH)-, -CH2CHF-, -CH2CH(CH3)-, -CH2CH(COOH)-, -CH2CH(OH)CH2-, -CH2CH(F)CH2- or -CH2CH(CH3)CH2-, and R 2 The second carbon in is in the R configuration. 2 is -CH2CH(OH)-, -CH2CHF- or -CH2CH(CH3)-, R 2 The second carbon in is in the R configuration. 2 is -CH2CHF-, R 2 The second carbon in is in the R configuration.

[0075] In some embodiments, R 2 is -CHCH(OH)CH-. In some embodiments, R 2is -CHCHFCH-. In some embodiments, R 2 is -(CH2)2CH(OH)-. In some embodiments, R 2 is -(CH2)2CHF-. In some embodiments, R 2 is -(CH2)3-. In some embodiments, R 2 is -CH2OCH2-. In some embodiments, R 2 is -CHSCH-. In some embodiments, R 2 is -CHFCHCH-. In some embodiments, R 2 is -CH(OH)CHCH-. In some embodiments, R 2 is -CH(CH3)CH2CH2-. In some embodiments, R 2 is -CHCH(CH)CH-. In some embodiments, R 2 is -CHCHCH(CH)-. In some embodiments, R 2 is -C(CH)CHCH-. In some embodiments, R 2 is -CHC(CH)CH-. In some embodiments, R 2 is -CHCHC(CH)-. In some embodiments, R 2 is -CH(CH)-O-CH-. In some embodiments, R 2 is -C(CH)-O-CH-. In some embodiments, R 2 is -CH2-O-CH(CH3)-. In some embodiments, R 2 is -CH-OC(CH)-. In some embodiments, R 2 is -CH-S(O)-CH-. In some embodiments, R 2 is -CH-S(O)-CH-. In some embodiments, R 2 is -CH(CH)-S-CH-. In some embodiments, R 2 is -C(CH)-S-CH-. In some embodiments, R 2is -CH-S-CH(CH)-. In some embodiments, R 2 is -CH-SC(CH)-. In some embodiments, R 2 is -CH(CH)-S(O)-CH-. In some embodiments, R 2 is -C(CH)-S(O)-CH-. In some embodiments, R 2 is -CH2-S(O)-CH(CH3)-. In some embodiments, R 2 is -CH-S(O)-C(CH)-. In some embodiments, R 2 is -CH(CH)-S(O)-CH-. In some embodiments, R 2 is -C(CH)-S(O)-CH-. In some embodiments, R 2 is -CH-S(O)-CH(CH)-. In some embodiments, R 2 is -CH-S(O)-C(CH)-. In some embodiments, R 2 is -CH-NH-C(O)-. In some embodiments, R 2 is -C(O)-NH-CH-. In some embodiments, R 2 is -C(O)-NH-CH(CH)-. In some embodiments, R 2 is -C(O)-NH-C(CH3)2-.

[0076] The following definitions apply to Formula III:

[0077] In some embodiments, the compound of the invention is a compound that includes a prostate-specific membrane antigen (PSMA) targeting moiety of formula III, or a salt or solvate of formula III: [ka] During the ceremony, R 0 is O or S, R 1ais -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -OPO3H2, -OSO3H, -B(OH)2 or [ka] and R 1b is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -B(OH)2 or [ka] and R 1c is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -B(OH)2 or [ka] and 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(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-, R 3 is the linker.

[0078] In some embodiments, the PSMA targeting moiety of formula III is a PSMA targeting moiety of formula IIIa: [ka] In the formula, R 1a , R 1b , R 1c , R 2 and R 3 is as defined in Formula III. In some embodiments, the PSMA targeting moiety is a salt or solvate of Formula IIIa.

[0079] The linker (R 3 ) can be any linker. In some embodiments, R 3 is a linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 20 Alkylenyl, alkenylenyl or alkynylenyl, or X-X which is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 20 In some embodiments, R is heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl. 3 is a linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 20 Alkylenyl or alkenylenyl, or X-X which is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 20 In some embodiments, R is heteroalkylenyl or heteroalkenylenyl. 3 is a linear or branched peptide linker.

[0080] In some embodiments, R 2-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)-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.

[0081] In some embodiments, R 2 is -CH(CH3)CH2CH2-. In some embodiments, R 2 is -CHCH(CH)CH-. In some embodiments, R 2 is -CHCHCH(CH)-. In some embodiments, R 2 is -C(CH)CHCH-. In some embodiments, R 2 is -CHC(CH)CH-. In some embodiments, R 2 is -CHCHC(CH)-. In some embodiments, R 2 is -CH(CH)-O-CH-. In some embodiments, R 2 is -C(CH)-O-CH-. In some embodiments, R 2 is -CH2-O-CH(CH3)-. In some embodiments, R 2 is -CH-OC(CH)-. In some embodiments, R 2 is -CH-S(O)-CH-. In some embodiments, R 2is -CH-S(O)-CH-. In some embodiments, R 2 is -CH(CH)-S-CH-. In some embodiments, R 2 is -C(CH)-S-CH-. In some embodiments, R 2 is -CH-S-CH(CH)-. In some embodiments, R 2 is -CH-SC(CH)-. In some embodiments, R 2 is -CH(CH)-S(O)-CH-. In some embodiments, R 2 is -C(CH)-S(O)-CH-. In some embodiments, R 2 is -CH2-S(O)-CH(CH3)-. In some embodiments, R 2 is -CH-S(O)-C(CH)-. In some embodiments, R 2 is -CH(CH)-S(O)-CH-. In some embodiments, R 2 is -C(CH)-S(O)-CH-. In some embodiments, R 2 is -CH-S(O)-CH(CH)-. In some embodiments, R 2 is -CH-S(O)-C(CH)-. In some embodiments, R 2 is -C(O)-NH-CH-. In some embodiments, R 2 is -C(O)-NH-CH(CH)-. In some embodiments, R 2 is -C(O)-NH-C(CH3)2-.

[0082] In some embodiments, R 2 is -CH2CH(CH3)CH2-, and R 2 The second carbon in is in the R configuration.

[0083] In some embodiments, the compound further comprises one or more radiolabeling groups attached to the linker, independently selected from a radiometal chelator optionally having a radiometal bound thereto, an aryl or heteroaryl substituted with a radioactive halogen, a prosthetic group comprising a trifluoroborate, or a prosthetic group comprising 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 has a radiometal bound thereto. In some embodiments, the compound comprises an aryl substituted with a radioactive halogen. In some embodiments, the compound comprises a prosthetic group comprising a trifluoroborate. In some embodiments, the compound comprises a prosthetic group comprising a silicon-fluorine-acceptor moiety. In some embodiments, the compound comprises a prosthetic group comprising a fluorophosphate. In some embodiments, the compound comprises a prosthetic group comprising a fluorosulfate. In some embodiments, the compound comprises a prosthetic group comprising a sulfonyl fluoride. In some embodiments, the fluorine in the above groups is 18 It's F.

[0084] In some embodiments, the one or more radiolabeling groups optionally include a radiometal chelator having a radiometal bound thereto, and a prosthetic group comprising trifluoroborate, optionally where one, two or three fluorines in the trifluoroborate are 18 It's F.

[0085] In some embodiments, a compound that includes a 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 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-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-, -C(O)-NH-CH2-, -C(O)-NH-CH(CH3)- or -C(O)-NH-C(CH3)2-.

[0086] Unless otherwise specified, the following definitions apply to any compound of formula II / IIa (or a salt / solvate thereof) and to any compound that contains a PSMA targeting moiety of formula III / IIla (or a salt / solvate thereof), i.e., the following definitions apply to compounds that contain a PSMA targeting moiety of formula III / IIIa (including, but not necessarily, when such compounds are compounds of formula II / IIa).

[0087] In some embodiments, R 0 is O. In another embodiment, R 0 is S.

[0088] 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, R3a is -CO2H, -SO2H, -SO3H, -PO2H, or -PO3H2. In some embodiments, R 1a is -COH. In some embodiments, R 1b is -COH. In some embodiments, R 1c is -COH. In some embodiments, R 1a and R 1b Each is -COH. In some embodiments, R 1a and R 1c Each is -COH. In some embodiments, R 1b and R 1c Each is -COH. In some embodiments, R 1a , R 1b and R 1c Each is -COH. In some embodiments, R 1a , R 1b and R 1c is an anionic or metal salt of the above.

[0089] In some embodiments, R 3 is a linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 20 Alkylenyl or alkenylenyl, or X-X which is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 20 It is heteroalkylenyl or heteroalkenylenyl.

[0090] In some embodiments, R 3 is a straight chain acyclic C3-C 15 In some embodiments, R 3 is a straight chain acyclic C3-C cyclic olefin in which 1 to 5 carbons are replaced by heteroatoms N, S and / or O. 15 In some embodiments, R 3 is a linear, acyclic, saturated C3-C alkyl group optionally substituted with 1 to 5 amine, amide, oxo, hydroxyl, thiol, methyl or ethyl groups.10 In some embodiments, R 3 is -(CH2) 3-15 In some embodiments, R 3 is -CH-. 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 -CH-O-CH-. In some embodiments, R 3 is -CH-S-CH-. In some embodiments, R 3 is -CH=CH-. In some embodiments, R 3 is -CH-C≡C-. In some embodiments, R 3 is a straight chain C3-C5 alkenylenyl and / or alkynylenyl.

[0091] In some embodiments, R 4 In some embodiments, R 4 is -S-. In some embodiments, R 4 is -NHC(O)-. In some embodiments, R 4 is -C(O)NH-. In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 is -S(O)-. In some embodiments, R 4 is -S(O)-. In some embodiments, R 4is -C(O)-(NH)-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 is -SS-. In some embodiments, R 4 is -S-CH-S-. In some embodiments, R 4 is -NH-NH-C(O)-. In some embodiments, R 4 is -C(O)-NH-NH-.

[0092] In some embodiments, R 3 is -(CH2) 3-15 - and R 4 is -C(O)NH-. In some embodiments, R 3 is -(CH2) 3-5 - and R 4 is -C(O)NH-. In some embodiments, R 3 is -(CH2)4-, R 4 is -C(O)NH-.

[0093] In some embodiments, R 5 is -(CH2) 0-3 CH(R 10 )(CH2) 0-3 In some embodiments, R 5 is -CH(R 10 In some embodiments, R 5 is -CHCH(R 10 In some embodiments, R5 is -CH(R 10 )CH-. In some embodiments, R 5 is -CH(R 10 )-.

[0094] In some embodiments, R 10 is a linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C2-C 19 X-X is alkyl, alkenyl or alkynyl, linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic, with only 1 to 3 heteroatoms; 19 It is heteroalkyl, heteroalkenyl or heteroalkynyl.

[0095] In some embodiments, R 10 is -CH2R 23 where R 23 is an optionally substituted C4-C 16 It is an aromatic ring system, a partially aromatic fused ring system or a fully aromatic fused ring system, in which 0-3 carbons are replaced by heteroatoms N, S and / or O, and the optional substituents are selected from OH groups, NH2 groups, NO2 groups, halogen groups, C1-C6 alkyl groups and / or C1-C6 alkoxy groups.

[0096] In some embodiments, R 10 teeth, [ka] (optionally modified with one, two or more, or a combination of halogen, OMe, SMe, NH2, NO2, CN, OH, or one or more additional nitrogen atoms in the ring).

[0097] In some embodiments, R 10 is C6-C 16 aryl or X6-X having 1 to 3 heteroatoms independently selected from N, S and / or O;16 In some embodiments, the C6-C 16 Aryl is benzyl. In some embodiments, the X-X 16 Heteroaryl is benzyloxyl or benzylthio.

[0098] In some embodiments, R 10 teeth, [ka] In some embodiments, R 10 teeth, [ka] In some embodiments, R 10 teeth, [ka] In some embodiments, R 10 teeth, [ka] In some embodiments, R 10 teeth, [ka] In some embodiments, R 10 teeth, [ka] In some embodiments, R 10 teeth, [ka] In some embodiments, R 10 teeth, [ka] In some embodiments, R10 teeth, [ka] In some embodiments, R 10 teeth, [ka] In some embodiments, R 10 teeth, [ka] In some embodiments, R 10 teeth, [ka] In some embodiments, R 10 teeth, [ka] In some embodiments, R 10 teeth, [ka] In some embodiments, R 10 teeth, [ka] In some embodiments, R 10 teeth, [ka] In some embodiments, R 10 In some embodiments, R 10 teeth, [ka] In some embodiments, R 10 teeth, [ka] In some embodiments, R 10 teeth, [ka] In some embodiments, R 10 teeth, [ka] It is.

[0099] In some embodiments, R 5 is -CH(R 10 )-, wherein R 10 is as defined in any of the above embodiments.

[0100] In some embodiments, R 5 is -(CH2) 0-3 CH(R 10 )(CH2) 0-3 - and R 10 is -(CH2)5CH3. In some embodiments, R 5 is -CH(R 10 )- and R 10 is -(CH2)5CH3. In some embodiments, R 5 is -(CH2) 0-3 CH(R 10 )(CH2) 0-3 -It is.

[0101] In some embodiments, R 10 is -CH 2 -R 23 In some embodiments, R 23 is phenyl substituted with one or two iodo groups and optionally further substituted with one oxy group. In some embodiments, R 5 is -(CH2) 0-3 CH(R 10 )(CH2) 0-3 -, wherein R 10 is -CH2R 23 and R23 is phenyl substituted with one or two iodo groups and optionally further substituted with one oxy group. In some embodiments, R 23 teeth, [ka] In some embodiments, R 23 teeth, [ka] In some embodiments, R 23 teeth, [ka] In some embodiments, R 23 teeth, [ka] In some embodiments, R 23 teeth, [ka] In some embodiments, R 23 teeth, [ka] In some embodiments, R 23 teeth, [ka] In some embodiments, R 23 teeth, [ka] It is.

[0102] In some embodiments, at least one R 9 or R 5 teeth, [ka] In some embodiments, at least one R 9 or R 5 teeth, [ka] In some embodiments, at least one R 9 or R 5 teeth, [ka] It is.

[0103] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] It is.

[0104] In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is methyl. In some embodiments, R 6 is ethyl.

[0105] In some embodiments, (Xaa 1 ) 1-4 consists of a single amino acid residue. 1 ) 1-4 is a dipeptide, wherein each Xaa 1 may be the same or different. In some embodiments, (Xaa 1 ) 1-4is a tripeptide, wherein each Xaa 1 may be the same, different, or a combination of amino acid residues. 1 ) 1-4 consists of four amino acid residues linked by peptide bonds, where each Xaa 1 may be the same, different, or a combination of amino acid residues. 1 are independently selected from the proteinogenic and non-proteinogenic amino acids listed in Table 1, and each amino group of the peptide backbone is optionally methylated.

[0106] In some embodiments, at least one R 9 is R 24 -R 25 -R 26 where R 24 -R 25 -R 26 are independently -(CH2) 0-3 -, C3-C8 cycloalkylene (0-3 of which are replaced by heteroatoms N, S or O, and optionally substituted with one or more OH, NH2, NO2, halogen, C1-C6 alkyl and / or C1-C6 alkoxy groups), and C4-C 16 arylene, in which 0-3 of the carbons are replaced by heteroatoms N, S or O, and optionally substituted with one or more OH, NH, NO, halogen, C-C alkyl and / or C-C alkoxy groups. In some embodiments, (Xaa 1 ) 1-4 is (Xaa 1 ) 0-3 NHR 27 C(O), where R 27 teeth, [ka] In some embodiments, at least one R9 teeth, [ka] In some embodiments, at least one R 9 teeth, [ka] In some embodiments, at least one R 9 teeth, [ka] In some embodiments, at least one R 8 is hydrogen. In some embodiments, all R 8 is hydrogen. In some embodiments, at least one Xaa 1 is a tranexamic acid residue. In some embodiments, (Xaa 1 ) 1-4 consists of a single tranexamic acid residue.

[0107] In some embodiments, R 3 is -(CH2)4-, and -(Xaa 1 ) 1-4 N(R 6 )R 5 R 4 -teeth, [ka] wherein in an alternative embodiment, R 10 is any of the Rs defined above. 10 In some such embodiments, R 10 -CH 2 -R 23 and R 23 is phenyl substituted with one or two iodo groups and optionally further substituted with one oxy group.

[0108] In some embodiments, R 3is -(CH2)4-, and -(Xaa 1 ) 1-4 N(R 6 )R 5 R 4 -teeth, [ka] wherein in an alternative embodiment, R 10 is any of the Rs defined above. 10 In some such embodiments, R 10 is -CH 2 -R 23 and R 23 is phenyl substituted with one or two iodo groups and optionally further substituted with one oxy group.

[0109] Unless otherwise indicated, the following definitions apply to any applicable compound of formula I / Ia (or a salt / solvate thereof), any compound of formula II / IIa (or a salt / solvate thereof), and also to compounds that contain a PSMA targeting moiety of formula III / IIIa (or a salt / solvate thereof), i.e., the following definitions apply to compounds that contain a PSMA targeting moiety of formula III / IIIa (including, but not necessarily, when such compounds are compounds of formula II / IIa).

[0110] R 7 may optionally include radiolabeling groups spaced apart using amino acid or peptide linkers. Thus, in some embodiments, R 7 is R X -(Xaa 2 ) 0-4 -, wherein R X is the N-terminal Xaa 2 or Xaa which can form an amide bond 2 R X Xaa can form an amide bond with 2 An example of a side chain is an amino group. XNon-limiting examples of amino acid residues that can form amides with R include Lys, Orn, Dab, Dap, Arg, homo-Arg, etc. In some embodiments, R X is the N-terminal Xaa 2 In another embodiment, Xaa 2 does not exist.

[0111] In some embodiments, R 7 may contain two radiolabeling groups, in which case an amino acid or peptide linker provides two attachment points for the radiolabeling groups. That is, in some embodiments, R 7 teeth, [ka] For example, the first R X is the N-terminal Xaa 2 and a second R X is Xaa 2 Alternatively, both R X The groups are different Xaa 2 It may be attached to a side chain or other functional group.

[0112] R 7 may contain both a radiolabeling group and an albumin binding group.

[0113] Therefore, a single R X In some embodiments having a group, R 7 teeth, [ka] In the formula, (Xaa 2 ) 0-4 (Xaa 2 ) 1-4 When R X is the N-terminal Xaa 2 or the N-terminus of Xaa 2 (Xaa3 ) 0-4 However, (Xaa 3 ) 1-4 When (Xaa 3 ) 1-4 is oriented to form an amide bond with the adjacent carbonyl and amine groups. X In another embodiment having a group, R 7 teeth, [ka] In the formula, (Xaa 2 ) 0-4 However, (Xaa 2 ) 1-4 When R X is the N-terminal Xaa 2 or the N-terminus of Xaa 2 (Xaa 3 ) 0-4 However, (Xaa 3 ) 1-4 When (Xaa 3 ) 1-4 is oriented to form an amide bond with the adjacent carbonyl and amine groups.

[0114] Albumin binding group R 28 may be any albumin binding group.

[0115] In some embodiments, the albumin binding group R 28 teeth, [ka] It is.

[0116] In some embodiments, the albumin binding group R 28 teeth, [ka] It is.

[0117] In some embodiments, the albumin binding group R 28 teeth, [ka] where R 12 is I, Br, F, Cl, H, OH, OCH3, NH2, NO2 or CH3.

[0118] In some embodiments, R 7 teeth, [ka] In the formula, (Xaa 2 ) 0-4 However, (Xaa 2 ) 1-4 When R X is the N-terminal Xaa 2 or the N-terminus of Xaa 2 It binds to the amino group of (e.g., the side chain of an alpha amino acid).

[0119] In another embodiment, R 7 teeth, [ka] In the formula, (Xaa 2 ) 0-4 However, (Xaa 2 ) 1-4 When R X is the N-terminal Xaa 2 or the N-terminus of Xaa 2 It binds to the amino group of (e.g., the side chain of an alpha amino acid).

[0120] In another embodiment, R 7 teeth, [ka] In the formula, (Xaa 2 ) 0-4 However, (Xaa 2 ) 1-4 When RX is the N-terminal Xaa 2 or the N-terminus of Xaa 2 It binds to the amino group of (e.g., the side chain of an alpha amino acid).

[0121] In some embodiments, R 11 is absent. In some embodiments, R 11 teeth, [ka] In some embodiments, R 11 teeth, [ka] In some embodiments, R 11 teeth, [ka] In some embodiments, R 11 teeth, [ka] In some embodiments, R 11 teeth, [ka] In some embodiments, R 11 teeth, [ka] In some embodiments, R 11 teeth, [ka] In some embodiments, R 11 teeth, [ka] In some embodiments, R 11 teeth, [ka] It is.

[0122] 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 is fluorine. In some embodiments, R 12 is chlorine. In some embodiments, R 12 is hydrogen. In some embodiments, R 12 is a 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-CH. In some embodiments, R 12 is a para iodine. In some embodiments, R 12 is a para chlorine. In some embodiments, R 12 is the para-OCH3.

[0123] In some embodiments, Xaa 2 In some embodiments, (Xaa 2 ) 0-4 is a single amino acid residue. 2 ) 0-4 is a dipeptide, wherein each Xaa 2 may be the same or different. In some embodiments, (Xaa 2 ) 0-4 is a tripeptide, wherein each Xaa 2may be the same, different, or a combination of amino acid residues. 2 ) 0-4 consists of four amino acid residues linked by peptide bonds, where each Xaa 2 may be the same, different, or a combination of amino acid residues. 2 are independently selected from proteinogenic and non-proteinogenic amino acids listed in Table 1, and each amino group of the peptide backbone is optionally methylated. 2 ) 1-4 Each R in 13 is hydrogen. In some embodiments, (Xaa 2 ) 1-4 At least one R in 13 is methyl. In some embodiments, (Xaa 2 ) 1-4 At least one R in 14 is -(CH2)2[O(CH2)2] 1-6 - (e.g., Xaa 2 is a residue of amino-dPEG™ 4-acid or amino-dPEG™ 6-acid).

[0124] In some embodiments, Xaa 3 In some embodiments, (Xaa 3 ) 0-4 is a single amino acid residue. 3 ) 0-4 is a dipeptide, wherein each Xaa 3 may be the same or different. In some embodiments, (Xaa 3 ) 0-4 is a tripeptide, wherein each Xaa 3 may be the same, different, or a combination of amino acid residues. 3 )0-4 consists of four amino acid residues linked by peptide bonds, where each Xaa 3 may be the same, different, or combinations thereof. In some embodiments, each Xaa 3 are independently selected from proteinogenic and non-proteinogenic amino acids listed in Table 1, and each amino group of the peptide backbone is optionally methylated. 3 ) 1-4 Each R in 13 is hydrogen. In some embodiments, (Xaa 3 ) 1-4 At least one R in 13 In some embodiments, (Xaa 3 ) 1-4 At least one R in 14 is -(CH2)2[O(CH2)2] 1-6 - (e.g., Xaa 3 is a residue of amino-dPEG™ 4-acid or amino-dPEG™ 6-acid).

[0125] In some embodiments, one or more R Xoptionally includes a radiometal bound to the radiometal. The radiometal chelator may be any radiometal chelator suitable for binding to a radiometal and functionalized for binding to an amino group. Many suitable radiometal chelators are known, for example those summarized in Price and Orvig, Chem. Soc. Rev., 2014, 43, 260-290 (incorporated by reference in its entirety). Non-limiting examples of radioisotope chelators include DOTA and derivatives, DOTAGA, NOTA, NODAGA, NODASA, CB-DO2A, 3p-C-DEPA, TCMC, DO3A, DTPA, 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, sarcofagin, sarcofagin derivatives optionally selected from SarAr, SarAr-NCS, diamSar, AmBaSar and BaBaSar, TRAP, AAZTA, DATA, DAT Examples of chelators include those selected from the group consisting of 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, desferrioxamine (DFO), DFO derivatives, and H6phospa. Non-limiting illustrative examples of radioisotope chelators and examples of radioisotopes chelated by these chelators are shown in Table 2. In an alternative embodiment, R X comprises a radioisotope chelator selected from those listed above or in Table 2, or is any other radioisotope chelator. One of skill in the art would be able to substitute an alternative chelator for any of the chelators listed herein.

[0126] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7]

[0127] In some embodiments, the radioisotope chelator is conjugated to a radioisotope, including but 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 Er, 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, 114mIn some embodiments, the chelator is a chelator of Table 2 and the attached radioisotope is a radioisotope shown in Table 2 as the binder of the chelator.

[0128] In some embodiments, the radioisotope chelator is not bound to a radioisotope.

[0129] In some embodiments, the chelator 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 Er, 213 Bi, 224 Ra, 212 Bi, 227 Th, 223 Ra, 64 Cu or 67 DOTA or its derivatives bound to Cu 225 H2-MACROPA bound to Ac, 227 Me-3,2-HOPO bound to Th, 225 Ac, 227 Th or 177 H4py4pa bound to Lu, 177 H4pypa bound to Lu, 68 NODAGA bound to Ga, 111 DTPA conjugated to In, or 89 This is DFO bound to Zr.

[0130] In some embodiments, the chelator is TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid), SarAr (1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexazabicyclo[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,N0-biphenyl). The picolinic acid derivatives are: bis(2-hydroxybenzyl)-ethylenediamine-N,N-diacetic acid), 2,3-HOPO (3-hydroxypyridin-2-one), PCTA (3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-1(15),11,13-triene-3,6,9,-triacetic acid), DFO (desferrioxamine), DTPA (diethylenetriaminepentaacetic acid), OCTAPA (N,N-bis(6-carboxy-2-pyridylmethyl)-ethylenediamine-N,N-diacetic acid) or another picolinic acid derivative.

[0131] One or more R's X mercaptoacetyl, hydrazinonicotinamide, dimercaptosuccinic acid, 1,2-ethylenediylbis-L-cysteine ​​diethyl ester, methylene diphosphonate, hexamethylpropyleneamine oxime and hexakis(methoxyisobutylisonitrile), etc. 99m Tc, 94m Tc, 186 Re or 188 In some embodiments, one or more R X comprises a chelator that is mercaptoacetyl, hydrazinonicotinamide, dimercaptosuccinic acid, 1,2-ethylenediylbis-L-cysteine ​​diethyl ester, methylene diphosphonate, hexamethylpropyleneamine oxime, or hexakis(methoxyisobutylisonitrile). In some of these embodiments, a radioisotope is attached to the chelator. In some such embodiments, the radioisotope is 99m Tc,94m Tc, 186 Re or 188 Re.

[0132] One or more R's X For example, 1,4,7-triazacyclononane-1,4-diacetate (NODA) 18 F-Aluminum fluoride ([ 18 In some embodiments, the chelator can include a chelator capable of binding [F]AlF. In some embodiments, the chelator is NODA. In some embodiments, the chelator can include a chelator capable of binding [F]AlF. 18 F]AlF is bonded.

[0133] One or more R's X is a trithiol chelate, 72 As or 77 The chelator may include a chelator capable of binding As. In some embodiments, the chelator is a trithiol chelate. In some embodiments, the chelator is 72 In some embodiments, the chelator is 77 It is bound to As.

[0134] One or more R's X may include an aryl group substituted with a radioisotope. In some embodiments, one or more of R X teeth, [ka] wherein A, B, C, D and E are independently C or N; R 15 is a radioactive halogen. In some embodiments, one or more of R X teeth, [ka] In some embodiments, one or more of R X teeth, [ka] In some embodiments, one or more of R X teeth, [ka] In some embodiments, one or more of R X teeth, [ka] In some embodiments, one or more of R X teeth, [ka] In some embodiments, one or more of R X teeth, [ka] In some embodiments, one or more of R X teeth, [ka] In some embodiments, one or more of R X teeth, [ka] In some of these embodiments, R 15 is independent, 211 At, 131 I, 124 I, 123 I, 77 Br or 18 In some of these embodiments, R 15 teeth, 18 It's F.

[0135] In some embodiments, one or more R X teeth, 18 F / 19 In some embodiments, one or more RX is R 16 R 17 BF3, wherein each R 16 is independent, [ka] and R 18 does not exist or [ka] Each -R 17 BF3 is independently one of those listed in Table 3 (below), Table 4 (below), or [ka] or a combination thereof, wherein R 19 and R 20 is independently a straight or branched C1-C5 alkyl group. In Tables 3 and 4, R in pyridine substituted with -OR, -SR, -NR-, -NHR, or -NR2 groups is a branched or straight C1-C5 alkyl group. In some embodiments, one or more -R 17 BF3 is independently selected from one or combinations of those listed in Table 3. In some embodiments, one or more -R 17 BF3 is independently selected from one or combinations of those listed in Table 4. In some embodiments, one fluorine is: 18 F. In some embodiments, all three fluorines are 19 It's F.

[0136] [Table 8] [Table 9]

[0137] [Table 10] [Table 11] [Table 12]

[0138] In some embodiments, R 17 BF3 is [ka] [ka] wherein R (if present) in the pyridine substituted with -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 It's F.

[0139] In some embodiments, R 17 BF3 is [ka] [ka] wherein R (if present) in the pyridine substituted with -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 [ka] In some embodiments, one fluorine is: 18 F. In some embodiments, all three fluorines are 19 It's F.

[0140] In some embodiments, one or more of -R 17 BF3 is [ka] In some embodiments, R 19 is methyl. In some embodiments, R 19 is ethyl. In some embodiments, R 19 is propyl. In some embodiments, R 19 is isopropyl. In some embodiments, R 19 is butyl. In some embodiments, R 19 is n-butyl. In some embodiments, R 19 is pentyl. In some embodiments, R 20 is methyl. In some embodiments, R 20 is ethyl. In some embodiments, R 20 is propyl. In some embodiments, R 20 is isopropyl. In some embodiments, R 20is butyl. In some embodiments, R 20 is n-butyl. In some embodiments, R 20 is pentyl. In some embodiments, R 19 and R 20 are both methyl. In some embodiments, one fluorine is 18 F. In some embodiments, all three fluorines are 19 It's F.

[0141] In some embodiments, one or more R X may comprise a prosthetic group comprising a silicon-fluorine-acceptor moiety. In some embodiments, the fluorine of the silicon-fluorine acceptor moiety is 18 F. Prosthetic groups that contain silicon-fluorine-acceptor moieties are independently [ka] or a combination thereof, wherein R 21 and R 22 are independently straight or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 10 In some embodiments, R is an alkyl group, an alkenyl group, or an alkynyl group. 21 and R 22 is independently selected from the group consisting of phenyl, tert-butyl, sec-propyl, or methyl. In some embodiments, the prosthetic group is [ka] In some embodiments, the prosthetic group is [ka] In some embodiments, the prosthetic group is [ka] In some embodiments, the prosthetic group is [ka] It is.

[0142] In some embodiments, one or more R X comprises a prosthetic group that comprises a fluorophosphate. In some embodiments, one or more of R X comprises a prosthetic group that comprises a fluorosulfate. In some embodiments, one or more of R X includes a prosthetic group that includes a sulfonyl fluoride. Such prosthetic groups are well known, commercially available, and readily attached (e.g., via an amide bond). 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 It's F.

[0143] Certain doubly labeled compounds (i.e., R 7 But two R X groups) have only one radioactive atom. For example, but not limited to, one R X The base is 18 may be labeled with F, and the other R X The base is 19 May contain only F or the other R X The group may include a chelator that is not chelated to a radioactive metal or a chelator that is chelated to a metal that is not a radioisotope. X The group may include an aryl substituted with a radioisotope, and the other R X The base is 19 May contain only F or the other R XThe group may include a chelator that is not chelated to a radioactive metal or a chelator that is chelated to a metal that is not a radioisotope. X The group may include a chelator attached to a radioisotope, and the other R X The base is 19 It may contain only F.

[0144] In some embodiments, R 7 The first R X group and the second R X group, the first R X The group is optionally a radiometal chelator having a radiometal attached thereto, and the second R X In some embodiments, the R 7 The first R X group and the second R X group, the first R X The group is optionally a radiometal chelator having a radiometal attached thereto, and the second R X The group is a prosthetic group that includes trifluoroborate.

[0145] In certain embodiments, the compounds of the invention are conjugated to a radioisotope for imaging PSMA-expressing tumors by positron emission tomography (PET) or single photon emission computed tomography (SPECT), and the compound is conjugated to a radioisotope that is a positron-emitting or gamma-emitting nuclide. Positron- or gamma-emitting radioisotopes include, but are not limited to: 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.

[0146] In certain embodiments, the compounds of the invention are conjugated to radioisotopes for use in the treatment of PSMA-expressing tumors. 165 Er, 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 Examples include radioisotopes such as Cu.

[0147] The compound of the invention may be HTK03149, or a salt or solvate thereof, optionally bound 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 Er,224 Ra, 212 Bi, 227 Th, 223 Ra, 64 Cu or 67 In some embodiments, the radiometal is 68 It's Ga.

[0148] The compounds of the invention may be HTK03169, HTK03161, HTK03177, HTK03187, HTK03153, HTK03170, HTK04053, HTK03189A, HTK03189B, HTK04018, HTK04033, HTK04040, HTK04036, HTK04037, HTK04041, HTK04028, HTK04048, HTK04050, HTK03162 or HTK04055, optionally bound to a radiometal, or a salt or solvate thereof. 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 Er, 224 Ra, 212 Bi, 227 Th, 223 Ra, 64 Cu or 67 In some embodiments, the radiometal is 68 In some embodiments, the radiometal is 177 This is Lu.

[0149] When the radiolabeling group comprises or is bound to a diagnostic radioisotope, the compound of a certain embodiment is disclosed for 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, comprising administering to the subject a composition comprising a compound of a certain embodiment and a pharma-ceutically acceptable excipient, and imaging the tissue of the subject, for example, by using PET or SPECT. When the tissue is diseased tissue (e.g., PSMA-expressing cancer), the subject may be treated with a PSMA-targeted therapy.

[0150] When the radiolabeling group comprises a therapeutic radioisotope, the use of a compound of certain embodiments (or a pharmaceutical composition thereof) is disclosed for treating a condition or disease (such as cancer) that expresses PSMA in a subject. Accordingly, the use of a compound of the present invention for preparing a medicament for treating a condition or disease that expresses PSMA in a subject is provided. Also provided is a method of treating a disease that expresses PSMA in a subject, comprising administering to the subject a composition comprising a compound of the present invention and a pharma- ceutically acceptable excipient. For example, but not limited to, the disease may be a PSMA-expressing cancer.

[0151] Expression of PSMA 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 November 19, 2015 jnumed.115.164442). Thus, the PSMA-expressing cancer may be, but is not limited to, prostate cancer, renal cancer, breast cancer, thyroid cancer, gastric cancer, colorectal cancer, bladder cancer, pancreatic cancer, lung cancer, liver cancer, brain cancer, melanoma, neuroendocrine tumors, ovarian cancer or sarcoma. In some embodiments, the cancer is prostate cancer.

[0152] Compounds containing retro-inverso peptide linkers

[0153] It is well known to those skilled in the art that the concept of retroinverso peptide design can be applied to further modify the linker constructs defined in the various compounds above. Without preconceived ideas about a given stereoisomer and without necessarily being bound to a given stereoisomer, when using the retroinverso approach, it is necessary to invert the preferred stereochemical configuration at a certain asymmetric atom, provided that the polarity of the linking group(s) that flank the relevant asymmetric atom, e.g., the N-terminus and C-terminus, is inverted in the design of the retroinverso peptide fragment. It is also well known that the amide bond in a peptide linker can be replaced by an alternative bond and, in certain cases, a given amino acid can be extended by an additional group of atoms, e.g., CH2 or C=O. It will therefore be clear to replace any of such linkers defined above (or elsewhere in this specification, e.g., in the examples) with a linker in which the polarity of the amino acid is inverted and / or the amide bond is replaced by an alternative bond (while the overall position and three-dimensional structure of the linker are maintained). This principle is illustrated in the following non-limiting example embodiments to illustrate how portions of molecules bearing the same or similar functional groups can be replaced with their retro-inverso counterparts, as will be readily apparent to those skilled in the art of peptide chemistry. [ka]

[0154] Accordingly, also disclosed are compounds of formula IV or formula V, as defined below.

[0155] Disclosed is a compound having formula IV, or a salt or solvate of formula IV: [ka] During the ceremony, R 0 is S or O, R 1ais -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -OPO3H2, -OSO3H, -B(OH)2 or [ka] and R 1b is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -B(OH)2 or [ka] and R 1c is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -B(OH)2 or [ka] and R 2-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-, -C H2C(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(C H3)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; R 3 is a linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 20Alkylenyl or alkenylenyl, or X-X which is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 20 heteroalkylenyl or heteroalkenylenyl, R 4 -O-, -S-, -Se-, -S(O)-, -S(O)2-, -NHC(O)-, -C(O)NH-, [ka] -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-, [ka] and R 5 is a linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 30 X-X is alkylenyl, alkenylenyl or alkynylenyl, or is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 30 heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; R 6 is hydrogen, methyl or ethyl, Xaa 1 is -N(R 8 )R 9 C(O)-, where each R 8 is independently hydrogen or methyl; 9 are independently straight or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 20 Alkylenyl, alkenylenyl or alkynylenyl, or X-X which is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 20heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; At least one R 9 or R 5 is -(CH2) 0-3 CH(R 10 )(CH2) 0-3 -, wherein R 10 teeth, Straight or branched chain, cyclic or acyclic, and / or aromatic or non-aromatic C2-C 19 X-X is alkyl, alkenyl or alkynyl, linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic, with only 1 to 3 heteroatoms; 19 heteroalkyl, heteroalkenyl or heteroalkynyl, -CH2R 23 (That R 23 is an optionally substituted C4-C 16 an aromatic ring system, a partially aromatic fused ring system or a fully aromatic fused ring system in which 0-3 carbons are replaced by heteroatoms N, S and / or O, the optional substituents being selected from OH, NH2, NO2, halogen, C1-C6 alkyl and / or C1-C6 alkoxy groups; or [ka] (optionally modified with one, two or more, or a combination of halogen, OMe, SMe, NH2, NO2, CN, OH or additional nitrogen atoms in the ring); R 7 is R X -(Xaa 2 ) 0-4 -, [ka] and R 28 is an albumin binder, Xaa 2 and Xaa3 When present, each independently represents -N(R 13 )R 14 C(O)—, where each R 13 is independently hydrogen or methyl; 14 are independently straight or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 20 Alkylenyl, alkenylenyl or alkynylenyl, or X-X which is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 20 heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; Each R X is independently a radiolabeling group selected from an optionally metal-bound radiometal chelator, a radioisotope-substituted aryl or heteroaryl, a trifluoroborate-containing prosthetic group, or a silicon-fluorine-acceptor moiety, a fluorophosphate, a fluorosulfate, or a sulfonyl fluoride-containing prosthetic group; R 7 -(Xaa 1 ) 1-4 -N(R 6 )-R 5 -R 4 -R 3 Any one or any combination of the amide bonds in the formula (I) may be selected from the group consisting of -O-, -S-, -Se-, -S(O)-, -S(O)2-, -NHC(O)-, -C(O)NH-, [ka] It is replaced by one or a combination selected from the group consisting of -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-.

[0156] In various embodiments of the compound of formula IV, or a salt or solvate of formula IV, the variable group R 0 , R 1a , R 1b , R 1c , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 or any of the variable definitions defined in the variable definitions above may be any such definition defined in formula II.

[0157] In some embodiments of the compound of formula IV, or a salt or solvate of formula IV, -N(R 6 )-R 5 -R 4 -teeth, [ka] wherein X is CH or N and Y is NH, S or O, any of these triaryl / heteroaryl groups being optionally modified with one, two or more, or combinations of halogen, OMe, SMe, NH, NO, CN, OH or one or more additional ring nitrogen atoms.

[0158] Also disclosed is a compound having the following formula V, or a salt or solvate of formula V: [ka] During the ceremony, R 0 is S or O, R 1a is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -OPO3H2, -OSO3H, -B(OH)2 or [ka] and R 1bis -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -B(OH)2 or [ka] and R 1c is -CO2H, -SO2H, -SO3H, -PO2H, -PO3H2, -B(OH)2 or [ka] and R 2-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-, -C H2C(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(C H3)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-, in which HC[CH2]CH represents a cyclopropyl ring; R 3 is a linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 20Alkylenyl or alkenylenyl, or X-X which is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 20 heteroalkylenyl or heteroalkenylenyl, R 4 -O-, -S-, -Se-, -S(O)-, -S(O)2-, -NHC(O)-, -C(O)NH-, [ka] -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-, [ka] and R 5 is a linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 30 X-X is alkylenyl, alkenylenyl or alkynylenyl, or is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 30 heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; R 6 is optional, Xaa 1 a carbonyl group which results in an amide bond, a phosphoryl group which results in a phosphoramidate / phosphonamidate bond, or a sulfonyl group which results in a sulfonamide bond, or 1 -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)-, Xaa 1 is -N(R 8 )R 9C(O)-, where each R 8 is independently hydrogen or methyl; 9 are independently straight or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 20 Alkylenyl, alkenylenyl or alkynylenyl, or X-X which is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 20 heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; At least one R 9 or R 5 is -(CH2) 0-3 CH(R 10 )(CH2) 0-3 -, wherein R 10 teeth, Straight or branched chain, cyclic or acyclic, and / or aromatic or non-aromatic C2-C 19 X-X is alkyl, alkenyl or alkynyl, linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic, with only 1 to 3 heteroatoms; 19 heteroalkyl, heteroalkenyl or heteroalkynyl, -CH2R 23 (That R 23 is an optionally substituted C4-C 16 an aromatic ring system, a partially aromatic fused ring system or a fully aromatic fused ring system in which 0-3 carbons are replaced by heteroatoms N, S and / or O, the optional substituents being selected from OH, NH2, NO2, halogen, C1-C6 alkyl and / or C1-C6 alkoxy groups; or [ka] (optionally modified with one, two or more, or a combination of halogen, OMe, SMe, NH2, NO2, CN, OH or additional nitrogen atoms in the ring); R7 is R X -(Xaa 2 ) 0-4 -, [ka] and R 28 is an albumin binder, Xaa 2 and Xaa 3 When present, each independently represents -N(R 13 )R 14 C(O)—, where each R 13 is independently hydrogen or methyl; 14 are independently straight or branched, cyclic or acyclic, and / or aromatic or non-aromatic C1-C 20 Alkylenyl, alkenylenyl or alkynylenyl, or X-X which is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic; 20 heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; Each R X is independently a radiolabeling group selected from an optionally metal-bound radiometal chelator, a radioisotope-substituted aryl or heteroaryl, a trifluoroborate-containing prosthetic group, or a silicon-fluorine-acceptor moiety, a fluorophosphate, a fluorosulfate, or a sulfonyl fluoride-containing prosthetic group.

[0159] In various embodiments of the compound of formula V, or a salt or solvate of formula V, the variable group R 0 , R 1a , R 1b , R 1c , R 2 , R 3 , R 4 , R 5 or any of the variable definitions defined in the variable definitions above, or the variable R 6 Or R 7The definition for may be any such definition defined in formula II.

[0160] The compounds provided herein incorporate peptides that may be synthesized by any of a variety of methods established in the art, including, but not limited to, solution and solid phase peptide synthesis using 9-fluorenylmethoxycarbonyl (Fmoc) and / or t-butyloxycarbonyl (Boc) chemistries, and / or other synthetic approaches.

[0161] Methods and techniques for solid-phase peptide synthesis are well established in the art. For example, a peptide may be synthesized by sequentially incorporating the amino acid residues of interest one by one. In such methods, peptide synthesis typically begins by coupling the C-terminal amino acid of the peptide of interest to a suitable resin. Prior to this, the reactive side chain and alpha amino group of the amino acid are protected from reaction by suitable protecting groups, and only the alpha carboxyl group is reacted with a functional group, such as an amine group, a hydroxyl group, or an alkyl halide group, on the solid support. After coupling of the C-terminal amino acid to the support, the protecting groups on the side chain and / or alpha amino group of that amino acid are selectively removed to couple the next amino acid of interest. This process is repeated until the desired peptide is fully synthesized, and once synthesized, the peptide can be cleaved from the support and purified. A non-limiting example of a solid-phase peptide synthesizer is the Aapptec Endeavor90 peptide synthesizer.

[0162] To couple additional amino acids, the Fmoc protecting group may be removed from the amino acid on the solid support under mildly basic conditions such as piperidine (20-50% v / v) in DMF, and the additional amino acid must be activated for coupling (e.g., at the alpha carboxylate). Non-limiting examples of activating reagents 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(pyrrolidino)phosphonium hexafluorophosphate (PyBOP). Racemization is minimized by using triazoles such as 1-hydroxy-benzotriazole (HOBt) and 1-hydroxy-7-aza-benzotriazole (HOAt). Coupling may be carried out in the presence of a suitable base such as N,N-diisopropylethylamine (DIPEA / DIEA), etc. For longer peptides, or if desired, peptide synthesis and ligation may be used.

[0163] Apart from forming a typical peptide bond to extend the peptide, the peptide may be extended in a branched manner by coupling to a side chain functional group (e.g., a carboxylic acid or amino group) (either by coupling a side chain to a side chain or by coupling a side chain to an amino or carboxylate of the main chain). Coupling to the amino acid side chain may be performed by any known method and may be performed on or off the resin. Non-limiting examples include amide formation between an amino acid side chain containing a carboxyl group (e.g., Asp, D-Asp, Glu, D-Glu, etc.) and an amino acid side chain containing an amino group (e.g., Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, etc.) or the N-terminus of a peptide; amide formation between an amino acid side chain containing an amino group (e.g., Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, etc.) and either an amino acid side chain containing a carboxyl group (e.g., Asp, D-Asp, Glu, D-Glu, etc.) or the C-terminus of a peptide; 1,2,3-triazole formation via click chemistry between an amino acid side chain containing an azide group (e.g., Lys(N3), D-Lys(N3), etc.) and an alkyne group (e.g., Pra, D-Pra, etc.). Whereas protecting groups on appropriate functional groups must be selectively removed prior to the formation of an amide bond, selective deprotection is not required when reacting an alkyne with an azide group to form a 1,2,3-triazole via a click reaction. 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). The protecting groups O-2-PhiPr and Mtt can be selectively deprotected under mildly acidic conditions such as 2.5% trifluoroacetic acid (TFA) in DCM.The protecting group alloc can be selectively deprotected using tetrakis(triphenylphosphine)palladium(0) and phenylsilane in DCM. The protecting groups Dde and ivDde can be selectively deprotected using 2-5% hydrazine in DMF. The deprotected side chains of Asp / Glu (L or D) and Lys / Orn / Dab / Dap (L or D) can then be coupled, for example, using the coupling reaction conditions described above.

[0164] The amide of the peptide backbone may be N-methylated (i.e., the alpha amino may be methylated). This methylation may be performed by directly using Fmoc-N-methylated amino acids during peptide synthesis. Alternatively, N-methylation may be performed under Mitsunobu conditions. First, the free primary amine groups are protected using a solution of 4-nitrobenzenesulfonyl chloride (Ns-Cl) and 2,4,6-trimethylpyridine (collidine) in NMP. N-methylation may then be performed in the presence of triphenylphosphine, diisopropyl azodicarboxylate (DIAD) and methanol. Then, N-deprotection may be performed using mercaptoethanol and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in NMP. HATU, HOAt and DIEA may be used to couple the protected amino acid to the N-methylated alpha amino group.

[0165] A PSMA binding moiety (such as Lys-ureido-Aad) may be assembled on the solid phase via the formation of a ureido bond between the amino groups of two amino acids. This can be accomplished by coupling an Fmoc-protected amino acid (such as Fmoc-Lys(ivDde)-OH) to Wang resin using standard activation / coupling strategies (e.g., Fmoc-protected amino acid (4 equivalents), HATU (4 equivalents) and N,N-diisopropylethylamine (7 equivalents) in N,N-dimethylformamide). The Fmoc protecting group is then removed with 20% piperidine in N,N-dimethylformamide. To form the ureido bond, the free amino group of the solid phase-bound amino acid is reacted with a second amino acid in which the carboxylate group is protected with a t-butyl group and the amino group is activated and converted to an isocyanate group (-N=C=O). Activation and conversion of the amino group to an isocyanate group can be achieved by reacting the amino group with phosgene or triphosgene. After formation of the ureido bond, the side chain functionality of the amino acid (e.g., ivDde on Lys) can be removed and then a linker, albumin binding motif and / or radiolabeling group (e.g., a radiometal chelator, etc.) can be coupled to the PSMA binding moiety.

[0166] Thioether (-S-) and ether (-O-) bonds (e.g. R 4The formation of the thioether (-S-) bond can be carried out either on the solid phase or in solution phase. For example, the formation of a thioether (-S-) bond can be carried out by coupling a thiol-containing compound (such as a thiol group on a cysteine ​​side chain) with an alkyl halide (such as 3-(Fmoc-amino)propyl bromide) in the presence of a base (such as N,N-diisopropylethylamine) in a suitable solvent (such as N,N-dimethylformamide). The formation of an ether (-O-) bond can be carried out by Mitsunobu reaction of an alcohol (such as a hydroxyl group on a serine or threonine side chain) with a phenol group (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). When the reaction is carried out in solution phase, the reactants used are preferably in equal molar ratio (1:1) 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 bound to the solid phase), the other reactant is usually used in excess (at least 3 equivalents of the reactant bound to the solid phase). After the reaction, excess unreacted reactants and reagents can be removed by sequentially washing the solid phase (resin) with a combination of solvents (e.g., N,N-dimethylformamide, methanol, and dichloromethane).

[0167] A non-peptide moiety (e.g., a radiolabel group, an albumin binding group, and / or a linker) may be coupled to the N-terminus of the peptide while the peptide is still attached to the solid support. This method is facilitated if the non-peptide moiety contains an activated carboxylate (and a protecting group, if necessary) so that the coupling can be performed on the resin. For example, but not limited to, a bifunctional chelator such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) tris(tert-butyl ester) may be activated in the presence of N-hydroxysuccinimide (NHS) and N,N'-dicyclohexylcarbodiimide (DCC) for coupling to the peptide. Alternatively, the non-peptide moiety may be incorporated into the compound by copper-catalyzed click reaction under either solution or solid-phase conditions. Copper-catalyzed click reaction is well established in the art. For example, 2-azidoacetic acid is first activated by NHS and DCC and coupled to the peptide. Subsequently, Cu in water and organic solvents (e.g., acetonitrile (ACN) and DMF) were 2+ and in the presence of sodium ascorbate, non-peptide moieties containing alkynes may be click-coupled to the azide-containing peptide.

[0168] The synthesis of radioactive metal chelators is well known, and many chelators are commercially available (e.g., from Sigma-Aldrich™ / Milipore Sigma™, etc.). Protocols for binding radioactive metals to chelators are also well known (e.g., see Example 1 below). The synthesis of silicon-fluorine-acceptor moieties can be carried out according to the procedures reported above (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 aryl groups substituted with radioactive isotopes is also easy.

[0169] R on PSMA-targeted compounds 16 R 17The synthesis of BF3 components can be carried out according to the procedures reported above (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). In general, BF3-containing motifs can be coupled to linkers via click chemistry by forming a 1,2,3-triazole ring between a BF3-containing azide (or alkynyl) group and an alkynyl (or azide) group on the linker, or by forming an amide bond between a BF3-containing carboxylate and an amino group on the linker. To generate azides, alkynes, or carboxylates containing BF3, first prepare azides, alkynes, or carboxylates containing boronate esters, then convert the boronate esters to BF3 in a mixture of HCl, DMF, and KHF2. For alkylBF3, azides, alkynes, or carboxylates containing boronate esters can be prepared by coupling alkyl halides containing boronate esters (such as iodomethylboronic acid pinacol ester) with azides, alkynes, or carboxylates containing amines (such as N,N-dimethylpropargylamine). For arylBF3, boronic esters can be prepared via Suzuki coupling using aryl halides (iodine or bromide) and bis(pinacolato)diboron.

[0170] According to a previously published procedure (Liu et al. Nat Protoc 2015 10:1423-1432, which is incorporated by reference in its entirety), PSMA-targeting compounds including BF3 were 18 F- 19 Through F isotope exchange reaction, 18It can be fluorinated with F. In general, about 100 nmol of a compound containing BF3 is 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 aqueous KHF2 solution. 18 F-fluoride solution (60 μl in saline) is added to the reaction mixture and the resulting solution is heated for 20 min at 80° C. At the end of the reaction, the desired product can be purified by solid phase extraction or by reversed-phase high performance liquid chromatography (HPLC) using a mixture of water and acetonitrile as the mobile phase.

[0171] Once the peptide is fully synthesized on the solid support, the desired peptide may be cleaved from the solid support using appropriate 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 simultaneously removed (i.e., deprotected). The crude peptide may be precipitated and recovered from the solution by adding cold ether followed by centrifugation. The peptide may be purified and characterized by standard separation techniques such as high performance liquid chromatography (HPLC) based on the size, charge and polarity of the peptide. The identity of the purified peptide may be confirmed by mass spectrometry or other similar approaches.

[0172] Synthesis scheme of HTK03149 and 68 Binding to Ga is shown in Figure 2 and described in further detail in the Examples below. Examples of general synthesis schemes for additional compounds are shown in Figures 3 and 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.

[0173] The present invention is further illustrated in the following examples.

[0174] Example 1: HTK03149

[0175] Common methods

[0176] All chemicals and solvents were obtained from commercial suppliers and used without further purification. PSMA target peptides were synthesized on an Endeavor90 peptide synthesizer from AAPPTec (Louisville, KY) using a solid-phase approach. Peptide purification was performed on an Agilent 1260 Infinity II Preparative System equipped with a Model 1260 Infinity II preparative binary pump, a Model 1260 Infinity variable wavelength detector (set at 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 FreeZone4.5 Plus lyophilizer from Labconco (Kansas City, MO). Mass spectrometry was performed using an AB SCIEX (Framingham, MA) 4000QTRAP mass spectrometry system with an ESI ion source. C18Sep-Pak cartridge (1cm 3 , 50 mg) was obtained from Waters (Milford, Mass.). 68 Ga was eluted from a generator from iThemba Labs (Somerset West, South Africa) using a dose calibrator, CRC®-25R / W, from Capintec (Ramsey, NJ). 68 The radioactivity of the Ga-labeled peptide was measured, and the radioactivity in mouse tissues obtained from the biodistribution study was counted using a Perkin Elmer (Waltham, MA) Wizard2 2480 automated gamma counter.

[0177] Synthesis of HTK03149

[0178] The structures of HTK03041 and HTK03149 are shown below, differing only in that HTK03041 has a Glu residue in the PSMA binding moiety (Lys-ureido-Glu) whereas HTK03149 has an Aad in the PSMA binding moiety (Lys-ureido-Aad), i.e. the side chain is one carbon longer. [ka]

[0179] As shown in Figure 2, the PSMA-targeting Lys-ureido-Aad moiety (peptidomimetic) was synthesized by solid-phase peptide chemistry. Fmoc-Lys(ivDde)-Wang resin (0.05 mmol, loading 0.58 mmol / g) was suspended in DMF for 30 min. The Fmoc was subsequently removed by treating the resin with 20% piperidine in DMF (3 × 8 min). To generate the isocyanate of the 2-aminoadipyl moiety, a solution of L-2-aminoadipic acid (Aad) di-tert-butyl ester hydrochloride (154.9 mg, 0.5 mmol, 10 equivalents relative to resin) and diisopropylethylamine (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 warmed to room temperature and stirred for 30 min to give a solution of the isocyanate of the 2-aminoadipyl moiety. An additional 87.1 μL of DIEA (0.5 mmole) 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 by 2% hydrazine in DMF (5×5 min). Fmoc-Ala(9-Anth)-OH was then coupled to the side chain of Lys using Fmoc-protected amino acid (4 eq.), HATU (4 eq.) and N,N-diisopropylethylamine (7 eq.). Elongation was then continued by addition of Fmoc-tranexamic acid and finally DOTA-tris(t-bu) ester (2-(4,7,10-tris(2-(t-butoxy)-2-oxoethyl)-1,4,7,10)-tetraazacyclododecan-1-yl)acetic acid).

[0180] The peptide was subsequently deprotected and simultaneously cleaved from the resin by treatment with 95 / 5 trifluoroacetic acid (TFA) / triisopropylsilane (TIS) for 2 hours at room temperature. After filtration, the peptide was precipitated by adding cold diethyl 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. Preparative HPLC conditions were 24% acetonitrile in water with 0.1% TFA, flow rate 30 mL / min. Retention time was 6.9 min. Yield of HTK03149 was 21.4%. ESI-MS: [M+H] + HTK03149C 54 H 75 N9O 16 Calculated value for 1106.5410; [M+H] + Actual value: 1106.0954.

[0181] Synthesis of Ga-HTK03149

[0182] To prepare Ga-HTK03149, a solution of HTK03149 was incubated with GaCl3 (5 equiv.) in NaOAc buffer (0.1 M, 500 μL, pH 4.2) at 80° C. for 15 min. 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, flow rate 30 mL / min. The retention time was 10.9 min. The yield of Ga-HTK03149 was 90.3%. ESI-MS: [M+H] + Ga-HTK03149C 54 H 74 N9O 16 Calculated for Ga: 1173.4509; [M+H] + Actual value: 1173.5450.

[0183] cell culture

[0184] The LNCaP cell line was obtained from ATCC (LNCaP clone FGC, CRL-1740). It was established from a metastatic site in the left supraclavicular lymph node of a human prostate adenocarcinoma. Cells were cultured in PRMI1640 medium supplemented with 10% FBS, penicillin (100 U / mL), and streptomycin (100 μg / mL) at 37 °C in a humidified incubator containing 5% CO2. Cells grown to 80-90% confluence were subsequently washed with sterile phosphate-buffered saline (1x PBS, pH 7.4) and harvested by trypsinization. The concentration of harvested cells was measured with a Hausser Scientific (Horsham, PA) hemocytometer.

[0185] PET / CT imaging and biodistribution

[0186] Imaging and biodistribution experiments were performed using NODSCID 1L2RγKO male mice. Mice were anesthetized with 2% isoflurane in oxygen by inhalation and injected with 1 × 10 7 LNCaP cells were implanted subcutaneously. Over a period of 5–6 weeks, tumors were allowed to grow and reach a diameter of 5–8 mm, after which mice were imaged or used for biodistribution studies.

[0187] PET imaging experiments were performed using a Siemens Inveon microPET / CT scanner. Each tumor-bearing mouse was injected with 6–8 MBq of Ga-68 labeled tracer via the tail vein under anesthesia (2% isoflurane in oxygen). The mice were allowed to recover and move freely in their cages. After 50 min, the mice were sedated again by inhalation of 2% isoflurane in oxygen and placed in the scanner. To reconstruct PET images, a 10-min CT scan was first performed for segmentation, localization, and attenuation correction. Then, a 10-min static PET imaging was performed to determine uptake in the tumor and other organs. During acquisition, the mice were kept warm by heating the footpads. For biodistribution studies, mice were injected with the radiotracer as described above. Mice were anesthetized by inhalation with 2% isoflurane and euthanized by CO2 inhalation. Blood was collected directly from the heart and organs / tissues of interest were harvested. Harvested organs / tissues were weighed and counted using a Perkin Elmer (Waltham, MA) Wizard2 2480 gamma counter. Uptake in each organ / tissue was normalized to dose using a standard curve and expressed as percentage of dose per gram of tissue (%ID / g). 68 Images taken 1 and 3 hours after intravenous injection of Ga-HTK03149 are shown, demonstrating very high tumor uptake (solid arrows) with minimal kidney uptake (dotted arrows) and very low activity in other organs.

[0188] Tables 5A and 5B show the biodistribution data at 1 and 3 hours post-injection for HTK03149, and Table 6 shows the biodistribution data at 1 hour post-injection for HTK03041.

[0189] [Table 13]

[0190] [Table 14]

[0191] [Table 15]

[0192] Comparing Tables 5A and 5B (HTK03149) with Table 6 (HTK03041) shows that the Lys-ureido-Aad PSMA targeting moiety, which has a longer side chain compared to Lys-ureido-Glu, results in significantly lower uptake of HTK03149 in the kidney and salivary glands than HTK03041, without sacrificing tumor to background contrast ratio. Thus, modifying Glu residues will improve imaging and therapeutics for diseases / conditions expressing PSMA.

[0193] 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

[0194] Common methods

[0195] The PSMA-targeting peptide was synthesized on an Endeavor90 peptide synthesizer from AAPPTec (Louisville, KY) using a solid-phase approach. Purification and quality control of the chilled radiolabeled peptides were performed on either (1) an Agilent HPLC system equipped with a Model 1200 quaternary pump, a Model 1200 UV absorbance detector (set at 220 nm), and a NaI scintillation detector from Bioscan (Washington, DC). (The operation of the Agilent HPLC system was controlled using Agilent ChemStation software. The HPLC columns used were a semi-preparative (Luna C18, 5μ, 250×10 mm) and an analytical (Luna C18, 5μ, 250×4.6 mm) column purchased from Phenomenex (Torrance, CA).) or (2) an Agilent 1260 Infinity II Preparative System equipped with a Model 1260 Infinity II preparative binary pump, a Model 1260 Infinity variable wavelength detector (set at 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 FreeZone 4.5 Plus lyophilizer from Labconco (Kansas City, MO). Mass spectrometry was performed using an AB SCIEX (Framingham, MA) 4000QTRAP mass spectrometry system with an ESI ion source. C18 Sep-Pak cartridges (1 cm 3 , 50 mg) was obtained from Waters (Milford, Mass.). A dose calibrator, CRC®-25R / W, from Capintec (Ramsey, NJ), was used to 68 The radioactivity of the Ga-labeled peptide was measured, and the radioactivity in mouse tissues obtained from the biodistribution study was counted using a Perkin Elmer (Waltham, MA) Wizard2 2480 automated gamma counter.

[0196] 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 shown in Figure 6.

[0197] Synthesis of HTK03169 and HTK04053

[0198] The PSMA-targeting Aad-ureido-lysine moiety (peptidomimetic) was synthesized by solid-phase peptide chemistry. Fmoc-Lys(ivDde)-Wang resin (0.10 mmol, loading 0.58 mmol / g) was suspended in DMF for 30 min. The Fmoc was subsequently removed by treating the resin with 20% piperidine in DMF (3 × 8 min). To generate the isocyanate of the 2-aminoadipyl moiety, a solution of L-2-aminoadipic acid (Aad) di-tert-butyl ester hydrochloride (154.9 mg, 0.5 mmol, 5 equivalents relative to resin) and diisopropylethylamine (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 above reaction at −78° C. The reaction was then warmed to room temperature and stirred for 30 min to give a solution of the isocyanate of the 2-aminoadipyl moiety. An additional 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 by 2% hydrazine in DMF (5×5 min). Fmoc-2-naphthylalanine (in the case of HTK03169) or Fmoc-3-iodo-L-phenylalanine (in the case of HTK04053) was then coupled to the side chain of Lys using Fmoc-protected amino acid (4 eq.), HATU (4 eq.) and DIEA (7 eq.). Elongation was then continued by addition of Fmoc-tranexamic acid and finally DOTA-tris(t-bu) ester (2-(4,7,10-tris(2-(t-butoxy)-2-oxoethyl)-1,4,7,10)-tetraazacyclododecan-1-yl)acetic acid).

[0199] The peptide was subsequently deprotected and simultaneously cleaved from the resin by treatment with 95 / 5 trifluoroacetic acid (TFA) / triisopropylsilane (TIS) for 2 hours at room temperature. After filtration, the peptide was precipitated by adding cold diethyl 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 HTK03169, the preparative HPLC conditions were 20% acetonitrile in water containing 0.1% TFA, flow rate 30 mL / min. The retention time was 9.0 min. The yield was 29.6%. ESI-MS: [M+H] + HTK03169C 50 H 73 N9O 16 Calculated value for 1056.5254; [M+H] + Found 1056.5647. For HTK04053, the semi-preparative HPLC conditions were 24% acetonitrile in water with 0.1% TFA, flow rate 4.5 mL / min. Retention time was 11.9 min. Yield was 47.6%. ESI-MS: [M+H] + HTK04053C 46 H 70 N9O 16 Calculated value for I: 1132.4063; [M+H] + Actual value: 1132.5523.

[0200] Synthesis of HTK03041, HTK03161, HTK03177, HTK03187, HTK03189 (A and B), HTK04018, HTK04033, and HTK04040

[0201] The PSMA targeting Asp-ureido-lysine moieties (for HTK03161), Glu-ureido-lysine moieties (for HTK03041), S-carboxymethylcysteine-ureido-lysine moieties (for HTK03177) and O-carboxymethylserine-ureido-lysine moieties (for HTK03187), racemic 2-aminopimelic acid-ureido-lysine moieties (for HTK03189A and B), 3-(carboxymethyl)sulfonyl-L-alanine-ureido-lysine moieties (for HTK04018), (4R)-4-fluoro-Glu-ureido-lysine moieties (for HTK04040) (peptidomimetics) were synthesized by solid phase peptide chemistry. Fmoc-Lys(ivDde)-Wang resin (0.1 mmol, loading 0.58 mmol / g) was suspended in DMF for 30 min. Fmoc was subsequently removed by treating the resin with 20% piperidine in DMF (3×8 min).To generate the isocyanate derivative, L-aspartic acid di-tert-butyl ester hydrochloride (140.9 mg, 0.5 mmol, 5 equivalents relative to resin), L-glutamic acid di-tert-butyl ester hydrochloride (147.9 mg, 0.5 mmol, 5 equivalents relative to resin), S-carboxymethylcysteine ​​di-tert-butyl ester hydrochloride (163.9 mg, 0.5 mmol, 5 equivalents relative to resin), O-carboxymethylserine di-tert-butyl ester hydrochloride (155.9 mg, 0.5 mmol, 5 equivalents relative to resin), 2-aminopimelic acid di-tert-butyl ester hydrochloride (156.9 mg, 0.5 mmol, 5 equivalents relative to resin) were added in CHCl (5 mL). A solution of 3-(carboxymethyl)sulfonyl-L-alanine di-tert-butyl ester (179.9 mg, 0.5 mmol, 5 equiv. relative to resin), (4R)-4-fluoro-L-glutamic acid di-tert-butyl ester hydrochloride (156.6 mg, 0.5 mmol, 5 equiv. relative to resin) or (4S)-4-fluoro-L-glutamic acid di-tert-butyl ester hydrochloride (156.6 mg, 0.5 mmol, 5 equiv. relative to resin), and DIEA (287.4 μL, 1.65 mmol, DIEA) 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 above reaction at −78° C. The reaction was then allowed to warm to room temperature and stirred for 30 min to give a solution of the derivative. An additional 87.1 μL of DIEA (0.5 mmole) 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 with 2% hydrazine in DMF (5×5 min). Fmoc-Ala(9-Anth)-OH was then coupled to the side chain of Lys using Fmoc-protected amino acid (4 eq.), HATU (4 eq.) and DIEA (7 eq.). The elongation was then continued by adding Fmoc-tranexamic acid and finally DOTA-tris(t-bu) ester.

[0202] The peptide was subsequently deprotected and simultaneously cleaved from the resin by treatment with 95 / 5 trifluoroacetic acid (TFA) / triisopropylsilane (TIS) for 2 hours at room temperature. After filtration, the peptide was precipitated by adding cold diethyl 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 HTK03161, the preparative HPLC conditions were 23% acetonitrile in water with 0.1% TFA, flow rate 30 mL / min. The retention time was 7.9 min. The yield was 17.2%. ESI-MS: [M+H] + HTK03161C 52 H 72 N9O 16 Calculated value for 1078.5097; [M+H] + Found 1078.4720. For HTK03041, the semi-preparative HPLC conditions were 31% acetonitrile in water with 0.1% TFA, flow rate 4.5 mL / min. Retention time was 7.2 min. Yield was 27%. ESI-MS: [M+H] + HTK03161C 53 H 74 N9O 16 Calculated for 1092.5; [M+H] + Found 1092.6. For HTK03177, the preparative HPLC conditions were 24% acetonitrile in water with 0.1% TFA, flow rate 30 mL / min. Retention time was 8.2 min. Yield was 34.0%. ESI-MS: [M+H] + HTK03177C 53 H 73 N9O 16 Calculated for S: 1124.4974; [M+H] + Found 1124.4980. For HTK03187, the semi-preparative HPLC conditions were 28% acetonitrile in water with 0.1% TFA, flow rate 4.5 mL / min. Retention time was 10.4 min. Yield was 30.3%. ESI-MS: [M+H] + HTK03187C 53 H 73 N9O 17Calculated value for 1108.5203; [M+H] + Found 1108.5101. For HTK03189, the semi-preparative HPLC conditions were 28% acetonitrile in water with 0.1% TFA, flow rate 4.5 mL / min. The retention time of HTK03189A was 13.9 min, yield 19.7%. The retention time of HTK03189B was 15.5 min, yield 15.6%. ESI-MS: [M+H] + HTK03189C 55 H 77 N9O 16 Calculated value for 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 with 0.1% TFA, flow rate 4.5 mL / min. Retention time was 9.2 min. ESI-MS: [M+H] + HTK04018C 53 H 73 N9O 18 Calculated for S: 1156.4873; [M+H] + Found 1156.3678. For HTK04033, the preparative HPLC conditions were 23% acetonitrile in water with 0.1% TFA, flow rate 30 mL / min. Retention time was 8.5 min. Yield was 45.7%. ESI-MS: [M+H] + HTK04033C 53 H 72 N9O 16 Calculated for F: 1110.5159; [M+H] + Found 1110.3887. For HTK04040, the preparative HPLC conditions were 23% acetonitrile in water with 0.1% TFA, flow rate 30 mL / min. Retention time was 9.4 min. Yield was 33.3%. ESI-MS: [M+H] + HTK04040C 53 H 72 N9O 16 Calculated for F: 1110.5159; [M+H] + Actual value: 1110.0578.

[0203] Synthesis of HTK04036, HTK04037 and HTK04041

[0204] The PSMA-targeting Aad-ureido-lysine moiety (peptidomimetic) was synthesized by solid-phase peptide chemistry. Fmoc-Lys(ivDde)-Wang resin (0.10 mmol, loading 0.58 mmol / g) was suspended in DMF for 30 min. The Fmoc was subsequently removed by treating the resin with 20% piperidine in DMF (3 × 8 min). To generate the isocyanate of the 2-aminoadipyl moiety, a solution of L-2-aminoadipic acid (Aad) di-tert-butyl ester hydrochloride (154.9 mg, 0.5 mmol, 5 equiv. relative to resin) and DIEA (287.4 μL, 1.65 mmol) 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 warmed to room temperature and stirred for 30 min to give a solution of the isocyanate of the 2-aminoadipyl moiety. An additional 87.1 μL of DIEA (0.5 mmole) 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 by 2% hydrazine in DMF (5×5 min). Fmoc-Ala(9-Anth)-OH was then coupled to the side chain of Lys using Fmoc-protected amino acid (4 eq.), HATU (4 eq.) and DIEA (7 eq.). Elongation was then continued by addition of Fmoc-4-aminomethylphenylacetic acid (for HTK04036), Fmoc-3-aminomethylphenylacetic acid (for HTK04037) or Fmoc-4-aminobenzoic acid (for HTK04041) and finally DOTA-tris(t-bu) ester.

[0205] The peptide was subsequently deprotected and simultaneously cleaved from the resin by treatment with 95 / 5 TFA / TIS for 2 hours at room temperature. After filtration, the peptide was precipitated by adding cold diethyl 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 HTK04036, the preparative HPLC conditions were 23% acetonitrile in water with 0.1% TFA, flow rate 30 mL / min. The retention time was 9.7 min. The yield was 28.2%. ESI-MS: [M+H] + HTK04036C 55 H 71 N9O 16 Calculated value for 1114.5097; [M+H] + Found 1114.3070. For HTK04037, the preparative HPLC conditions were 23% acetonitrile in water with 0.1% TFA, flow rate 30 mL / min. Retention time was 11.6 min. Yield was 27.0%. ESI-MS: [M+H] + HTK04037C 55 H 71 N9O 16 Calculated value for 1114.5097; [M+H] + Found 1114.3629. For HTK04041, the semi-preparative HPLC conditions were 23% acetonitrile in water with 0.1% TFA, flow rate 4.5 mL / min. Retention time was 10.8 min. Yield was 12.8%. ESI-MS: [M+H] + HTK04041C 53 H 67 N9O 16 Calculated value for 1086.4784; [M+H] + Actual value: 1086.4066.

[0206] Synthesis of HTK03153 and HTK03170

[0207] The PSMA-targeting Aad-ureido-lysine moiety (peptidomimetic) was synthesized by solid-phase peptide chemistry. Fmoc-Lys(ivDde)-Wang resin (0.10 mmol, loading 0.58 mmol / g) was suspended in DMF for 30 min. The Fmoc was subsequently removed by treating the resin with 20% piperidine in DMF (3 × 8 min). To generate the isocyanate of the 2-aminoadipyl moiety, a solution of L-2-aminoadipic acid (Aad) di-tert-butyl ester hydrochloride (154.9 mg, 0.5 mmol, 5 equiv. relative to resin) and DIEA (287.4 μL, 1.65 mmol) 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 warmed to room temperature and stirred for 30 min to give a solution of the isocyanate of the 2-aminoadipyl moiety. An additional 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 by 2% hydrazine in DMF (5×5 min). 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 with Fmoc-protected amino acid (4 eq.), HATU (4 eq.) and DIEA (7 eq.). Elongation was then continued by adding 4-(p-chlorophenyl)butyric acid (HTK03153) or 4-(p-methoxyphenyl)butyric acid (HTK03170) coupled to the same peptide-coupling resin using Fmoc-based chemistry. After removal of the ivDde-protecting group with 2% hydrazine in DMF (5×5 min), DOTA-tris(t-bu) ester was coupled to the side chain of Lys to give the precursor.

[0208] The peptide was subsequently deprotected and simultaneously cleaved from the resin by treatment with 95 / 5 TFA / TIS for 2 hours at room temperature. After filtration, the peptide was precipitated by adding cold diethyl 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, flow rate 30 mL / min. The retention time was 7.9 min. ESI-MS: [M+H] + HTK03153C 72 H 99 N 12 O 19 Calculated for Cl: 1471.6916; [M+H] + Found 1471.1257. For HTK03170, the semi-preparative HPLC conditions were 34% acetonitrile in water with 0.1% TFA, flow rate 4.5 mL / min. Retention time was 13.1 min. ESI-MS: [M+2H] 2+ HTK03170C 73 H 102 N 12 O 20 Calculated for 734.3745; [M+2H] 2+ Actual value: 734.5822.

[0209] Synthesis of HTK04028, HTK04048 and HTK04050

[0210] The synthetic procedures for constructing the core structure of HTK04028 were the same as those for HTK03187 as described above, for HTK04048 the same as those for HTK03177 as described above, and for HTK04050 the same as those for HTK04033 as described above. After Fmoc-tranexamic acid, the elongation was continued by adding Fmoc-Lys(ivDde)-OH, Fmoc-Gly-OH, and 4-(p-methoxyphenyl)butyric acid using Fmoc-based chemistry. All couplings were performed in DMF with Fmoc-protected amino acids (4 eq.), HATU (4 eq.), and DIEA (7 eq.). After removal of the ivDde-protecting group with 2% hydrazine in DMF (5×5 min), DOTA-tris(t-bu) ester was coupled to the side chain of Lys to give the precursor.

[0211] The peptide was subsequently deprotected and simultaneously cleaved from the resin by treatment with 95 / 5 TFA / TIS for 2 hours at room temperature. After filtration, the peptide was precipitated by adding cold diethyl 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 HTK04028, the preparative HPLC conditions were 28% acetonitrile in water with 0.1% TFA, flow rate 30 mL / min. The retention time was 14.8 min. The yield was 21.4%. ESI-MS: [M+H] + HTK04028C 72 H 100 N 12 O 21 Calculated value for 1469.7204; [M+H] + Found 1469.7000. For HTK04048, the semi-preparative HPLC conditions were 35% acetonitrile in water with 0.1% TFA, flow rate 4.5 mL / min. Retention time was 11.7 min. Yield was 53.4%. ESI-MS: [M+H] + HTK04048C 72 H 100 N 12 O 20Calculated for S: 1485.6976; [M+H] + Found 1485.9910. For HTK04050, the semi-preparative HPLC conditions were 35% acetonitrile in water with 0.1% TFA, flow rate 4.5 mL / min. Retention time was 11.4 min. Yield was 17.5%. ESI-MS: [M+H] + HTK04050C 72 H 99 N 12 O 20 Calculated for F: 1471.7161; [M+H] + Actual value: 1471.9511.

[0212] Synthesis of non-radioactive Ga-complexed standards

[0213] To prepare the non-radioactive Ga-complexed standards, solutions of each precursor were incubated with GaCl3 (5 equiv.) in NaOAc buffer (0.1 M, 500 μL, pH 4.2) at 80 °C for 15 min. 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 with 0.1% TFA, flow rate 4.5 mL / min. The retention time was 9.3 min. The yield was 89%. ESI-MS: [M+H] + Ga-HTK03041C 53 H 72 N9O 16 Calculated for Ga: 1159.4; [M+H] + Found 1159.4. For Ga-HTK03161, the semi-preparative HPLC conditions were 29% acetonitrile in water with 0.1% TFA, flow rate 4.5 mL / min. Retention time was 11.3 min. Yield was 37.4%. ESI-MS: [M+H] + Ga-HTK03161C 52 H 69 N9O 16 Calculated for Ga: 1145.4196; [M+H] +Found 1146.1355. For Ga-HTK03169, the semi-preparative HPLC conditions were 25% acetonitrile in water with 0.1% TFA, flow rate 4.5 mL / min. Retention time was 14.1 min. Yield was 55.0%. ESI-MS: [M+H] + Ga-HTK03169C 50 H 70 N9O 16 Calculated for Ga: 1122.4275; [M+H] + Found 1122.3041. For Ga-HTK03177, the semi-preparative HPLC conditions were 32% acetonitrile in water with 0.1% TFA, flow rate 4.5 mL / min. Retention time was 7.8 min. Yield was 55.9%. ESI-MS: [M+H] + Ga-HTK03177C 53 H 70 N9O 16 Calculated for SGa: 1190.3995; [M+H] + Found 1190.3061. For Ga-HTK03187, the semi-preparative HPLC conditions were 29% acetonitrile in water with 0.1% TFA, flow rate 4.5 mL / min. Retention time was 13.3 min. Yield was 52.8%. ESI-MS: [M+H] + Ga-HTK03187C 53 H 70 N9O 17 Calculated for Ga: 1174.4224; [M+H] +Found 1174.3425. For Ga-HTK03189A, semi-preparative HPLC conditions were 30% acetonitrile in water with 0.1% TFA, flow rate 4.5 mL / min. Retention time was 13.0 min. Yield was 52.6%. ESI-MS: [M+H]+ calculated for Ga-HTK03189A C55H74N9O16Ga 1186.4588; [M+H]+ found 1186.4164. For Ga-HTK03189B, semi-preparative HPLC conditions were 30% acetonitrile in water with 0.1% TFA, flow rate 4.5 mL / min. Retention time was 13.9 min. Yield was 42.1%. ESI-MS: [M+H]+ calcd for Ga-HTK03189B C55H74N9O16Ga 1186.4588; [M+H]+ found 1186.3279. For Ga-HTK04033, semi-preparative HPLC conditions were 29% acetonitrile in water with 0.1% TFA, flow rate 4.5 mL / min. Retention time was 13.3 min. Yield was 59.5%. ESI-MS: [M+H]+ calcd for Ga-HTK04033 C53H70N9O16FGa 1177.4259; [M+H]+ found 1178.4800. For Ga-HTK04036, semi-preparative HPLC conditions were 29% acetonitrile in water with 0.1% TFA, flow rate 4.5 mL / min. Retention time was 13.1 min. Yield was 61.3%. ESI-MS: [M+H]+ calcd for Ga-HTK04036 C55H69N9O16Ga 1181.4196; [M+H]+ found 1181.4720. For Ga-HTK04037, semi-preparative HPLC conditions were 29% acetonitrile in water with 0.1% TFA, flow rate 4.5 mL / min. Retention time was 15.6 min. Yield was 54.2%. ESI-MS: [M+H]+ calcd 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, flow rate 4.5 mL / min. The retention time was 10.2 min. The yield was 46.5%.ESI-MS: [M+H]+ calcd for Ga-HTK04040 C53H70N9O16FGa 1177.4259; [M+H]+ found 1176.7043. For Ga-HTK04041, semi-preparative HPLC conditions were 29% acetonitrile in water with 0.1% TFA, flow rate 4.5 mL / min. Retention time was 14.4 min. Yield was 55.2%. ESI-MS: [M+H]+ calcd for Ga-HTK04041 C53H65N9O16Ga 1153.3883; [M+H]+ found 1153.5379. For Ga-HTK04053, semi-preparative HPLC conditions were 25% acetonitrile in water with 0.1% TFA, flow rate 4.5 mL / min. Retention time was 12.4 min. Yield was 74.7%. ESI-MS: [M+H]+ calculated for Ga-HTK04053 C46H68N9O16Ga 1199.3163; [M+H]+ found 1199.5712.

[0214] Synthesis of Ga-68 labeled compounds

[0215] [ 68 The eluted [Ga]GaCl3 was eluted from the iThemba Labs generator with a total of 4 mL of 0.1 M HCl. 68 The Ga]GaCl3 solution was added to 2 mL of concentrated HCl. This radioactive mixture was then added to a DGA resin column and washed with 3 mL of 5 M HCl. The column was then air-dried and 0.5 mL of water was used to transfer the [Ga]GaCl3 solution to a vial containing a solution of unlabeled precursor (25 μg) in 0.7 mL of HEPES buffer (2 M, pH 5.3). 68 [Ga]GaCl3 (0.10-0.50 GBq) was eluted. The reaction mixture was heated in a microwave oven (Danby, DMW7700WDB) for 1 min at power setting 2. The mixture was purified by semi-preparative HPLC column and quality control was performed via analytical HPLC with co-injection of unlabeled standards. Radiochemical yields (decay corrected) were >50% and radiochemical purities >95%.

[0216] Synthesis of Lu-complexed standards

[0217] To prepare the standards of HTK03149, HTK03153, HTK03170, HTK04028, HTK04048 and HTK04050 complexed with non-radioactive Lu, the precursor solution was incubated with LuCl3 (5 eq.) in NaOAc buffer (0.1 M, 500 μL, pH 4.2) at 90 °C for 30 min. 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 with 0.1% TFA, flow rate 4.5 mL / min. The retention time was 8.4 min. The yield of Lu-HTK03149 was 91.3%. ESI-MS: [M+H] + Lu-HTK03149C 54 H 74 N9O 16 Calculated for Lu: 1173.4509; [M+H] + Found 1173.5450. For Lu-HTK03153, the HPLC conditions were 39% acetonitrile in water with 0.1% TFA, flow rate 4.5 mL / min. Retention time was 8.1 min. Yield of Lu-HTK03153 was 62.5%. ESI-MS: [M+H] + Lu-HTK03153C 72 H 96 N 12 O 19 Calculated for ClLu 1643.6089; [M+H] + Found 1643.9000. For Lu-HTK03170, the HPLC conditions were 34% acetonitrile in water with 0.1% TFA, flow rate 4.5 mL / min. Retention time was 15.4 min. The yield of Lu-HTK03170 was 94.7%. ESI-MS: [M+H] + Lu-HTK03170C 73 H 99 N 12 O 20 Calculated for Lu: 1639.6585; [M+H] +Found 1639.6933. For Lu-HTK04028, the HPLC conditions were 35% acetonitrile in water with 0.1% TFA, flow rate 4.5 mL / min. Retention time was 11.5 min. Yield of Lu-HTK04028 was 29.4%. ESI-MS: [M+H] + Lu-HTK04028C 72 H 97 N 12 O 21 Calculated for Lu: 1641.6377; [M+H] + Found 1641.7775. For Lu-HTK04048, the HPLC conditions were 35% acetonitrile in water with 0.1% TFA, flow rate 4.5 mL / min. Retention time was 13.9 min. Yield of Lu-HTK04048 was 70.2%. ESI-MS: [M+H] + Lu-HTK04048C 72 H 97 N 12 O 20 Calculated for SLu 1657.6149; [M+H] + Found 1657.8672. For Lu-HTK04050, the HPLC conditions were 35% acetonitrile in water with 0.1% TFA, flow rate 4.5 mL / min. Retention time was 13.2 min. Yield of Lu-HTK04050 was 44.9%. ESI-MS: [M+H] + Lu-HTK04050C 72 H 96 N 12 O 20 Calculated for FLu 1643.6334; [M+H] + Actual value: 1644.7152.

[0218] Synthesis of Lu-177 labeled compounds

[0219] [ 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 min. The mixture was purified by a semi-preparative HPLC column and quality control was performed via an analytical HPLC column with co-injection of unlabeled standards. The radiochemical yield (decay corrected) was >50% and the radiochemical purity was >95%.

[0220] Synthesis of HTK03162 and HTK04055

[0221] The diazide-containing intermediate HTK03156 for synthesizing HTK03162 and the diazide-containing intermediate HTK04039 for synthesizing HTK04055 were each synthesized by solid-phase methods. The synthetic procedures for preparing their core structures were the same as those for syntheses of HTK03149 (for HTK03156) and HTK03187 (for HTK04039). After coupling of Fmoc tranexamic acid, the elongation was continued by adding Fmoc-Lys(Fmoc)-OH. The coupling was performed in DMF with Fmoc-protected amino acid (4 eq.), HATU (4 eq.) and DIEA (7 eq.). After removing the Fmoc protecting group, Fmoc-Aad(OtBu)-OH was coupled to both the side chain and N-terminus of Lys. The coupling was performed with Fmoc-protected amino acid (5 eq.), HATU (5 eq.) and DIEA (9 eq.) in DMF. 2-azidoacetic acid (5 eq.) was coupled to the N-terminus with DIEA (5 eq.) and N-hydroxysuccinimide (6 eq.) to give a diazide-containing intermediate. Upon completion, 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 diethyl 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 with 0.1% TFA, flow rate 30 mL / min. Retention time was 4.8 min and the precursor yield was 39%. ESI-MS: [M+H] + C 60 H 82 N 15 O 18 Calculated value for 1300.5962; [M+H] + Found 1300.6369. For HTK04039, the preparative HPLC conditions were 31% acetonitrile in water with 0.1% TFA, flow rate 30 mL / min. Retention time was 8.0 min, and the precursor yield was 5.8%. ESI-MS: [M+H] + C 59 H 79 N15 O 19 Calculated value: 1302.5755; [M+H] + Actual value: 1302.6022.

[0222] 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 equiv.) were dissolved in 300 μL of acetonitrile, and the solution was adjusted to basic conditions (pH ∼8) with 1 M K2CO3. Subsequently, a solution of 1 M CuSO4 (28.5 μL, 5 equiv.) and 1 M sodium ascorbate (57 μL, 10 equiv.) was 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 eluted 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: [M+H] + C 72 H 104 B2F6N 17 O 18 Calculated value 1630.7836; [M+H] + Actual value: 1630.8000.

[0223] 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 equiv.) were dissolved in 300 μL of acetonitrile, and the solution was adjusted to basic conditions (pH ∼8) with 1 M K2CO3. Subsequently, a solution of 1 M CuSO4 (7.5 μL, 5 equiv.) and 1 M sodium ascorbate (15 μL, 10 equiv.) was 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 eluted 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: [M+H] + C71 H 101 B2F6N 17 O 19 Calculated value: 1632.7628; [M+H] + Actual value: 1632.6622.

[0224] Synthesis of F-18 labeled compounds

[0225] H2 18 By irradiating O with 18-MeV protons (Advanced Cyclotron Systems Inc), a carrier-free [ 18 The [F]fluoride was obtained and trapped on an anion exchange resin column (preactivated with brine and washed with DI water). The [F]fluoride was then eluted using HCl-pyridazine buffer (pH 2.0). 18 [F]fluoride was eluted from the column. Unlabeled trifluoroborate precursor HTK03162 or HTK04055 (100 nmol) was suspended in DMF (15 μL). The eluted [F]fluoride was added to the reaction vessel containing the solution of HTK03162 or HTK04055. 18 [F]fluoride (30-100 GBq) was added. The vial was heated on a heating block at 80 °C for 20 min and quenched by the addition of 1 mL of water. The mixture was purified by semi-preparative HPLC column and quality controlled via analytical HPLC column with co-injection of unlabeled standards. Radiochemical yields (decay corrected) were >10% and radiochemical purities >95%.

[0226] cell culture

[0227] The LNCaP cell line was obtained from ATCC (LNCaP clone FGC, CRL-1740). It was established from a metastatic site in the left supraclavicular lymph node of a human prostate adenocarcinoma. Cells were cultured in PRMI1640 medium supplemented with 10% FBS, penicillin (100 U / mL), and streptomycin (100 μg / mL) at 37 °C in a humidified incubator containing 5% CO2. Cells grown to 80-90% confluence were subsequently washed with sterile phosphate-buffered saline (1x PBS, pH 7.4) and harvested by trypsinization. The concentration of harvested cells was measured with a Hausser Scientific (Horsham, PA) hemocytometer.

[0228] PET / CT, SPECT / CT imaging and biodistribution studies

[0229] Imaging and biodistribution experiments were performed using NODSCID 1L2RγKO male mice. Mice were anesthetized with 2% isoflurane in oxygen by inhalation and injected with 1 × 10 7 LNCaP cells were implanted subcutaneously. Over a period of 5–6 weeks, tumors were allowed to grow and reach a diameter of 5–8 mm, after which mice were imaged or used in biodistribution studies.

[0230] PET imaging experiments were performed using a Siemens Inveon microPET / CT scanner. Each tumor-bearing mouse was injected with 6–8 MBq of Ga-68 or F-18 labeled tracer via the tail vein under anesthesia (2% isoflurane in oxygen). The mice were allowed to recover and move freely in their cages. After 50 min, the mice were sedated again by inhalation of 2% isoflurane in oxygen and placed in the scanner. To reconstruct PET images, a 10-min CT scan was first performed for segmentation, localization, and attenuation correction. Then, a 10-min static PET imaging was performed to determine uptake in the tumor and other organs.

[0231] SPECT / CT imaging experiments were performed using a U-SPECT-II / CT scanner from MILabs (Utrecht, the Netherlands). Each tumor-bearing mouse was anesthetized (2% isoflurane in oxygen) with approximately 37 MBq of 177 Lu-labeled tracer was injected via the tail vein. Mice were allowed to recover and move freely in their cages and were imaged 1, 4, 24, 72 and 120 hours after injection. At each time point, mice were re-sedated and placed in the scanner. First, a 5-minute CT scan was performed for anatomical references at voltage settings of 60 kV and current of 615 μA, followed by a 60-minute static emission scan in list mode using an ultra-high resolution multi-pinhole rat-mouse (pinhole size 1 mm) collimator. Data were reconstructed using U-SPECT II software with a window width of 20% in three energy windows. The photopeak window was set at 208 keV, the lower scatter window was set at 170 keV, and the higher scatter window was set at 255 keV. Reconstruction parameters used were maximum likelihood-expectation maximization (3 iterations), pixel-based subsetting expectation maximization (16 subsets), and a 0.5 mm post-processing filter (Gaussian blur). Images were decay-corrected to injection time in PMOD (PMOD Technologies, Switzerland) and converted to DICOM for qualitative visualization in Inveon Research Workplace (Siemens Medical Solutions USA, Inc.).

[0232] For biodistribution studies, mice were injected with the radiotracer as described above. 68 The Ga test takes 1 hour. 177At 1, 4, 24, 72, or 120 hours (Lu's study), mice were anesthetized with 2% isoflurane inhalation and euthanized by CO2 inhalation. Blood was collected directly from the heart, and organs / tissues of interest were harvested. Harvested organs / tissues were weighed and counted using a Perkin Elmer (Waltham, MA) Wizard2 2480 gamma counter. Uptake in each organ / tissue was normalized to the dose using a standard curve and expressed as a percentage of the dose per gram of tissue (%ID / g).

[0233] The results of Example 2 are shown in Tables 7A, 7B, and 8-13 below, and in Figures 7-13.

[0234] [Table 16] [Table 17]

[0235] [Table 18]

[0236] [Table 19]

[0237] [Table 20]

[0238] [Table 21]

[0239] [Table 22]

[0240] [Table 23]

[0241] [Table 24]

[0242] Example 1 shows that modifying the Glu side chain in the PSMA targeting moiety Lys-ureido-Glu in compounds of formula I, II, and III (e.g., by lengthening the Glu side chain) can significantly reduce tracer uptake in kidney and salivary gland without sacrificing tumor-to-background contrast ratio for radiolabeled tracers (HTK03041 vs. HTK03149). The results in Example 2 further confirm that modifying the Glu side chain improves imaging and therapeutic agents for diseases / conditions expressing PSMA. In particular, compounds of formula I, II, or III, where R 2 Compounds in which the R is methylene (-CH-) or propylene (-CH-CH-CH-), or closely related derivatives thereof (e.g., -CH-O-CH-, -CH-S-CH-, or -CH-CHF-), show reduced uptake in the kidney and salivary gland while retaining binding to PSMA-expressing tumors. In contrast, the results in Example 2 show that R 2 Replacement of with butylene (-CH2-CH2-CH2-CH2-) or its derivatives has further been shown to result in lower uptake in PSMA-expressing tumors (see compounds HTK03189A and HTK03189B) and significantly weaken binding to PSMA.

[0243] In Example 2, among the compounds of formulae I, II and III, R 2 is a compound (R 2It has further been shown that certain combinations of ethylenes (e.g., when R is a substituted ethylene or other ethylene derivative) can reduce uptake in the kidney and salivary glands while preserving binding to PSMA-expressing tumors. 2 When is -CH2-CHF- (HTK04033 and HTK04040), the results of the present invention show that the compounds of the present invention can still bind well to PSMA and have significantly less uptake in the kidney and salivary gland. Notably, HTK04040 (S isomer) has a relatively high kidney uptake (76%ID / g), but this value is still significantly lower than the uptake of HTK03041 (170%ID / g) that does not have a fluoro substituent. Thus, these results show that small substituents (e.g., F, CH3, OH) do not prevent PSMA binding.

[0244] Furthermore, the results show that conjugation of an albumin binder further enhances tumor uptake, resulting in improved tumor:kidney and tumor:salivary gland uptake ratios, especially over time.

[0245] The present invention has been described in connection with one or more embodiments. However, it will be apparent to those skilled in the art that many changes and modifications can be made without departing from the scope of the present invention, as defined in the following claims. That is, the scope of the present invention should not be limited by the preferred embodiments shown in the above examples, but should be accorded the broadest interpretation consistent with the description as a whole.

[0246] The contents of U.S. Provisional Patent Application No. 63 / 006,643, filed April 7, 2020, and U.S. Provisional Patent Application No. 62 / 865,088, filed June 21, 2019, are incorporated herein by reference in their entireties. To the extent that there may be any conflict among the definitions herein, the definitions herein shall control in the above paragraphs.

Claims

1. A compound having formula II below, or a salt or solvate of formula II: 【Chemistry 1】 During the ceremony, R ０ is O or S, R １ａ But -CO ２ H, -SO ２ H, -SO ３ H, -PO ２ H, -PO ３ H ２ , -OPO ３ H ２ , -OSO ３ H, -B(OH) ２ or 【Chemistry 2】 and R １ｂ But -CO ２ H, -SO ２ H, -SO ３ H, -PO ２ H, -PO ３ H ２ , -B(OH) ２ or 【Chemistry 3】 and R １ｃ But -CO ２ H, -SO ２ H, -SO ３ H, -PO ２ H, -PO ３ H ２ , -B(OH) ２ or 【Chemistry 4】 and R ２ が、-CH ２ -、-CH(OH)-、-CHF-、-CF ２ -、-CH(CH ３ )-、-C(CH ３ ) ２ -、-CH ２ CH(OH)-、-CH ２ CHF-、-CHFCH ２ -、-CF ２ CH ２ -、-CH ２ CF ２ -、-CH(OH)CH ２ -、-CH(CH ３ )CH ２ -、-CH ２ CH(CH ３ )-、-C(CH ３ ) ２ CH ２ -、-CH ２ C(CH ３ ) ２ -、-CH ２ CH(OH)CH ２ -、-CH ２ 3.5 ２ -、-(CH ２ ) ２ CH(OH)-、-(CH ２ ) ２ H ２ ) ３ -、-CH ２ SO ２ -、-CH ２ P.S. ２ -、-CHFCH ２ CH ２ -、-CH(OH)CH ２ CH ２ -、-CH(CH ３ )CH ２ CH ２ -、-CH ２ CH(CH ３ )CH ２ -、-CH ２ CH ２ CH(CH ３ )-、-C(CH ３ ) ２ CH ２ CH ２ -、-CH ２ C(CH ３ ) ２ CH ２ -、-CH ２ CH ２ C(CH ３ ) ２ -、-CH(CH ３ )-O-CH ２ -、-C(CH ３ ) ２ -O-CH ２ -、-CH ２ -O-CH(CH ３ )-、-CH ２ -O-C(CH ３ ) ２ -、-CH ２ -S(O)-CH ２ -、-CH ２ -S(O) ２ -CH ２ -、-CH(CH ３ )-S-CH ２ -、-C(CH ３ ) ２ -S-CH ２ -、-CH ２ -S-CH(CH ３ )-、-CH ２ -S-C(CH ３ ) ２ -、-CH(CH ３ )-S(O)-CH ２ -、-C(CH ３ ) ２ -S(O)-CH ２ -、-CH ２ -S(O)-CH(CH ３ )-、-CH ２ -S(O)-C(CH ３ ) ２ -、-CH(CH ３ )-S(O) ２ -CH ２ -、-C(CH ３ ) ２ -S(O) ２ -CH ２ -、-CH ２ -S(O) ２ -CH(CH ３ )-、-CH ２ -S(O) ２ -C(CH ３ ) ２ --, --CH ２ -NH-C(O)-, -C(O)-NH-CH ２ -, -C(O)-NH-CH(CH ３ )- or -C(O)-NH-C(CH ３ ) ２ - and R ３ is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C １ -C ２０ Alkylenyl, alkenylenyl or alkynylenyl, or linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic X ２ -X ２０ heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; ( ４ が、. ２ 、!!\\@ !、!!@@、 【Chemistry 5】 -C(O)-(NH) ２ -C(O)-,-OC(O)NH,-NHC(O)O-,-NHC(O)NH-,-OC(S)NH, -NHC(S)O-, -NHC(S)NH-, -S-S-, -S-CH ２ -S-、-NH-NH-C(O)-、-C(O)-NH-NHであり、 R ５ is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C １ -C ３０ Alkylenyl, alkenylenyl or alkynylenyl, or linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic X ２ -X ３０ heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; R ６ is hydrogen, methyl or ethyl; Xaa １ But -N(R ８ ) R ９ C(O)-, where each R ８ is independently hydrogen or methyl; ９ are independently linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C １ -C ２０ Alkylenyl, alkenylenyl or alkynylenyl, or linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic X ２ -X ２０ heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; At least one R ９ Or R ５ But -(CH ２ ) ０－３ CH(R １０ ) (CH ２ ) ０－３ -, where R １０ but, Linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C ２ -C １９ X is alkyl, alkenyl or alkynyl, linear or branched with only 1 to 3 heteroatoms, cyclic or acyclic, and / or aromatic or non-aromatic; ２ -X １９ heteroalkyl, heteroalkenyl, or heteroalkynyl; -CH ２ R ２３ (That R ２３ is an optionally substituted C ４ -C １６ An aromatic ring system, a partially aromatic fused ring system, or a fully aromatic fused ring system, in which 0 to 3 carbons are replaced by heteroatoms N, S, and / or O, and the optional substituents are OH groups, NH ２ Base, NO ２ Group, halogen group, C １ -C ６ Alkyl group and / or C １ -C ６ alkoxyl groups), or 【Chemistry 6】 (Optionally, halogen, OMe, SMe, NH ２ , NO ２ , CN, OH or an additional ring nitrogen atom; R ７ But, R Ｘ -(Xaa ２ ) ０－４ --, 【Chemistry 7】 and R ２８ is an albumin binder, Xaa ２ and Xaa ３ is, when present, independently -N(R １３ ) R １４ C(O)—, where each R １３ is independently hydrogen or methyl; １４ are independently linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C １ -C ２０ Alkylenyl, alkenylenyl or alkynylenyl, or linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic X ２ -X ２０ heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; Each R Ｘ is independently a radiolabeling group selected from a radiometal chelator optionally having a radiometal bound thereto, an aryl or heteroaryl substituted with a radioactive halogen, a prosthetic group comprising a trifluoroborate, a prosthetic group comprising a silicon-fluorine-acceptor moiety, or a prosthetic group comprising a fluorophosphate, a fluorosulfate, a sulfonyl fluoride, or combinations thereof.

2. In the above formula, R ０ The compound of claim 1 , wherein

3. In the above formula, R １ａ But -CO ２ H, -SO ２ H, -SO ３ H, -PO ２ H, -PO ３ H ２ , O.P.O. ３ H ２ , OSO ３ H and R ２ａ But -CO ２ H, -SO ２ H, -SO ３ H, -PO ２ H, -PO ３ H ２ and R ３ａ But -CO ２ H, -SO ２ H, -SO ３ H, -PO ２ H, -PO ３ H ２ 3. The compound according to claim 1 or 2,

4. In the above formula, R １ａ , R １ｂ and R １ｃ Each of ２ 3. The compound of claim 1 or 2, wherein:

5. In the above formula, R ２ But -CH ２ -, -CHOH-, -CHF-, -CH ２ CHOH-, -CH ２ CHF-, -CH ２ CHOHCH ２ --, --CH ２ CHFCH ２ -, -(CH ２ ) ２ CHOH-,-(CH ２ ) ２ CHF-, -(CH ２ ) ３ --, --CH ２ OCH ２ - or -CH ２ SCH ２ The compound according to any one of claims 1 to 4, wherein

6. In the above formula, R ２ is, -CH ２ -, -CH(OH)-, -CHF-, -CF ２ -, -CH(CH ３ ), -C(CH ３ ), ２ -, -CH ２ CH(OH)-, -CH ２ CHF-, -CHFCH ２ -, -CF ２ CH ２ -, -CH ２ CF ２ -, -CH(OH)CH ２ -, -CH(CH ３ ),CH ２ -, -CH ２ CH(CH ３ ), -C(CH ３ ), ２ CH ２ -, -CH ２ C(CH ３ ), ２ -, -CH ２ CH(OH)CH ２ -, -CH ２ CHFCH ２ -, -(CH ２ ), ２ CH(OH)-, -(CH ２ ), ２ CHF-, -(CH ２ ), ３ -, -CH ２ OCH ２ -, -CH ２ SCH ２ -, -CHFCH ２ CH ２ -, -CH(OH)CH ２ CH ２ -, -CH(CH ３ ),CH ２ CH ２ -, -CH ２ CH(CH ３ ),CH ２ -, -CH ２ CH ２ CH(CH ３ ), -C(CH ３ ), ２ CH ２ CH ２ -、-CH ２ C(CH ３ ) ２ CH ２ -、-CH ２ CH ２ C(CH ３ ) ２ -、-CH(CH ３ )-O-CH ２ -、-C(CH ３ ) ２ -O-CH ２ -、-CH ２ -O-CH(CH ３ )-、-CH ２ -O-C(CH ３ ) ２ -、-CH ２ -S(O)-CH ２ -、-CH ２ -S(O) ２ -CH ２ -、-CH(CH ３ )-S-CH ２ -、-C(CH ３ ) ２ -S-CH ２ -、-CH ２ -S-CH(CH ３ )-、-CH ２ -S-C(CH ３ ) ２ -、-CH(CH ３ )-S(O)-CH ２ -、-C(CH ３ ) ２ -S(O)-CH ２ -、-CH ２ -S(O)-CH(CH ３ )-、-CH ２ -S(O)-C(CH ３ ) ２ -、-CH(CH ３ )-S(O) ２ -CH ２ -、-C(CH ３ ) ２ -S(O) ２ -CH ２ -、-CH ２ -S(O) ２ -CH(CH ３ )-、-CH ２ -S(O) ２ -C(CH ３ ) ２ -, -C(O)-NH-CH ２ -, -C(O)-NH-CH(CH ３ )- or -C(O)-NH-C(CH ３ ) ２ The compound according to any one of claims 1 to 4, wherein

7. In the above formula, R ２ But -(CH ２ ) ３ The compound according to any one of claims 1 to 4, wherein

8. In the above formula, R ２ is, -CH ２ CH(OH)CH ２ -, -CH ２ CHFCH ２ -, -(CH ２ ) ２ CH(OH)-, -(CH ２ ) ２ CHF-, -(CH ２ ) ３ -, -CH ２ OCH ２ -, -CH ２ SCH ２ -, -CHFCH ２ CH ２ -, -CH(OH)CH ２ CH ２ -, -CH(CH ３ )CH ２ CH ２ -, -CH ２ CH(CH ３ )CH ２ -, -CH ２ CH ２ CH(CH ３ )-, -C(CH ３ ) ２ CH ２ CH ２ -, -CH ２ C(CH ３ ) ２ CH ２ -, -CH ２ CH ２ C(CH ３ ) ２ -, -CH(CH ３ )-O-CH ２ -, -C(CH ３ ) ２ -O-CH ２ -, -CH ２ -O-CH(CH ３ )-, -CH ２ -O-C(CH ３ ) ２ -, -CH ２ -S(O)-CH ２ -, -CH ２ -S(O) ２ -CH ２ -, -CH(CH ３ )-S-CH ２ -, -C(CH ３ ) ２ -S-CH ２ --, --CH ２ -S-CH(CH ３ ) -, -CH ２ -S-C(CH ３ ) ２ -, -CH(CH ３ )-S(O)-CH ２ -, -C(CH ３ ) ２ -S(O)-CH ２ --, --CH ２ -S(O)-CH(CH ３ ) -, -CH ２ -S(O)-C(CH ３ ) ２ -, -CH(CH ３ ) -S(O) ２ -CH ２ -, -C(CH ３ ) ２ -S (O) ２ -CH ２ --, --CH ２ -S (O) ２ -CH(CH ３ ) -, -CH ２ -S (O) ２ -C(CH ３ ) ２ --, --CH ２ -NH-C(O)-, -C(O)-NH-CH ２ -, -C(O)-NH-CH(CH ３ )- or -C(O)-NH-C(CH ３ ) ２ The compound according to any one of claims 1 to 4, wherein

9. In the above formula, R ２ But -CH ２ -O-CH ２ - or -CH ２ -S-CH ２ The compound according to claim 8, wherein

10. In the above formula, R ２ is, -CH ２ -, -CH(OH)-, -CHF-, -CF ２ -, -CH(CH ３ ), -C(CH ３ ), ２ -, -CHFCH ２ -, -CF ２ CH ２ -, -CH(OH)CH ２ -, -CH(CH ３ ),CH ２ -, -C(CH ３ ), ２ CH ２ -, -(CH ２ ), ２ CH(OH)-, -(CH ２ ), ２ CHF-, -(CH ２ ), ３ -, -CH ２ OCH ２ -, -CH ２ SCH ２ -, -CHFCH ２ CH ２ -, -CH(OH)CH ２ CH ２ -, -CH(CH ３ ),CH ２ CH ２ -, -CH ２ CH ２ CH(CH ３ ), -C(CH ３ ), ２ CH ２ CH ２ -, -CH ２ CH ２ C(CH ３ ), ２ -, -CH(CH ３ ), -O-CH ２ -, -C(CH ３ ), ２ -O-CH ２ -, -CH ２ -O-CH(CH ３ ), -CH ２ -O-C(CH ３ ), ２ -, -CH ２ -S(O)-CH ２ --, --CH ２ -S (O) ２ -CH ２ -, -CH(CH ３ )-S-CH ２ -, -C(CH ３ ) ２ -S-CH ２ --, --CH ２ -S-CH(CH ３ ) -, -CH ２ -S-C(CH ３ ) ２ -, -CH(CH ３ )-S(O)-CH ２ -, -C(CH ３ ) ２ -S(O)-CH ２ --, --CH ２ -S(O)-CH(CH ３ ) -, -CH ２ -S(O)-C(CH ３ ) ２ -, -CH(CH ３ ) -S(O) ２ -CH ２ -, -C(CH ３ ) ２ -S (O) ２ -CH ２ --, --CH ２ -S (O) ２ -CH(CH ３ ) -, -CH ２ -S (O) ２ -C(CH ３ ) ２ --, --CH ２ -NH-C(O)-, -C(O)-NH-CH ２ -, -C(O)-NH-CH(CH ３ )- or -C(O)-NH-C(CH ３ ) ２ The compound according to any one of claims 1 to 4, wherein

11. In the above formula, R ２ is -(CH ２ ) ２ CHF -, -(CH ２ ) ３ -, -CH ２ OCH ２ -, -CH ２ SCH ２ -, -CHFCH ２ CH ２ -, -CH(OH)CH ２ CH ２ -, -CH(CH ３ )CH ２ CH ２ -, -CH ２ CH ２ CH(CH ３ ) -, -C(CH ３ ) ２ CH ２ CH ２ -, -CH ２ CH ２ C(CH ３ ) ２ -, -CH(CH ３ ) - O - CH ２ -, -C(CH ３ ) ２ - O - CH ２ -, -CH ２ - O - CH(CH ３ ) -, -CH ２ - O - C(CH ３ ) ２ -, -CH ２ - S(O) - CH ２ -, -CH ２ - S(O) ２ - CH ２ -, -CH(CH ３ ) - S - CH ２ -, -C(CH ３ ) ２ - S - CH ２ -, -CH ２ - S - CH(CH ３ ) -, -CH ２ - S - C(CH ３ ) ２ -, -CH(CH ３ ) - S(O) - CH ２ -, -C(CH ３ ) ２ -S(O)-CH ２ --, --CH ２ -S(O)-CH(CH ３ ) -, -CH ２ -S(O)-C(CH ３ ) ２ -, -CH(CH ３ ) -S(O) ２ -CH ２ -, -C(CH ３ ) ２ -S (O) ２ -CH ２ --, --CH ２ -S (O) ２ -CH(CH ３ ) -, -CH ２ -S (O) ２ -C(CH ３ ) ２ -, -C(O)-NH-CH ２ -, -C(O)-NH-CH(CH ３ )- or -C(O)-NH-C(CH ３ ) ２ The compound according to any one of claims 1 to 4, wherein

12. In the above formula, R ２ But -CH ２ CH(OH)-,-CH ２ CHF-, -CH ２ CH (CH ３ ) -, -CH ２ CH(OH)CH ２ --, --CH ２ CH(F)CH ２ - or -CH ２ CH (CH ３ ) CH ２ - and R ２ The compound according to any one of claims 1 to 4, wherein the second carbon in the formula (I) is in the R configuration.

13. In the above formula, R ３ is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C １ -C ２０ Alkylenyl or alkenylenyl, or linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic X ２ -X ２０ The compound of any one of claims 1 to 12, which is heteroalkylenyl or heteroalkenylenyl.

14. In the above formula, R ３ But -CH ２ -, -(CH ２ ) ２ -, linear acyclic C ３ -C １５ Alkylenyl, linear acyclic C ３ -C １５ Alkylenyl in which 1 to 5 of the carbons are replaced by heteroatoms N, S and / or O; or a straight chain acyclic saturated C ３ -C １０ 13. The compound according to any one of claims 1 to 12, which is alkylenyl optionally substituted with 1 to 5 amine, amide, oxo, hydroxyl, thiol, methyl or ethyl groups.

15. In the above formula, R ３ But -CH ２ -, -(CH ２ ) ２ -, -(CH ２ ) ３ , -(CH ２ ) ４ -, -(CH ２ ) ５ --, --CH ２ -O-CH ２ - or -CH ２ -S-CH ２ The compound according to any one of claims 1 to 12, wherein

16. In the above formula, R ３ is -CH=CH-, -CH ２ -C≡C- or linear C ３ -C ５ The compound according to any one of claims 1 to 12, which is alkenylenyl or alkynylenyl.

17. In the above formula, R ３ But -(CH ２ ) ４ 16. The compound of claim 15,

18. In the above formula, R ４ is -O-, -S-, -S(O)-, -S(O) ２ -, -NHC(O)-, -C(O)NH-, 【Chemistry 8】 The compound according to any one of claims 1 to 17,

19. In the above formula, R ４ is -C(O)-(NH) ２ -C(O)-, -OC(O)NH, -NHC(O)C-, -NHC(O)NH-, -OC(S)NH, -NHC(S)O-, -NHC(S)NH-, -NHC(O)C(O)NH-, -S-S-, -S-CH ２ The compound according to any one of claims 1 to 17, which is -S-, -NH-NH-C(O)- or -C(O)-NH-NH-.

20. In the above formula, R ４ is -O-, -S-, -NHC(O)-, -C(O)NH-, 【Chemistry 9】 The compound according to any one of claims 1 to 17,

21. In the above formula, R ４ The compound according to any one of claims 1 to 17, wherein is -OC(O)NH-, -NHC(O)O-, -NHC(O)NH-, -OC(S)NH, -NHC(S)O- or -NHC(S)NH-.

22. In the above formula, R ４ The compound according to any one of claims 1 to 17, wherein is -C(O)NH-.

23. In the above formula, at least one R ９ Or R ５ but, 【Chemistry 10】 The compound according to any one of claims 1 to 22,

24. In the above formula, at least one R ９ Or R ５ but, 【Chemistry 11】 The compound according to any one of claims 1 to 22,

25. In the above formula, at least one R ９ But, R ２４ -R ２５ -R ２６ and R ２４ -R ２５ -R ２６ are independently -(CH ２ ) ０－３ -, C ３ -C ８ Cycloalkylene, in which 0-3 of the carbons are replaced by heteroatoms N, S or O, and optionally one or more OH groups, NH ２ Base, NO ２ Group, halogen group, C １ -C ６ Alkyl group and / or C １ -C ６ The cycloalkylene substituted with an alkoxy group, and C ４ -C １６ Arylene, in which 0 to 3 of the carbons are replaced by heteroatoms N, S or O, and optionally one or more OH groups, NH ２ Base, NO ２ Group, halogen group, C １ -C ６ Alkyl group and / or C １ -C ６ The compound according to any one of claims 1 to 24, wherein said arylene is selected from said arylenes substituted with alkoxy groups.

26. In the above formula, (Xaa １ ) １－４ But, (Xaa １ ) ０－３ NHR ２７ C(O), and its R ２７ but, 【Chemistry 12】 The compound according to any one of claims 1 to 25,

27. In the above formula, R ５ But -(CH ２ ) ０－３ CH(R １０ ) (CH ２ ) ０－３ The compound according to any one of claims 1 to 26, wherein

28. In the above formula, R １０ But -CH ２ -R ２３ The compound according to any one of claims 1 to 27,

29. In the above formula, R ２３ 30. The compound of claim 28, wherein is phenyl substituted with one or two iodo groups, optionally further substituted with one oxy group.

30. In the above formula, R １０ is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C ２ -C １９ X is alkyl, alkenyl or alkynyl, linear or branched with only 1 to 3 heteroatoms, cyclic or acyclic, and / or aromatic or non-aromatic; ２ -X １９ Heteroalkyl, heteroalkenyl, or heteroalkynyl, or -CH ２ R ２３ (That R ２３ is optionally substituted C ４ -C １６ An aromatic ring system, a partially aromatic fused ring system, or a fully aromatic fused ring system, in which 0 to 3 carbons are replaced by heteroatoms N, S, and / or O, and the optional substituents are OH groups, NH ２ Base, NO ２ Group, halogen group, C １ -C ６ Alkyl group and / or C １ -C ６ 28. The compound according to any one of claims 1 to 27, wherein the aryl group is selected from the group consisting of aryl, ... and aryl alkoxyl groups.

31. In the above formula, R １０ but, 【Chemistry 13】 The compound according to any one of claims 1 to 27,

32. In the above formula, R １０ but, 【Chemistry 14】 and optionally halogen, OMe, SMe, NH ２ , NO ２ 28. The compound of any one of claims 1 to 27, modified with one, two or more, or a combination of, CN, OH or additional ring nitrogen atoms.

33. In the above formula, R １０ but, 【Chemistry 15】 The compound according to any one of claims 1 to 27,

34. In the above formula, -(Xaa １ ) １－４ N (R ６ ) R ５ R ４ -but, 【Chemistry 16】 The compound according to any one of claims 1 to 33,

35. In the above formula, R ６ The compound according to any one of claims 1 to 33, wherein is methyl.

36. In the above formula, R ７ But, R Ｘ -(Xaa ２ ) ０－４ The compound according to any one of claims 1 to 35, wherein

37. In the above formula, R ２８ but, 【Chemistry 17】 and R １２ is I, Br, F, Cl, H, OH, OCH ３ , N.H. ２ , NO ２ or CH ３ The compound according to any one of claims 1 to 36,

38. In the above formula, R ７ but, R Ｘ -(A｡｡) ２ ) ０－４ -、 【Chemistry 18】 and R １１ But it doesn't exist, 【Chemistry 19】 The compound according to any one of claims 1 to 35,

39. In the above formula, R ７ The first R Ｘ group and the second R Ｘ group, and the first R Ｘ group is a radiometal chelator optionally having a radiometal bound thereto, said second R Ｘ The compound of any one of claims 1 to 38, wherein the group is a prosthetic group that comprises trifluoroborate.

40. 1. A compound comprising a prostate-specific membrane antigen (PSMA) targeting moiety of formula III, or a salt or solvate of formula III: 【Chemistry 20】 During the ceremony, R ０ is O or S, R １ａ But -CO ２ H, -SO ２ H, -SO ３ H, -PO ２ H, -PO ３ H ２ , -OPO ３ H ２ , -OSO ３ H, -B(OH) ２ or 【Chemistry 21】 and R １ｂ But -CO ２ H, -SO ２ H, -SO ３ H, -PO ２ H, -PO ３ H ２ , -B(OH) ２ or 【Chemical 22】 and R １ｃ But -CO ２ H, -SO ２ H, -SO ３ H, -PO ２ H, -PO ３ H ２ , -B(OH) ２ or 【Chemistry 23】 and R ２ が、-CH(CH ３ )CH ２ CH ２ -、-CH ２ CH(CH ３ )CH ２ -、-CH ２ CH ２ CH(CH ３ )-、-C(CH ３ ) ２ CH ２ CH ２ -、-CH ２ C(CH ３ ) ２ CH ２ -、-CH ２ CH ２ C(CH ３ ) ２ -、-CH(CH ３ )-O-CH ２ -、-C(CH ３ ) ２ -O-CH ２ -、-CH ２ -O-CH(CH ３ )-、-CH ２ -O-C(CH ３ ) ２ -、-CH ２ -S(O)-CH ２ -、-CH ２ -S(O) ２ -CH ２ -、-CH(CH ３ )-S-CH ２ -、-C(CH ３ ) ２ -S-CH ２ -、-CH ２ -S-CH(CH ３ )-、-CH ２ -S-C(CH ３ ) ２ -、-CH(CH ３ )-S(O)-CH ２ -、-C(CH ３ ) ２ -S(O)-CH ２ -、-CH ２ -S(O)-CH(CH ３ )-、-CH ２ -S(O)-C(CH ３ ) ２ -、-CH(CH ３ )-S(O) ２ -CH ２ -、-C(CH ３ ) ２ -S(O) ２ -CH ２ -、-CH ２ -S(O) ２ -CH(CH ３ )-、-CH ２ -S(O) ２ -C(CH ３ ) ２ -、-C(O)-NH-CH ２ -、-C(O)-NH-CH(CH ３ )-または-C(O)-NH-C(CH ３ ) ２ -であり、 R ３ is a linker.

41. 41. The compound of claim 40, wherein the compound further comprises one or more radiolabeling groups attached to the linker, the radiolabeling groups independently selected from a radiometal chelator optionally having a radiometal bound thereto, an aryl or heteroaryl substituted with a radioactive halogen, a prosthetic group comprising a trifluoroborate, or a prosthetic group comprising a silicon-fluorine-acceptor moiety, a fluorophosphate, a fluorosulfate, or a sulfonyl fluoride.

42. 42. The compound of claim 41, wherein the one or more radiolabeling groups optionally include a radiometal chelator having a radiometal bound thereto, and a prosthetic group comprising trifluoroborate.

43. In the above formula, R ０ The compound according to any one of claims 40 to 42, wherein is O.

44. In the above formula, R １ａ But -CO ２ H, -SO ２ H, -SO ３ H, -PO ２ H, -PO ３ H ２ , O.P.O. ３ H ２ , OSO ３ H and R ２ａ But -CO ２ H, -SO ２ H, -SO ３ H, -PO ２ H, -PO ３ H ２ and R ３ａ But -CO ２ H, -SO ２ H, -SO ３ H, -PO ２ H, -PO ３ H ２ The compound according to any one of claims 40 to 43,

45. In the above formula, R １ａ , R １ｂ and R １ｃ Each of ２ The compound according to any one of claims 40 to 43, wherein R is H.

46. In the above formula, R ２ is, -CH(CH ３ )CH ２ CH ２ -, -CH ２ CH ２ CH(CH ３ )-, -C(CH ３ ) ２ CH ２ CH ２ -, -CH ２ CH ２ C(CH ３ ) ２ -, -CH(CH ３ )-O-CH ２ -, -C(CH ３ ) ２ -O-CH ２ -, -CH ２ -O-CH(CH ３ )-, -CH ２ -O-C(CH ３ ) ２ -, -CH ２ -S(O)-CH ２ -, -CH ２ -S(O) ２ -CH ２ -, -CH(CH ３ )-S-CH ２ -, -C(CH ３ ) ２ -S-CH ２ -, -CH ２ -S-CH(CH ３ )-, -CH ２ -S-C(CH ３ ) ２ -, -CH(CH ３ )-S(O)-CH ２ -, -C(CH ３ ) ２ -S(O)-CH ２ -, -CH ２ -S(O)-CH(CH ３ )-, -CH ２ -S(O)-C(CH ３ ) ２ -, -CH(CH ３ )-S(O) ２ -CH ２ -, -C(CH ３ ) ２ -S (O) ２ -CH ２ --, --CH ２ -S (O) ２ -CH(CH ３ ) -, -CH ２ -S (O) ２ -C(CH ３ ) ２ -, -C(O)-NH-CH ２ -, -C(O)-NH-CH(CH ３ )- or -C(O)-NH-C(CH ３ ) ２ The compound according to any one of claims 40 to 45, wherein

47. In the above formula, R ２ is, -CH(CH ３ )CH ２ CH ２ -, -CH ２ CH(CH ３ )CH ２ -, -CH ２ CH ２ CH(CH ３ )-, -C(CH ３ ) ２ CH ２ CH ２ -, -CH ２ C(CH ３ ) ２ CH ２ -, -CH ２ CH ２ C(CH ３ ) ２ -, -CH(CH ３ )-O-CH ２ -, -C(CH ３ ) ２ -O-CH ２ -, -CH ２ -O-CH(CH ３ ), -CH ２ -O-C(CH ３ ) ２ -, -CH ２ -S(O)-CH ２ -, -CH ２ -S(O) ２ -CH ２ -, -CH(CH ３ )-S-CH ２ -, -C(CH ３ ) ２ -S-CH ２ -, -CH ２ -S-CH(CH ３ ), -CH ２ -S-C(CH ３ ) ２ -, -CH(CH ３ )-S(O)-CH ２ -, -C(CH ３ ) ２ -S(O)-CH ２ -, -CH ２ -S(O)-CH(CH ３ ), -CH ２ -S(O)-C(CH ３ ) ２ -, -CH(CH ３ ) -S(O) ２ -CH ２ -, -C(CH ３ ) ２ -S (O) ２ -CH ２ --, --CH ２ -S (O) ２ -CH(CH ３ )- or -CH ２ -S (O) ２ -C(CH ３ ) ２ The compound according to any one of claims 40 to 45,

48. In the above formula, R ２ But -CH ２ CH (CH ３ ) CH ２ -, and R ２ The compound according to any one of claims 40 to 45, wherein the second carbon in the formula (I) is in the R configuration.

49. In the above formula, R ３ is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C １ -C ２０ Alkylenyl, alkenylenyl or alkynylenyl, or linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic X ２ -X ２０ The compound of any one of claims 40 to 48, which is heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl.

50. 50. A compound according to any one of claims 1 to 49, comprising a positron or gamma emitting radioisotope for use in imaging prostate specific membrane antigen (PSMA) expressing tissue in a subject.

51. 50. A compound according to any one of claims 1 to 49, comprising a therapeutic radioisotope, for use in treating a condition or disease expressing prostate specific membrane antigen (PSMA) in a subject.

52. A compound having formula IV or a salt or solvate of formula IV: 【Chemistry 24】 During the ceremony, R ０ is S or O, R １ａ But -CO ２ H, -SO ２ H, -SO ３ H, -PO ２ H, -PO ３ H ２ , -OPO ３ H ２ , -OSO ３ H, -B(OH) ２ or 【Chemistry 25】 and R １ｂ But -CO ２ H, -SO ２ H, -SO ３ H, -PO ２ H, -PO ３ H ２ , -B(OH) ２ or 【Chemistry 26】 and R １ｃ But -CO ２ H, -SO ２ H, -SO ３ H, -PO ２ H, -PO ３ H ２ , -B(OH) ２ or 【Chemical 27】 and R ２ が、-CH ２ -、-CH(OH)-、-CHF-、-CF ２ -、-CH(CH ３ )-、-C(CH ３ ) ２ -、-CH ２ CH(OH)-、-CH ２ CHF-、-CHFCH ２ -、-CF ２ CH ２ -、-CH ２ CF ２ -、-CH(OH)CH ２ -、-CH(CH ３ )CH ２ -、-CH ２ CH(CH ３ )-、-C(CH ３ ) ２ CH ２ -、-CH ２ C(CH ３ ) ２ -、-CH ２ CH(OH)CH ２ -、-CH ２ 3.5 ２ -、-(CH ２ ) ２ CH(OH)-、-(CH ２ ) ２ H ２ ) ３ -、-CH ２ SO ２ -、-CH ２ P.S. ２ -、-CHFCH ２ CH ２ -、-CH(OH)CH ２ CH ２ -、-CH(CH ３ )CH ２ CH ２ -、-CH ２ CH(CH ３ )CH ２ -、-CH ２ CH ２ CH(CH ３ )-、-C(CH ３ ) ２ CH ２ CH ２ -、-CH ２ C(CH ３ ) ２ CH ２ -、-CH ２ CH ２ C(CH ３ ) ２ -、-CH(CH ３ )-O-CH ２ -、-C(CH ３ ) ２ -O-CH ２ -、-CH ２ -O-CH(CH ３ )-、-CH ２ -O-C(CH ３ ) ２ -、-CH ２ -S(O)-CH ２ -、-CH ２ -S(O) ２ -CH ２ -、-CH(CH ３ )-S-CH ２ -、-C(CH ３ ) ２ -S-CH ２ -、-CH ２ -S-CH(CH ３ )-、-CH ２ -S-C(CH ３ ) ２ -、-CH(CH ３ )-S(O)-、CH ２ -、-C(CH ３ ) ２ -S(O)-CH ２ -、-CH ２ -S(O)-CH(CH ３ )-、-CH ２ -S(O)-C(CH ３ ) ２ -、-CH(CH ３ )-S(O) ２ -CH ２ -、-C(CH ３ ) ２ -S(O) ２ -CH ２ -、-CH ２ -S(O) ２ -CH(CH ３ )-、-CH ２ -S(O) ２ -C(CH ３ ) ２ --, --CH ２ -NH-C(O)-, -C(O)-NH-CH ２ -, -C(O)-NH-CH(CH ３ )-, -C(O)-NH-C(CH ３ ) ２ --, --CH ２ SeCH ２ -, -CH(COOH)-, -CH ２ CH(COOH)-,-CH ２ CH(COOH)CH ２ --, --CH ２ CH ２ CH(COOH)-, -CH=CH-, -CH=CHCH ２ -, -C≡CCH ２ -, -HC[CH ２ ]CH- or -HC[CH ２ ]CHCH ２ -, where HC[CH ２ ]CH represents a cyclopropyl ring; R ３ is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C １ -C ２０ Alkylenyl or alkenylenyl, or linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic X ２ -X ２０ heteroalkylenyl or heteroalkenylenyl, ( ４ が、. ２ 、!!\\@ !、!!@@、 【Chemistry 28】 -C(O)-(NH) ２ -C(O)-,-OC(O)NH,-NHC(O)O-,-NHC(O)NH-,-OC(S)NH, -NHC(S)O-, -NHC(S)NH-, -S-S-, -S-CH ２ -S-、-NH-NH-C(O)-NH-NH-、 【Chemical 29】 and R ５ is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C １ -C ３０ Alkylenyl, alkenylenyl or alkynylenyl, or linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic X ２ -X ３０ heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; R ６ is hydrogen, methyl or ethyl; Xaa １ But -N(R ８ ) R ９ C(O)-, where each R ８ is independently hydrogen or methyl; ９ are independently linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C １ -C ２０ Alkylenyl, alkenylenyl or alkynylenyl, or linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic X ２ -X ２０ heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; At least one R ９ Or R ５ But -(CH ２ ) ０－３ CH(R １０ ) (CH ２ ) ０－３ -, where R １０ but, Linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C ２ -C １９ X is alkyl, alkenyl or alkynyl, linear or branched with only 1 to 3 heteroatoms, cyclic or acyclic, and / or aromatic or non-aromatic; ２ -X １９ heteroalkyl, heteroalkenyl, or heteroalkynyl; -CH ２ R ２３ (That R ２３ is an optionally substituted C ４ -C １６ An aromatic ring system, a partially aromatic fused ring system, or a fully aromatic fused ring system, in which 0 to 3 carbons are replaced by heteroatoms N, S, and / or O, and the optional substituents are OH groups, NH ２ Base, NO ２ Group, halogen group, C １ -C ６ Alkyl group and / or C １ -C ６ alkoxyl groups), or 【Chemistry 30】 (Optionally, halogen, OMe, SMe, NH ２ , NO ２ , CN, OH or an additional ring nitrogen atom; R ７ But, R Ｘ -(Xaa ２ ) ０－４ --, 【Chemistry 31】 and R ２８ is an albumin binder, Xaa ２ and Xaa ３ is, when present, independently -N(R １３ ) R １４ C(O)—, where each R １３ is independently hydrogen or methyl; １４ are independently linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C １ -C ２０ Alkylenyl, alkenylenyl or alkynylenyl, or linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic X ２ -X ２０ heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; Each R Ｘ is independently a radiolabeling group selected from an optionally metal-bound radiometal chelator, a radioisotope-substituted aryl or heteroaryl, a trifluoroborate-containing prosthetic group, or a silicon-fluorine-acceptor moiety, a fluorophosphate, a fluorosulfate, or a sulfonyl fluoride-containing prosthetic group; R ７ -(Xaa １ ) １－４ -N(R ６ )-R ５ -R ４ -R ３ Any one or any combination of the amide bonds in ２ -, -NHC(O)-, -C(O)NH-, 【Chemistry 32】 -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-CH ２ The compound is replaced by one or a combination selected from the group consisting of -S-, -NH-NH-C(O)-, and -C(O)-NH-NH-.

53. The -N(R ６ )-R ５ -R ４ -but, 【Chemical 33】 where X is CH or N, Y is NH, S or O, and any of these triaryl / heteroaryl groups may be selected from halogen, OMe, SMe, NH ２ , NO ２ 53. The compound of claim 52, optionally modified with one, two or more, or combinations of: , CN, OH or one or more additional nitrogen atoms in the ring.

54. A compound having the following formula V, or a salt or solvate of formula V: 【Chemical 34】 During the ceremony, R ０ is S or O, R １ａ But -CO ２ H, -SO ２ H, -SO ３ H, -PO ２ H, -PO ３ H ２ , -OPO ３ H ２ , -OSO ３ H, -B(OH) ２ or 【Chemistry 35】 and R １ｂ But -CO ２ H, -SO ２ H, -SO ３ H, -PO ２ H, -PO ３ H ２ , -B(OH) ２ or 【Chemical 36】 and R １ｃ But -CO ２ H, -SO ２ H, -SO ３ H, -PO ２ H, -PO ３ H ２ , -B(OH) ２ or 【Chemical 37】 and R ２ が、-CH ２ -、-CH(OH)-、-CHF-、-CF ２ -、-CH(CH ３ )-、-C(CH ３ ) ２ -、-CH ２ CH(OH)-、-CH ２ CHF-、-CHFCH ２ -、-CF ２ CH ２ -、-CH ２ CF ２ -、-CH(OH)CH ２ -、-CH(CH ３ )CH ２ -、-CH ２ CH(CH ３ )-、-C(CH ３ ) ２ CH ２ -、-CH ２ C(CH ３ ) ２ -、-CH ２ CH(OH)CH ２ -、-CH ２ 3.5 ２ -、-(CH ２ ) ２ CH(OH)-、-(CH ２ ) ２ H ２ ) ３ -、-CH ２ SO ２ -、-CH ２ P.S. ２ -、-CHFCH ２ CH ２ -、-CH(OH)CH ２ CH ２ -、-CH(CH ３ )CH ２ CH ２ -、-CH ２ CH(CH ３ )CH ２ -、-CH ２ CH ２ CH(CH ３ )-、-C(CH ３ ) ２ CH ２ CH ２ -、-CH ２ C(CH ３ ) ２ CH ２ -、-CH ２ CH ２ C(CH ３ ) ２ -、-CH(CH ３ )-O-CH ２ -、-C(CH ３ ) ２ -O-CH ２ -、-CH ２ -O-CH(CH ３ )-、-CH ２ -O-C(CH ３ ) ２ -、-CH ２ -S(O)-CH ２ -、-CH ２ -S(O) ２ -CH ２ -、-CH(CH ３ )-S-CH ２ -、-C(CH ３ ) ２ -S-CH ２ -、-CH ２ -S-CH(CH ３ )-、-CH ２ -S-C(CH ３ ) ２ -、-CH(CH ３ )-S(O)-、CH ２ -、-C(CH ３ ) ２ -S(O)-CH ２ -、-CH ２ -S(O)-CH(CH ３ )-、-CH ２ -S(O)-C(CH ３ ) ２ -、-CH(CH ３ )-S(O) ２ -CH ２ -、-C(CH ３ ) ２ -S(O) ２ -CH ２ -、-CH ２ -S(O) ２ -CH(CH ３ )-、-CH ２ -S(O) ２ -C(CH ３ ) ２ --, --CH ２ -NH-C(O)-, -C(O)-NH-CH ２ -, -C(O)-NH-CH(CH ３ )-, -C(O)-NH-C(CH ３ ) ２ --, --CH ２ SeCH ２ -, -CH(COOH)-, -CH ２ CH(COOH)-,-CH ２ CH(COOH)CH ２ --, --CH ２ CH ２ CH(COOH)-, -CH=CH-, -CH=CHCH ２ -, -C≡CCH ２ -, -HC[CH ２ ]CH- or -HC[CH ２ ]CHCH ２ -, where HC[CH ２ ]CH represents a cyclopropyl ring; R ３ is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C １ -C ２０ Alkylenyl or alkenylenyl, or linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic X ２ -X ２０ heteroalkylenyl or heteroalkenylenyl, ( ４ が、. ２ 、!!\\@ !、!!@@、 【Chemical Formula 38】 -C(O)-(NH) ２ -C(O)-,-OC(O)NH,-NHC(O)O-,-NHC(O)NH-,-OC(S)NH, -NHC(S)O-, -NHC(S)NH-, -S-S-, -S-CH ２ -S-、-NH-NH-C(O)-NH-NH-、 【Chemical 39】 and R ５ is linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C １ -C ３０ Alkylenyl, alkenylenyl or alkynylenyl, or linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic X ２ -X ３０ heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; R ６ optionally, Xaa １ or a carbonyl group which is attached to the α-nitrogen in １ -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)-, Xaa １ But -N(R ８ ) R ９ C(O)-, where each R ８ is independently hydrogen or methyl; ９ are independently linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C １ -C ２０ Alkylenyl, alkenylenyl or alkynylenyl, or linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic X ２ -X ２０ heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; At least one R ９ Or R ５ But -(CH ２ ) ０－３ CH(R １０ ) (CH ２ ) ０－３ -, where R １０ but, Linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C ２ -C １９ X is alkyl, alkenyl or alkynyl, linear or branched with only 1 to 3 heteroatoms, cyclic or acyclic, and / or aromatic or non-aromatic; ２ -X １９ heteroalkyl, heteroalkenyl, or heteroalkynyl; -CH ２ R ２３ (That R ２３ is an optionally substituted C ４ -C １６ An aromatic ring system, a partially aromatic fused ring system, or a fully aromatic fused ring system, in which 0 to 3 carbons are replaced by heteroatoms N, S, and / or O, and the optional substituents are OH groups, NH ２ Base, NO ２ Group, halogen group, C １ -C ６ Alkyl group and / or C １ -C ６ alkoxyl groups), or 【Chemistry 40】 (Optionally, halogen, OMe, SMe, NH ２ , NO ２ , CN, OH or an additional ring nitrogen atom; R ７ But, R Ｘ -(Xaa ２ ) ０－４ --, 【Chemistry 41】 and R ２８ is an albumin binder, Xaa ２ and Xaa ３ is, when present, independently -N(R １３ ) R １４ C(O)—, where each R １３ is independently hydrogen or methyl; １４ are independently linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic C １ -C ２０ Alkylenyl, alkenylenyl or alkynylenyl, or linear or branched, cyclic or acyclic, and / or aromatic or non-aromatic X ２ -X ２０ heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; Each R Ｘ is independently a radiolabeling group selected from an optionally metal-bound radiometal chelator, a radioisotope-substituted aryl or heteroaryl, a trifluoroborate-containing prosthetic group, or a silicon-fluorine-acceptor moiety, a fluorophosphate, a fluorosulfate, or a sulfonyl fluoride-containing prosthetic group.

55. In the above formula, R ２８ but, 【Chemistry 42】 In the above formula, R １２ is I, Br, F, Cl, H, OH, OCH ３ , N.H. ２ , NO ２ or CH ３ The compound according to any one of claims 52 to 54,

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