Claims for Patent: 12,070,513

Summary for Patent: 12,070,513

Title:	PSMA-binding agents and uses thereof
Abstract:	Prostate-specific membrane antigen (PSMA) binding compounds having radioisotope substituents are described, as well as chemical precursors thereof. Compounds include pyridine containing compounds, compounds having phenylhydrazine structures, and acylated lysine compounds. The compounds allow ready incorporation of radionuclides for single photon emission computed tomography (SPECT) and positron emission tomography (PET) for imaging, for example, prostate cancer cells and angiogenesis.
Inventor(s):	Martin G. Pomper, Ronnie Charles Mease, Ying Chen
Assignee:	Johns Hopkins University
Application Number:	US17/237,850
Patent Claims:	1. A composition comprising a pharmaceutically acceptable carrier and a compound having the structure wherein Z is tetrazole or CO2Q; each Q is independently selected from hydrogen or a protecting group; and wherein m is 0, 1, 2, 3, 4, 5, or 6; R is a pyridine ring selected from the group consisting of wherein X is fluorine, iodine, a radioisotope of fluorine, a radioisotope of iodine, chlorine, bromine, a radioisotope of bromine, a radioisotope of astatine, NO2 NH2, N+(R2)3, Sn(R2)3, Si(R2)3, Hg(R2), B(OH)2, —NHNH2, —NHN═CHR3, —NHNH—CH2R3, n is 1, 2, 3, 4, or 5; Y is O, S, N(R′), C(O), NR′C(O), C(O)N(R′), OC(O), C(O)(O), NR′C(O)NR′, NR′C(S)NR′, NR'S(O)2, S(CH2)p, NR′(CH2)p, O(CH2)p, OC(O)CHR8NHC(O), NHC(O) CHR8NHC(O), or a covalent bond; wherein p is 1, 2, or 3, R′is H or C1-C6 alkyl, and R8 is hydrogen, alkyl, aryl, or heteroaryl, each of which may be substituted; R2 is a C1-C6 alkyl; and R3 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl each of which is substituted by fluorine, iodine, a radioisotope of fluorine, a radioisotope of iodine, chlorine, bromine, a radioisotope of bromine, or a radioisotope of astatine, NO2, NH2, N+(R2)3, Sn(R2)3, Si(R2)3, Hg(R2), or B(OH)2; OR m is 0, 1, 2, 3, 4, 5, or 6; Y is O, S, N(R′), C(O), NR′C(O), C(O)N(R′), OC(O), C(O)(O), NR′C(O)NR′, NR′C(S)NR′, NR′, NR'S(O)2, S(CH2)P, NR′—(CH2)P, O(CH2)P, OC(O)CHR8NHC(O), NHC(O) CHR8NHC(O), or a covalent bond; wherein p is 1, 2, or 3,R′ is H or C1-C6 alkyl, R8 is hydrogen, alkyl, aryl, or heteroaryl, each of which may be substituted; R is X′ is selected from the group consisting of NHNH2, —NHN═CHR3, —NHNH—CH2R3; R3 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl each of which is substituted by fluorine, iodine, a radioisotope of fluorine, a radioisotope of iodine, chlorine, bromine, a radioisotope of bromine, or a radioisotope of astatine, NO2, NH2, N+(R2)3, Sn(R2)3, Si(R2)3, Hg(R2), or B(OH)2; R2 is C1-C6 alkyl, n is 1, 2, 3, 4, or 5; OR m is 4, Y is NR′, and R is wherein G is O, NR′ or a covalent bond; R′is H or C1-C6 alkyl; p is 1, 2, 3, or 4, and R7 is selected from the group consisting of NH2, N═CHR3, NH—CH2R3, wherein R3 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl each of which is substituted by fluorine, iodine, a radioisotope of fluorine, a radioisotope of iodine, chlorine, bromine, a radioisotope of bromine, or a radioisotope of astatine, NO2, NH2, N+(R2)3, Sn(R2)3, Si(R2)3, Hg(R2), or B(OH)2; and R2 is C1-C6 alkyl. 2. A composition according to claim 1, wherein Z is CO2Q. 3. A composition according to claim 1, wherein Q is hydrogen. 4. A composition according to claim 1, wherein m is 1, 2, 3, or 4. 5. A composition according to claim 1, having the structure wherein m is 0, 1, 2, 3, 4, 5, or 6; R is a pyridine ring selected from the group consisting of wherein X is fluorine, iodine, a radioisotope of fluorine, a radioisotope of iodine, chlorine, bromine, a radioisotope of bromine, a radioisotope of astatine NO2, NH2, N+(R2)3, Sn(R2)3, Si(R2)3, Hg(R2), B(OH)2, —NHNH2, —NHN═CHR3, —NHNH—CH2R3, each Q is independently selected from hydrogen or a protecting group; Y is O, S, N(R′), C(O), NR′C(O), C(O)N(R′), OC(O), C(O)(O), NR′C(O)NR′, NR′C(S)NR′, NR′, NR′S(O)2, S(CH2)p, NR′—(CH2)p, O(CH2)p, OC(O)CHR8NHC(O), NHC(O) CHR8NHC(O), or a covalent bond; wherein p is 1, 2, or 3, R′is H or C1-C6 alkyl, and R8 is hydrogen, alkyl, aryl, or heteroaryl, each of which may be substituted; Z is tetrazole or CO2Q; R2 is C1-C6 alkyl; and R3 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl each of which is substituted by fluorine, iodine, a radioisotope of fluorine, a radioisotope of iodine, chlorine, bromine, a radioisotope of bromine, or a radioisotope of astatine, NO2, NH2, N+(R2)3, Sn(R2)3, Si(R2) 3, Hg(R2), or B(OH)2. 6. A composition according to claim 5, having the structure wherein m is not 0. 7. A composition A compound according to claim 6, whereine Z is CO2Q, Q is hydrogen, and m is 4. 8. A composition according to claim 5, having the structure wherein m is not 0. 9. A composition according to claim 8, wherein Z is CO2Q, Q is hydrogen, and m is 1, 2, or 3. 10. A composition according to claim 1, wherein m is 0, 1, 2, 3, 4, 5, or 6; Y is O, S, N(R′), C(O), NR′C(O), C(O)N(R′), OC(O), C(O)(O), NR′C(O)NR′, NR′C(S)NR′, NR′, NR'S(O)2, S(CH2)p, NR′—(CH2)p, O(CH2)p, OC(O)CHR8NHC(O), NHC(O) CHR8NHC(O), or a covalent bond; wherein p is 1, 2, or 3, R′is H or C1-C6 alkyl, and R8 is hydrogen, alkyl, aryl, or heteroaryl, each of which may be substituted; R is wherein X′ is selected from the group consisting of NHNH2, —NHN═CHR3, —NHNH—CH2R3 wherein R3 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl each of which is substituted by fluorine, iodine, a radioisotope of fluorine, a radioisotope of iodine, bromine, a radioisotope of bromine, or a radioisotope of astatine, NO2, NH2, N+(R2)3, Sn(R2)3, Si(R2)3, Hg(R2), and B(OH)2 where R2 is C1-C6 alkyl, n is 1, 2, 3, 4, or 5. 11. A composition according to claim 1, wherein n is 1. 12. A composition according to claim 1, wherein X or X′is fluorine, iodine, or a radioisotope of fluorine or iodine, bromine, a radioisotope of bromine, or a radioisotope of astatine. 13. A composition according to claim 1, wherein X or X′ is fluorine, iodine, or a radioisotope of fluorine or iodine. 14. A composition according to claim 1, wherein m is 4, Y is NR′, and R is wherein G is O, NR′ or a covalent bond; p is 1, 2, 3, or 4, and R7 is selected from the group consisting of NH2, N═CHR3, NH—CH2R3, wherein R3 is alkyl, alkenyl, alkynyl, aryl, heteroaryl each of which is substituted by fluorine, iodine, a radioisotope of fluorine, a radioisotope of iodine, chlorine, bromine, a radioisotope of bromine, or a radioisotope of astatine, NO2, NH2, N+(R2)3, Sn(R2)3, Si(R2)3, Hg(R2), or B(OH), wherein R2 is C1-C6 alkyl. 15. A composition according to claim 14, wherein G is O or NR′. 16. A composition according to claim 1, wherein the radioisotope of fluorine is 18F, the radioisotope of iodine is selected from the group consisting of 123I, 124I, 125I, 126I, and 131I, the radioisotope of bromine is selected from the group consisting of 75Br, 76Br, 77Br, 80Br, 80mBr, 82Br, and 83Br, and the radioisotope of astatine is 211At. 17. A composition according to claim 1 selected from the group consisting of 18. A composition according to claim 1, having the structure 19. A composition according to claim 1, having the structure 20. A method of imaging one or more cells, organs or tissues comprising exposing the cell to or administering to an organism an effective amount of a composition according to claim 16. 21. The method according to claim 20, wherein the one or more organs or tissues includes prostate tissue, kidney tissue, brain tissue vascular tissue or tumor tissue. 22. A method of treating a tumor comprising administering a therapeutically effective amount of a composition according to claim 1 comprising a therapeutically effective radioisotope. 23. A kit comprising a composition according to claim 1.