Claims for Patent: 5,279,811

Summary for Patent: 5,279,811

Title:	Ester-substituted diaminedithiols and radiolabeled complexes thereof
Abstract:	Radiopharmaceuticals consisting essentially of a lipophilic, charge neutral radionuclide complex of a diaminedithiol ligand having 1-4 ester groups of the formula --A--COOR where A is a straight or branched chain alkylene of 0-10 carbon atoms and R is an alkyl group of 1-10 carbon atoms are useful in radioimaging brain perfusion in primates. Ester-substituted diaminedithiols in sterile, pharmaceutically acceptable form, and kits of the diaminedithiols and sterile, non-pyrogenic reducing agents for reducing preselected radionuclides are also provided. Technetium-99m is a preferred radionuclide.
Inventor(s):	Bergstein; Paul L. (Norwood, MA), Cheesman; Edward H. (Townsend, MA), Watson; Alan D. (Andover, MA)
Assignee:	The Du Pont Merck Pharmaceutical Company (Wilmington, DE)
Application Number:	07/143,561
Patent Claims:	1. A radiopharmaceutical comprising a lipophilic, charge neutral complex of a radionuclide and a diaminedithiol ligand wherein the diaminedithiol is selected from the following formula A and B; ##STR12## or a pharmaceutically suitable salt thereof wherein; each of R.sub.1 -R.sub.12 individually is selected from the group consisting of H, alkyl of 1-10 carbon atoms and --A--COOR wherein A is a straight or branched chain alkylene of 0-10 carbon atoms, n, o, and p are independently 1 or 2, and R is (a) alkyl of 1-10 carbon atoms, (b) phenyl or benzyl optionally substituted with up to 5 ring substituents each selected from alkyl of 1-4 carbon atoms, fluoro, chloro, bromo, nitro, alkoxy of 1-4 carbon atoms, carboxyl, or a carboxylic acid ester of 1-4 carbon atoms, or (c) a 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O or X, with the proviso that at lest one of R.sub.1 -R.sub.12 is --A--COOR, said ester-substituted diamindeithiol in sterile, pharmaceutically acceptable form. 2. A radiopharmaceutical of claim 1 wherein the radionuclide is a radioactive isotope of Tc, Ru, Cu, Co, Pt, Fe, Os, Ir, W, Re, Cr, Mo, Mn, Ni, Rh, Pd, Nb, or Ta. 3. A radiopharmaceutical of claim 1 wherein the radionuclide is technetium-99m. 4. A radiopharmaceutical to claim 1 wherein the diaminedithiol has the formula: ##STR13## wherein each of R.sup.1 -R.sup.12 individually is selected from the group consisting of H. alkyl of 1-6 carbon atoms and --A--COOR wherein A is a straight or branched chain alkylene of 0-6 carbon atoms, n, o and p are independently 1 or 2, and R is alkyl of 1-6 carbon atoms, with the proviso that at least one of R.sup.1 --R.sup.12 is --A--COOR. 5. A radiopharmaceutical of claim 4 wherein the radionuclide is a radioactive isotope of Tc, Ru, Cu, Co, Pt, Fe, Os, Jr, W, Re, Cr, Mo, Mn, Ni, Rh, Pd, Nb, or Ta. 6. A radiopharmaceutical of claim 4 wherein the radionuclide is technetium-99m. 7. A radiopharmaceutical of claim 6 wherein R and any alkyl in R.sup.1 -R.sup.12 is from 1-3 carbon atoms. 8. A radiopharmaceutical of claim 6 wherein A is a straight chain alkylene of 0-3 carbon atoms. 9. A radiopharmaceutical of claim 6 wherein n, o and p are 1. and 1-4 of R.sup.1 -R.sup.12 is --A--COOR. 10. A radiopharmaceutical of claim 9 wherein the diaminedithiol is non-aminated, and R and any alkyl in R.sup.1 -R.sup.12 is from 1-3 carbon atoms. 11. A radiopharmaceutical of claim 5 wherein R.sup.3 and R.sup.10 are --A--COOR and R.sup.4 and R.sup.9 are H and n, o and p are 1. 12. A radiopharmaceutical of claim 6 wherein A is a bond and R is ethyl. 13. A radiopharmaceutical of claim 6 wherein A is a bond and the stereochemistry at the position where that bond is attached to the diaminedithiol backbone is L. 14. A radiopharmaceutical of claim 6 wherein n, o and p are 1. and R.sup.3 and R.sup.10 are --A--COOR where A is a straight chain alkylene of 0-3 carbon atoms and R is alkyl of 1-3 carbon atoms, R.sup.4 and R.sup.9 are H, and R.sup.1, R.sup.2, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.11 and R.sup.12 individually are selected from the group consisting of H and alkyl of 1-3 carbon atoms. 15. The radiopharmaceutical of claim 6 wherein the diaminedithiol is N,N'-1.2-ethylenedi-ylbis-L-cysteine, diethyl ester. 16. The radiopharmaceutical of claim 6 wherein the diaminedithiol is N,N'-1.2-ethylene-diylbis-L-cysteine, dimethylester, dihydrochloride. 17. The radiopharmaceutical of claim 6 wherein the diaminedithol is N,N'-1,2-ethylene-diylbis-L-cysteine, di-n-polyester, dihydrochloride. 18. A process of radioimaging comprising (i) administering parenterally to a mammal an effective amount of the composition of claim 1 in a pharmaceutically suitable carrier, and (ii) radioimaging the brain of the mammal after allowing sufficient time for the composition to localize in the brain. 19. A process of radioimaging comprising (i) administering parenterally to a mammal an effective amount of the composition of claim 2 in a pharmaceutically suitable carrier, and (ii) radioimaging the brain of the mammal after allowing sufficient time for the composition to localize in the brain. 20. A process of radioimaging comprising (i) administering parenterally to a mammal an effective amount of the composition of claim 3 in a pharmaceutically suitable carrier, and (ii) radioimaging the brain of the mammal after allowing sufficient time for the composition to localize in the brain. 21. A process of radioimaging comprising (i) administering parenterally to a mammal an effective amount of the composition of claim 4 in a pharmaceutically suitable carrier, and (ii) radioimaging the brain of the mammal after allowing sufficient time for the composition to localize in the brain. 22. A process of radioimaging comprising (i) administering parenterally to a mammal an effective amount of the composition of claim 5 in a pharmaceutically suitable carrier, and (ii) radioimaging the brain of the mammal after allowing sufficient time for the composition to localize in the brain. 23. A process of radioimaging comprising (i) administering parenterally to a mammal an effective amount of the composition of claim 6 in a pharmaceutically suitable carrier, and (ii) radioimaging the brain of the mammal after allowing sufficient time for the composition to localize in the brain. 24. A process of radioimaging comprising (i) administering parenterally to a mammal an effective amount of the composition of claim 7 in a pharmaceutically suitable carrier, and (ii) radioimaging the brain of the mammal after allowing sufficient time for the composition to localize in the brain. 25. A process of radioimaging comprising (i) administering parenterally to a mammal an effective amount of the composition of claim 8 in a pharmaceutically suitable carrier, and (ii) radioimaging the brain of the mammal after allowing sufficient time for the composition to localize in the brain. 26. A process of radioimaging comprising (i) administering parenterally to a mammal an effective amount of the composition of claim 9 in a pharmaceutically suitable carrier, and (ii) radioimaging the brain of the mammal after allowing sufficient time for the composition to localize in the brain. 27. A process of radioimaging comprising (i) administering parenterally to a mammal an effective amount of the composition of claim 6 in a pharmaceutically suitable carrier, and (ii) radioimaging the brain of the mammal after allowing sufficient time for the composition to localize in the brain. 28. A process of radioimaging comprising (i) administering parenterally to a mammal an effective amount of the composition of claim 11 in a pharmaceutically suitable carrier, and (ii) radioimaging the brain of the mammal after allowing sufficient time for the composition to localize in the brain. 29. A process of radioimaging comprising (i) administering parenterally to a mammal an effective amount of the composition of claim 12 in a pharmaceutically suitable carrier, and (ii) radioimaging the brain of the mammal after allowing sufficient time for the composition to localize in the brain. 30. A process of radioimaging comprising (i) administering parenterally to a mammal an effective amount of the composition of claim 13 in a pharmaceutically suitable carrier, and (ii) radioimaging the brain of the mammal after allowing sufficient time for the composition to localize in the brain. 31. A process of radioimaging comprising (i) administering parenterally to a mammal an effective amount of the composition of claim 14 in a pharmaceutically suitable carrier, and (ii) radioimaging the brain of the mammal after allowing sufficient time for the composition to localize in the brain. 32. A process of radioimaging comprising (i) administering parentally to a mammal an effective amount of the composition of claim 15 in a pharmaceutically suitable carrier, and (ii) radioimaging the brain of the mammal after allowing sufficient time for the composition to localize in the brain. 33. A process of radioimaging comprising (i) administering parenterally to a mammal an effective amount of the composition of claim 11 in a pharmaceutically suitable carrier, and (ii) radioimaging the brain of the mammal after allowing sufficient time for the composition to localize in the brain. 34. A process of radioimaging comprising (i) administering parenterally to a mammal an effective amount of the composition of claim 11 in a pharmaceutically suitable carrier, and (ii) radioimaging the brain of the mammal after allowing sufficient time for the composition to localize in the brain.