EVALUATION OF TECHNETIUM-99M-TRIAMIDE-MERCAPTIDE COMPLEXES DESIGNED TO IDENTIFY PROPERTIES FAVORING RENAL TUBULAR TRANSPORT

To aid in the design of an improved Tc-99m-labeled renal agent, severa l new [(TcO)-Tc-99m(MAG,)](2-) analogs were synthesized to determine t he effects of varying the position and chemical form of the terminal c harged group on renal clearance. Methods: Clearance, extraction effici ency and plasma protein binding were measured in six Sprague-Dawley ra ts per complex for ortho, meta and para isomers of [(TcO)-Tc-99m(MAG(2 )-ABA)](2-), with MAG(2)- = mercaptoacetylglycylglycyl- and ABA = amin obenzoate; [(TcO)-Tc-99m(MAG(2)-pASA)](2-), with pASA = p-aminosalicyl ate; [(TCO)-T-99m(MAG(2)-AMS](2-), With AMS = aminomethylsulfonate; an d [(TCO)-T-99m(MAG(2)-AMp](3-), With AMp = aminomethylphosphonate. For agents with relatively poor clearances, hepatobiliary excretion was e valuated by using a camera-based method. Results: The clearances of th e ortho, meta and para isomers of [(TcO)-Tc-99m(MAG(2)-ABA)](2-) were 17%, 20% and 59% of those of OIH, respectively. The clearances of [(TC O)-T-99m(MAG(2)-pASA)](2-), [(TCO)-T-99m(MAG(2)-AMS)](2-) and [(TcO)-T c-99m(MAG(2)-AMP)](3-) were 32%, 46% and 39% those of OIH, respectivel y. Conclusion: Optimal tubular transport appears to require a terminal anionic group; a planar carboxylate is preferred over nonplanar -SO3- or -PO32- substituents, suggesting that the smaller size and/or plana r shape of the carboxylate group are probably more important than the total charge or charge distribution. Optimal transport also appears to depend on the oxo-carboxylate conformation (syn or anti) and the oxo- carboxylate distance, although these relationships can be modulated by steric interactions. These structure-distribution relationships are i mportant factors to consider in the future design of renal radiopharma ceuticals.