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Evaluation of Technetium-99m-Triamide-Mercaptide Complexes Designed to Identify Properties Favoring Renal Tubular Transport

Departments of Radiology and Chemistry, Emory University, Atlanta, Georgia
College of Pharmacy, University of New Mexico, Albuquerque, New Mexico

Correspondence: For correspondence or reprints contact: Andrew Taylor, Jr., Department of Radiology, Emory University Hospital, Atlanta, GA 30322.

ABSTRACT

To aid in the design of an improved ^99mTc-labeled renal agent, several new [^99mTcO(MAG₃)]^2- analogs were synthesized to determine the effects of varying the position and chemical form of the terminal charged group on renal clearance. Methods: Clearance, extraction efficiency and plasma protein binding were measured in six Sprague-Dawley rats per complex for ortho, meta and para isomers of [^99mTcO(MAG₂-ABA)]^2-, with MAG_2- = mercaptoacetylglycylglycyl- and ABA = aminobenzoate; [^99mTcO(MAG_2--pASA)]^2-, with pASA = p-aminosalicylate; [^99mTcO(MAG_2--AMS]^2-, with AMS = aminomethylsulfonate; and [^99mTcO(MAG₂-AMP]^3-, with AMP = aminomethylphosphonate. For agents with relatively poor clearances, hepatobiliary excretion was evaluated by using a camera-based method. Results: The clearances of the ortho, meta and para isomers of [^99mTcO(MAG₂-ABA)]^2- were 17%, 20% and 59% of those of OIH, respectively. The clearances of [^99mTcO(MAG₂-pASA)]^2-, [^99mTcO(MAG₂-AMS)]^2- and [^99mTcO(MAG₂-AMP)]^3- were 32%, 46% and 39% those of OIH, respectively. Conclusion: Optimal tubular transport appears to require a terminal anionic group; a planar carboxylate is preferred over nonplanar -SO₃^– or -PO₃^2– substituents, suggesting that the smaller size and/or planar 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 important factors to consider in the future design of renal radiopharmaceuticals.

Key Words: technetium-99m MAG₃ complexes • renal clearance • renal imaging