Tissue distribution properties of technetium-99m-diamide-dimercaptide complexes and potential use as renal radiopharmaceuticals

• Published in: Journal of medicinal chemistry 1986-10, Vol.29 (10), p.1933-1940
• Main Authors: Kasina, Sudhakar, Fritzberg, Alan R, Johnson, Dennis L, Eshima, Dennis
• Format: Article
• Language: English
• Subjects: Amides - metabolism; Animals; Applied sciences; Biological and medical sciences; Contrast media. Radiopharmaceuticals; Exact sciences and technology; Kidney Tubules - metabolism; Ligands; Medical sciences; Mice; Other techniques and industries; Pharmacology. Drug treatments; Radioisotope Renography; Structure-Activity Relationship; Sulfides - metabolism; Technetium - metabolism; Tissue Distribution
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00160a023

A series of new ligands and the corresponding technetium-99m chelates based on diamide dimercaptide donor groups were synthesized as derivatives of technetium-99m 1,2-bis(2-thioacetamido)ethane, a complex shown to be excreted by renal tubular secretion. Chelation with 99mTc resulted in single radiochemical products or the expected numbers of stereoisomers. They were purified by high-performance liquid chromatography (HPLC) and evaluated in mice as potential renal tubular function agents. The in vivo properties were sensitive to the presence of functional groups, the positional isomerism of the carboxylate group functionality, and the chelate ring stereochemistry of the ligand. The presence of methyl groups slowed renal transit and decreased renal specificity. Cyclohexyl rings fused to the ethylene bridge of the center chelate ring decreased renal excretion while aromatic rings essentially abolished renal excretion. Slow hepatobiliary clearance was observed as an alternate mode of excretion. Polar groups, such as hydroxyl, carboxylate, and carboxamide, increased renal excretion rates and specificity in a stereochemically dependent manner. 99mTc chelates of 1,3-bis(2-thioacetamido)-2-hydroxypropane, 3,4-bis(2-thioacetamido)butanoate and 1,8-dimercapto-2,7-dioxo-3,6-diazanonanoate were identified as promising new renal radiopharmaceuticals.