Synthesis of C-14 radiolabeled glucagon receptor antagonist and its use in a human mass balance study

The synthesis of the radiolabeled glucagon receptor antagonist 1-[¹⁴ C] was accomplished based on decarboxylative iodination of acid 2 followed by "reattachment" of ¹⁴ C carboxylic function. The method allowed a significant reduction in the number of steps in preparation of the radiolabeled compound. Iodide 4, obtained by the halodecarboxylation, was converted to cyanide 5-[¹⁴ C], which was hydrolyzed to provide the radiolabeled acid 2-[¹⁴ C]. Coupling with β-alanine fragment and hydrolysis of ester 6-[¹⁴ C] completed the synthesis of the target molecule 1-[¹⁴ C]. The resulting compound was utilized in a mass balance and metabolism study where hepatic oxidation followed by a trace amount of sulfate conjugation and elimination was the main clearance pathway for 1 in humans.