SYNTHESIS OF TRITIUM-LABELED RENIN INHIBITOR DITEKIREN

In the search for a radioactive form of the peptidomimetic renin inhib itor, ditekiren, with a metabolically suitable radiolabel for conducti ng drug disposition studies, we prepared [H-3]ditekiren with tritium l abels in the N-methyl-histidine moiety and in the leu-val alcohol tran sition state insert. [His-H-3]ditekiren was obtained by first introduc ing two iodine substituents into the N-methyl-histidine moiety of the parent drug, followed by catalytic hydrodehalogenation with tritium ga s. Administration of this labeled drug to monkeys, however, resulted i n prolonged retention of radioactivity in the test animals, even thoug h little or no tritiated water was detected in urine. This suggested i n vivo production of a labeled fragment from the drug, e.g., N-methyl- [H-3]histidine, which became incorporated into the endogenous amino ac id pool. These results, together with similar earlier findings after a dministration of [[H-3]ditekiren labeled in the proline moiety of the drug, led us to synthesize [[H-3]ditekiren labeled in the ''unnatural' ' leu-val alcohol (LVA) portion of the molecule. [LVA-H-3]ditekiren wa s obtained by first oxidizing the parent drug to produce an LVA-keto a nalog, which was then reduced with sodium borotritide to give a mixtur e of tritium labeled ditekiren and its LVA-epimer. The two epimeric la beled materials were separated and purified by means of preparative hi gh performance liquid chromatography (HPLC). The tritium label in [LVA -H-3]ditekiren was found to be metabolically suitable for conducting d rug disposition studies, with no liability for tritiated water product ion or prolonged retention of radioactivity in tissues of test animals .