Synthesis of tritium labeled renin inhibitor ditekiren

✍ Scribed by Richard S. P. Hsi; Wayne T. Stolle; Gordon L. Bundy

• Publisher: John Wiley and Sons
• Year: 1994
• Tongue: French
• Weight: 527 KB
• Volume: 34
• Category: Article
• ISSN: 0022-2135
• DOI: 10.1002/jlcr.2580341207

✦ Synopsis

Abstract

In the search for a radioactive form of the peptidomimetic renin inhibitor, ditekiren, with a metabolically suitable radiolabel for conducting drug disposition studies, we prepared [^3^H]ditekiren with tritium labels in the N‐methyl‐histidine moiety and in the leu‐val alcohol transition‐state insert. [His‐^3^H]ditekiren was obtained by first introducing two iodine substituents into the N‐methyl‐histidine moiety of the parent drug, followed by catalytic hydrodehalogenation with tritium gas. Administration of this labeled drug to monkeys, however, resulted in prolonged retention of radioactivity in the test animals, even though little or no tritiated water was detected in urine. This suggested in vivo production of a labeled fragment from the drug, e.g., N‐methyl‐[^3^H]histidine, which became incorporated into the endogenous amino acid pool. These results, together with similar earlier findings after administration of [^3^H]ditekiren labeled in the proline moiety of the drug, led us to synthesize [^3^H]ditekiren labeled in the “unnatural” leu‐val alcohol (LVA) portion of the molecule. [LVA‐^3^H]ditekiren was obtained by first oxidizing the parent drug to produce an LVA‐keto analog, which was then reduced with sodium borotritide to give a mixture of tritium labeled ditekiren and its LVA‐epimer. The two epimeric labeled materials were separated and purified by means of preparative high performance liquid chromatography (HPLC). The tritium label in [LVA‐^3^H]ditekiren was found to be metabolically suitable for conducting drug disposition studies, with no liability for tritiated water production or prolonged retention of radioactivity in tissues of test animals.