Syntheses of dual-radioisotope-labeled CP-I,a GABA_A receptor partial agonist

摘要

CP-I, 2-{[2-(3-fluoropyrid-2-yl)-1H-imidazol-1-yl] methyl}-1-pro-pyl-5-cyano-1 H-benzimidazole (compound 1), is a potent subtype-selective partial agonist at the GABA_A receptor complex. This agonist significantly reduces in rate both spontaneous locomotor activity and the latency to assume a sleep posture without the well-known side effects of commonly available hypnotics. Significant metabolic scission of CP-I to benzimida-zole alcohol 2 and fluoropyridine imidazole 3 in an NADPH-dependent manner was observed from initial in vitro biotrans-formation studies using non-labeled CP-I (Figure 1).The further metabolic stability studies of compounds 2 and 3 in the presence of NADPH showed that 2 was inert while 3 was extensively metabolized. Therefore, both C-14- and H-3-labeled CP-I were synthesized for use in in vivo biotransformation studies. For the ~14C-labeled compounds, the label was placed on either side of C_8, the site of metabolic fragmentation, whereas the ~3H labeled was placed on the right-hand side.