A prodrug of NMDA/glycine site antagonist, L-703,717, with improved BBB permeability: 4-acetoxy derivative and its positron-emitter labeled analog

4-Acetoxy derivative (1) of L-703,717, a high-affinity (IC50=4.5 nM) antagonist for the glycine site of NMDA receptors, was synthesized and its brain uptake was examined using a carbon-11 labeled analog (11C]1). Initial radioactivity in the brain after intravenous injection of 11C]1 was a 2-fold that of 11C]L-703,717 in mice. Rapid bioconversion of 11C]1 into 11C]L-703,717 was demonstrated by metabolite analyses of rat brain after 11C]1 injection. Ex vivo autoradiography of 11C]1 in rat brain showed the same cerebellar localization of radioactivity as 11C]L-703,717. These results indicate that 1 is a promising pharmacological tool as a prodrug of L-703,717 with improved BBB permeability.