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=4.5nM) 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-703,717in 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