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

Chem Pharm Bull (Tokyo). 2001 Feb;49(2):147-50. doi: 10.1248/cpb.49.147.

Abstract

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.

MeSH terms

  • Animals
  • Blood-Brain Barrier*
  • Excitatory Amino Acid Antagonists / pharmacokinetics
  • Hydroxyquinolines / pharmacokinetics*
  • Male
  • Mice
  • Prodrugs / pharmacokinetics*
  • Quinolones / pharmacokinetics*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Glycine / antagonists & inhibitors*
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Tomography, Emission-Computed

Substances

  • Excitatory Amino Acid Antagonists
  • Hydroxyquinolines
  • L 703717
  • Prodrugs
  • Quinolones
  • Receptors, Glycine
  • Receptors, N-Methyl-D-Aspartate