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.
Haradahira
T
T
Division of Advanced Technology for Medical Imaging, National Institute of Radiological Sciences, Chiba, Japan. terushi@nirs.go.jp
Zhang
M R
MR
Maeda
J
J
Okauchi
T
T
Kida
T
T
Kawabe
K
K
Sasaki
S
S
Suhara
T
T
Suzuki
K
K
D000818:Animals; D001812:Blood-Brain Barrier; D018691:Excitatory Amino Acid Antagonists / Q000493:pharmacokinetics; D006912:Hydroxyquinolines / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D011355:Prodrugs / Q000493:pharmacokinetics*; D015363:Quinolones / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D014055:Tomography, Emission-Computed
D018691:Excitatory Amino Acid Antagonists; D006912:Hydroxyquinolines; C119669:L 703717; D011355:Prodrugs; D015363:Quinolones; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate