Modulation of [H-3]MK-801 binding to NMDA receptors in vivo and in vitro

[H-3]MK-801 binding in vivo was used to determine the occupancy of NMDA rec eptor ligands shown to allosterically modulate binding in vitro. ED50 value s (mg/kg) were obtained for the channel blockers (+)-5-methyl-10,11-dihydro -5,4-dibenzo[a,d]cyclohepten-5,10-imine maleate ((+)-MK-801, 0.2), 1-(1-phe nylcyclohexyl)piperidine (phencyclidine, PCP, 1.7) and ketamine (4.4). Anta gonists at the glutamate (DL-(2-carboxypiperazine-4-yl)propyl-1-phosphonate (DL-CPP, 5.7)) and glycine site (7-Chloro-4-hydroxy-3-(3-phenoxy)-phenyl-2 (H)quinolinone (L-701,324, 14.1), 3R( +)cis-4-methyl-pyrrollid-2-one (L-687 ,414, 15.1)) inhibited [H-3]MK-801 binding in vivo to varying maximum level s (69%, 103% and 45%, respectively). NR2B subunit-selective compounds actin g at the ifenprodil site inhibited [H-3]MK-801 in vivo by a maximum of 52-7 2% and gave ED50 values (mg/kg) of: (+/-)-(1S*,2S*)-1-(4-hydroxyphenyl)-2-( 4-hydroxy-4-phenylpiperidino)- 1-propanol ((+/-)CP- 101,606), 1.9; ( +/-)-( 3R,4S)-3-[4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl]chroman-4,7-diol ((+/- )CP-283,097), 1.8; (+/-)-(R*,S*)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phe nylmethyl)-1-piperidine propanol ((+/-)Ro 25-6981), 1.0; ifenprodil, 6.0. T he glycine site agonist D-serine stimulated binding to 151% of control with an ED50 of 1.7 mg/kg. Results show that [H-3]MK-801 binding in vivo may be used to measure receptor occupancy of ligands acting not only within the i on channel but also at modulatory sites on the NMDA receptor complex. (C) 2 000 Elsevier Science B.V. All rights reserved.