title: Radiosynthesis and pharmacological evaluation of [11C]EMD-95885: a high affinity ligand for NR2B-containing NMDA receptors.
abstract: EMD-95885, 6-[3-[4-(4-fluorobenzyl)piperidino]propionyl]-3H-benzoxazol-2-one (1) has been described as a selective antagonist for the NMDA receptors containing NR2B subunits, displaying an IC50 of 3.9 nM for this subtype. EMD-95885 (1) has been synthesized in good overall yield and labelled with carbon-11 ( T1/2 : 20.4 min) at its benzoxazolinone moiety using [11C]phosgene. The pharmacological profile of [11C]EMD-95885 ([11C]-1) was evaluated in vivo in rats with biodistribution studies and brain radioactivity monitored with intracerebral radiosensitive beta-microprobes. The brain uptake of [11C]-1 was homogeneous (0.4-0.6%ID/mL) across the different brain structures studied. This in vivo brain regional distribution of [11C]-1 was not consistent with the known distribution of NR2B subunits. Also as a measure of specificity the hippocampus/cerebellum ratio reached 0.8 throughout the time course of the experiment supporting the lack of specificity. Competition studies with the NR2B prototypic ligand ifenprodil and EMD-95885 (1), 30 min before the radioligand injection, displayed homogeneous reduction of [11C]-1 uptake of 40-60%. Pre-treatment of rats with DTG (sigma ligand), MDL105519 (glycine site antagonist) and MK801 (ion channel blocker) had no inhibitory effect on [11C]-1 uptake. Use of haloperidol as a blocking drug also resulted in a homogeneous inhibition of [11C]-1 uptake by 66-60%, which does not reflect binding to dopamine or sigma receptors. Due to the homogeneous radioligand uptake and inhibition and no measure of cerebral blood flow effects during these blocking studies it is uncertain whether any specific binding is observed. In view of these results, [11C]EMD-95885 ([11C]-1) does not have the required properties for imaging NR2B containing NMDA receptors using positron emission tomography.
authors.affiliation: Service Hospitalier Frédéric Joliot, Département de Recherche Médicale, CEA/DSV, 4 Place du Général Leclerc, F-91401 Orsay, France.
authors.forename: G
authors.initials: G
authors.lastname: Roger
authors.forename: F
authors.initials: F
authors.lastname: Dollé
authors.forename: B
authors.initials: B
authors.lastname: De Bruin
authors.forename: X
authors.initials: X
authors.lastname: Liu
authors.forename: L
authors.initials: L
authors.lastname: Besret
authors.forename: Y
authors.initials: Y
authors.lastname: Bramoullé
authors.forename: C
authors.initials: C
authors.lastname: Coulon
authors.forename: M
authors.initials: M
authors.lastname: Ottaviani
authors.forename: M
authors.initials: M
authors.lastname: Bottlaender
authors.forename: H
authors.initials: H
authors.lastname: Valette
authors.forename: M
authors.initials: M
authors.lastname: Kassiou
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002250:Carbon Radioisotopes; D004341:Drug Evaluation; D008024:Ligands; D008297:Male; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry* / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D002250:Carbon Radioisotopes; C108194:EMD 95885; D008024:Ligands; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate