title: Synthesis, radiosynthesis and in vivo evaluation of 5-[3-(4-benzylpiperidin-1-yl)prop-1-ynyl]-1,3-dihydrobenzoimidazol-2-[(11)C]one, as a potent NR(1A)/2B subtype selective NMDA PET radiotracer.
abstract: Recently, a new series of potent and highly subtype-selective 1-(heteroarylalkynyl)-4-benzylpiperidine antagonists of the NMDA receptors has been described by Pfizer Laboratories. In this series, 5-[3-(4-benzylpiperidin-1-yl)prop-1-ynyl]-1,3-dihydrobenzoimidazol-2-one (1) was identified as a selective antagonist for the NR1(A)/2B subtype, displaying IC(50) values for inhibition of the NMDA responses of 5.3 nM for this subtype (compared to NR1(A)/2A: 35 microM and NR1(A)/2C>100 microM) and was active in rat at a relatively low dosage (10mg/kg po). Derivative 1 has been synthesized in four chemical steps in good overall yield and labelled with carbon-11 at its benzoimidazolone ring using [(11)C]phosgene. The pharmacological profile of [(11)C]-1 was evaluated in vivo in rats with biodistribution studies and brain radioactivity monitored with intracerebral radiosensitive beta-microprobes. The brain uptake of [(11)C]-1 was extremely low (0.07% I.D./mL on average at 30 min) and rather uniform across the different brain structures. This in vivo brain regional distribution of [(11)C]-1 did not match with autoradiographic or binding data obtained with other NR2B subtype-selective NMDA ligands. Competition studies with ifenprodil (20 mg/kg, ip, 30 min before the radiotracer injection) failed to demonstrate specific binding of the radiotracer in the brain. In view of these results, and especially considering the low brain penetration of the radiotracer, [(11)C]-1 does not have the required properties for imaging NMDA receptors using positron emission tomography.
authors.affiliation: Département de Recherche Médicale, CEA/DSV, 4 Place du Général Leclerc, F-91401 Orsay, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Roger
authors.forename: Béatrice
authors.initials: B
authors.lastname: Lagnel
authors.forename: Laurent
authors.initials: L
authors.lastname: Besret
authors.forename: Yann
authors.initials: Y
authors.lastname: Bramoullé
authors.forename: Christine
authors.initials: C
authors.lastname: Coulon
authors.forename: Michelle
authors.initials: M
authors.lastname: Ottaviani
authors.forename: Michael
authors.initials: M
authors.lastname: Kassiou
authors.forename: Michel
authors.initials: M
authors.lastname: Bottlaender
authors.forename: Héric
authors.initials: H
authors.lastname: Valette
authors.forename: Frédéric
authors.initials: F
authors.lastname: Dollé
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D001923:Brain Chemistry; D002250:Carbon Radioisotopes / Q000737:chemistry* / Q000493:pharmacokinetics; D007093:Imidazoles / Q000737:chemistry*; D007553:Isotope Labeling; D007700:Kinetics; D008297:Male; D015394:Molecular Structure; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
chemical_list: C488633:5-(3-(4-benzylpiperidin-1-yl)prop-1-ynyl)-1,3-dihydrobenzoimidazol-2-((11)C)one; D002250:Carbon Radioisotopes; D007093:Imidazoles; D010880:Piperidines; D011725:Pyridines; D016194:Receptors, N-Methyl-D-Aspartate; C010739:ifenprodil