title: Measurement of glycine binding site of N-methyl-D-asparate receptors in living human brain using 4-acetoxy derivative of L-703,717, 4-acetoxy-7-chloro-3-[3-(4-[11c] methoxybenzyl) phenyl]-2(1H)-quinolone (AcL703) with positron emission tomography.
abstract: N-methyl-D-aspartate (NMDA) receptors are of major interest in brain functions and neuropsychiatric disorders. However, at present there are few suitable radioligands for in vivo imaging of NMDA receptors. 7-choloro-4-hydroxy-3-[3-(4-methoxybenzyl) phenyl]-2(1H)-quinolone (L-703,717) is one of the potent ligands for the glycine-binding site of NMDA receptors. 4-Acetoxy derivative of L-703,717 (AcL703) is a candidate, as a positron emission tomography (PET) ligand for NMDA receptors, because of its better permeability at the blood-brain barrier compared with L-703,717. After intravenous injection of 624-851 MBq of [11C]AcL703, dynamic PET scan was performed on six healthy males for 90 min. Regions-of-interest were located on the cerebral cortices, cerebellar cortex, and cerebral white matter. The binding potential (BP) was calculated from the ratio of the area under the curve (AUC) of radioactivities from 40 to 90 min in the target region to that in white matter. Regional radioactivities reached close to equilibrium in all regions after about 40 min postinjection. Regional brain uptake of [11C]AcL703 at 40 min after injection was 0.00028-0.00065% of the injected dose/milliliter. Radioactivity concentration of [11C]AcL703 was highest in the cerebellar cortex and lowest in white matter. AUC in the cerebellar cortex was higher than those of cerebral cortices, thalamus, striatum, and white matter. BP in the cerebellar cortex was twofold higher than in the cerebral cortices (cerebellar cortex: BP=2.20+/-0.72; cerebral cortices: BP=1.05+/-0.45). Despite the low brain uptake of [11C]AcL703, regional distributions were in good agreement with our previous studies of rodents. This indicates the possibility of in vivo evaluation of NMDA receptors using PET with [11C]AcL703 in living human brain.
authors.affiliation: Department of Molecular Neuroimaging, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Matsumoto
authors.forename: Terushi
authors.initials: T
authors.lastname: Haradahira
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ito
authors.forename: Yota
authors.initials: Y
authors.lastname: Fujimura
authors.forename: Chie
authors.initials: C
authors.lastname: Seki
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ikoma
authors.forename: Jun
authors.initials: J
authors.lastname: Maeda
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Arakawa
authors.forename: Akihiro
authors.initials: A
authors.lastname: Takano
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Takahashi
authors.forename: Makoto
authors.initials: M
authors.lastname: Higuchi
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Suzuki
authors.forename: Kenji
authors.initials: K
authors.lastname: Fukui
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Suhara
mesh_terms: D000328:Adult; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002087:Butyrates / Q000493:pharmacokinetics*; D003524:Cyclosporins / Q000494:pharmacology; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005240:Feasibility Studies; D005998:Glycine / Q000494:pharmacology*; D006801:Humans; D006912:Hydroxyquinolines / Q000493:pharmacokinetics*; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods*; D011760:Pyrrolidinones / Q000493:pharmacokinetics*; D015363:Quinolones / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: C118006:2-(2-oxopyrrolidin-1-yl)butanoic acid; D002087:Butyrates; D003524:Cyclosporins; D004791:Enzyme Inhibitors; D006912:Hydroxyquinolines; C119669:L 703717; D011760:Pyrrolidinones; D015363:Quinolones; D019275:Radiopharmaceuticals; D016194:Receptors, N-Methyl-D-Aspartate; D005998:Glycine