title: Difference in brain distributions of carbon 11-labeled 4-hydroxy-2(1H)-quinolones as PET radioligands for the glycine-binding site of the NMDA ion channel.
abstract: High-affinity iodine- and ethyl-C-5 substituted analogs of 4-hydroxy-3-(3-[11C]methoxyphenyl)-2(1H)-quinolone ([11C]4HQ) were synthesized as new positron emission tomography radioligands for the glycine-binding sites of the N-methyl-d-aspartate (NMDA) ion channel. Although both radioligands showed high in vitro specific binding to rat brain slices, their binding characteristics were quite different from each other. 5-Ethyl-[11C]4HQ (5Et-[11C]4HQ) showed higher in vitro binding in the forebrain regions than in the cerebellum, bindings that were strongly inhibited by both glycine-site agonists and antagonists. In contrast, 5-iodo-[11C]4HQ (5I-[11C]4HQ) showed a homogeneous in vitro binding throughout the brain, which was inhibited by antagonists but not by agonists. This difference in in vitro binding between 5Et-[11C]4HQ and 5I-[11C]4HQ was quite similar to that previously observed between [11C]L-703,717 and [11C]4HQ, both glycine-site antagonists. In vivo brain uptakes of these 11C-labeled 4-hydroxyquinolones were examined in mice. Initial brain uptakes of 5Et- and 5I-[11C]4HQ at 1 min after intravenous injections were comparable to that of [11C]4HQ, but they were 1.3-2.1 times higher than that of [11C]L-703,717. The treatment with an anticoagulant, warfarin, only slightly increased the initial uptakes of [11C]4HQ and 5Et-[11C]4HQ in contrast to [11C]L-703,717. The in vivo regional brain distributions were slightly different between the two radioligands. Pretreatment with nonradioactive ligand (2 mg/kg) slightly inhibited the binding of 5Et-[11C]4HQ (16-36% inhibition) but not that of 5I-[11C]4HQ. In this study, it was found that a small structural change in [11C]4HQ resulted in a major change in binding characteristics and distributions, suggesting the existence of two binding sites for [11C]4-hydroxyquinolones on the NMDA ion channel - agonist-sensitive and agonist-insensitive (or antagonist-preferring) sites.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Fuchigami
authors.forename: Terushi
authors.initials: T
authors.lastname: Haradahira
authors.forename: Noriko
authors.initials: N
authors.lastname: Fujimoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Okauchi
authors.forename: Jun
authors.initials: J
authors.lastname: Maeda
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Suzuki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Suhara
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Yamamoto
authors.forename: Shigeki
authors.initials: S
authors.lastname: Sasaki
authors.forename: Takahiro
authors.initials: T
authors.lastname: Mukai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Mikako
authors.initials: M
authors.lastname: Ogawa
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Magata
authors.forename: Minoru
authors.initials: M
authors.lastname: Maeda
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D001921:Brain / Q000000981:diagnostic imaging*; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D005998:Glycine / Q000737:chemistry; D006912:Hydroxyquinolines / Q000493:pharmacokinetics*; D007473:Ion Channels / Q000378:metabolism; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods*; D011869:Radioligand Assay / Q000379:methods*; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000037:antagonists & inhibitors*; D014018:Tissue Distribution; D014859:Warfarin / Q000494:pharmacology
chemical_list: D000925:Anticoagulants; D002250:Carbon Radioisotopes; D006912:Hydroxyquinolines; D007473:Ion Channels; D016194:Receptors, N-Methyl-D-Aspartate; D014859:Warfarin; C034010:4-hydroxyquinoline; D005998:Glycine