title: Effects of endogenous agonists, glycine and D-serine, on in vivo specific binding of [11C]L-703,717, a PET radioligand for the glycine-binding site of NMDA receptors.
abstract: A positron-emitter (carbon-11) labeled antagonist for the glycine-binding site of NMDA receptors, [(11)C]L-703,717, has a unique in vivo binding characteristic, in which it preferentially binds to cerebellar-specific NMDA receptors consisting of a GluRepsilon3 subunit and eventually accumulates in rodent cerebellum under in vivo conditions, but not under in vitro conditions. In order to understand the in vivo-specific site and subunit localization of this radioligand, we examined the effect of the endogenous glycine site agonists, glycine and D-serine, on in vivo [(11)C]L-703,717 binding. An increase in extracellular glycine concentration by treatment with a glycine transporter 1 (GlyT1)-selective inhibitor, NFPS ethyl ester, significantly decreased the cerebellar localization of [(11)C]L-703,717 in rats. D-serine is known to be concentrated in mammalian forebrain regions. The lack of D-serine detection in the cerebellum may be due to the fact that it has the highest enzymatic activity of D-amino acid oxidase (DAO). It was found that the cerebellar localization of [(11)C]L-703,717 is greatly diminished in mutant mice lacking DAO, in which D-serine content in the cerebellum is drastically increased from a nondetectable level in normal mice. These studies indicate that [(11)C]L-703,717 is susceptible to inhibition by glycine site agonists in its in vivo binding, and suggest that regional differences in inhibitions by endogenous agonists may be a crucial factor in the site- and subunit-specific binding of this glycine-site antagonist.
authors.affiliation: Department of Medical Imaging, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555, Japan. terushi@nirs.go.jp
authors.forename: Terushi
authors.initials: T
authors.lastname: Haradahira
authors.forename: Takashi
authors.initials: T
authors.lastname: Okauchi
authors.forename: Jun
authors.initials: J
authors.lastname: Maeda
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
authors.forename: Toru
authors.initials: T
authors.lastname: Nishikawa
authors.forename: Ryouichi
authors.initials: R
authors.lastname: Konno
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Suzuki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Suhara
mesh_terms: D026921:Amino Acid Transport Systems, Neutral / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001667:Binding, Competitive / Q000187:drug effects / Q000235:genetics; D002250:Carbon Radioisotopes; D002531:Cerebellum / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D003605:D-Amino-Acid Oxidase / Q000172:deficiency / Q000235:genetics; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D005998:Glycine / Q000378:metabolism / Q000494:pharmacology*; D050487:Glycine Plasma Membrane Transport Proteins; D006912:Hydroxyquinolines / Q000493:pharmacokinetics*; D008024:Ligands; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D015363:Quinolones / Q000493:pharmacokinetics*; D011869:Radioligand Assay; D011877:Radionuclide Imaging; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000378:metabolism; D012521:Sarcosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D012694:Serine / Q000378:metabolism / Q000494:pharmacology*; D013237:Stereoisomerism; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D026921:Amino Acid Transport Systems, Neutral; D002250:Carbon Radioisotopes; D050487:Glycine Plasma Membrane Transport Proteins; D006912:Hydroxyquinolines; C119669:L 703717; D008024:Ligands; C435025:N-(3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)-3-(4'-phenylphenoxy)propyl)sarcosine; C432823:NR2C NMDA receptor; D015363:Quinolones; D016194:Receptors, N-Methyl-D-Aspartate; C493267:Slc6a9 protein, mouse; C493266:Slc6a9 protein, rat; D012694:Serine; D003605:D-Amino-Acid Oxidase; D005998:Glycine; D012521:Sarcosine