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

• Published in: Synapse (New York, N.Y.) N.Y.), 2003-11, Vol.50 (2), p.130-136
• Main Authors: Haradahira, Terushi, Okauchi, Takashi, Maeda, Jun, Zhang, Ming-Rong, Nishikawa, Toru, Konno, Ryouichi, Suzuki, Kazutoshi, Suhara, Tetsuya
• Format: Article
• Language: English
• Subjects: Amino Acid Transport Systems, Neutral - antagonists & inhibitors; Amino Acid Transport Systems, Neutral - metabolism; Animals; Binding Sites - drug effects; Binding Sites - physiology; Binding, Competitive - drug effects; Binding, Competitive - genetics; Carbon Radioisotopes; Cerebellum - diagnostic imaging; Cerebellum - drug effects; Cerebellum - metabolism; D-Amino-Acid Oxidase - deficiency; D-Amino-Acid Oxidase - genetics; D-serine; Extracellular Fluid - drug effects; Extracellular Fluid - metabolism; glycine; Glycine - metabolism; Glycine - pharmacology; glycine binding site; Glycine Plasma Membrane Transport Proteins; Hydroxyquinolines - pharmacokinetics; L-703; Ligands; L‐703,717; Male; Mice; Mice, Knockout; Neurons - diagnostic imaging; Neurons - drug effects; Neurons - metabolism; NMDA receptor; PET; Quinolones - pharmacokinetics; Radioligand Assay; Radionuclide Imaging; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate - agonists; Receptors, N-Methyl-D-Aspartate - metabolism; Sarcosine - analogs & derivatives; Sarcosine - pharmacology; Serine - metabolism; Serine - pharmacology; Stereoisomerism; Synaptic Transmission - drug effects; Synaptic Transmission - physiology; Up-Regulation - drug effects; Up-Regulation - physiology
• ISSN: 0887-4476; 1098-2396
• DOI: 10.1002/syn.10254

A positron‐emitter (carbon‐11) labeled antagonist for the glycine‐binding site of NMDA receptors, [11C]L‐703,717, has a unique in vivo binding characteristic, in which it preferentially binds to cerebellar‐specific NMDA receptors consisting of a GluRϵ3 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 [11C]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 [11C]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 [11C]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 [11C]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. Synapse 50:130–136, 2003. © 2003 Wiley‐Liss, Inc.