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

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 GluRe3 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 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