Identification and Evaluation of [11C]GSK931145 as a Novel Ligand for Imaging the Type 1 Glycine Transporter With Positron Emission Tomography

The type-1 glycine transporter (GlyT1) is an important target for the development of new medications for schizophrenia. A specific and selective positron emission tomography (PET) GlyT1 ligand would facilitate drug development studies to determine whether a drug reaches this target and help establish suitable doses for clinical trials. This article describes the evaluation of three candidate GlyT1 PET radioligands (GSK931145, GSK565710, and GSK991022) selected from a library of compounds based on favorable physicochemical and pharmacological properties. Each candidate was successfully labeled using [C-11]methyl iodide or [C-11]methyl triflate and administered to a pig pre- and postadministration with a pharmacological dose of a GlyT1 inhibitor to determine their suitability as PET ligands in the porcine brain in vivo. All three candidate ligands were analyzed quantitatively with compartment analyses employing a plasma input function. [C-11]GSK931145 showed good brain penetration and a heterogeneous distribution in agreement with reported GlyT1 localization. Following pretreatment with GSK565710, uptake of [C-11]GSK931145 was reduced to homogeneous levels. Although [C-11]GSK565710 also showed good brain penetration and a heterogeneous distribution, the apparent level of specific binding was reduced compared to [C-11]GSK931145. In contrast, [C-11]GSK991022 showed a much lower brain penetration and resultant signal following pretreatment with GSK565710. Based on these findings [C-11]GSK931145 was identified as the most promising ligand for imaging GlyT1 in the porcine brain, possessing good brain penetration, specific signal, and reversible kinetics. [C-11]GSK931145 is now being progressed into higher species. Synapse 64:542-549, 2010. (C) 2010 Wiley-Liss, Inc.