title: Identification and evaluation of [11C]GSK931145 as a novel ligand for imaging the type 1 glycine transporter with positron emission tomography.
abstract: 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 [(11)C]methyl iodide or [(11)C]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. [(11)C]GSK931145 showed good brain penetration and a heterogeneous distribution in agreement with reported GlyT1 localization. Following pretreatment with GSK565710, uptake of [(11)C]GSK931145 was reduced to homogeneous levels. Although [(11)C]GSK565710 also showed good brain penetration and a heterogeneous distribution, the apparent level of specific binding was reduced compared to [(11)C]GSK931145. In contrast, [(11)C]GSK991022 showed a much lower brain penetration and resultant signal following pretreatment with GSK565710. Based on these findings [(11)C]GSK931145 was identified as the most promising ligand for imaging GlyT1 in the porcine brain, possessing good brain penetration, specific signal, and reversible kinetics. [(11)C]GSK931145 is now being progressed into higher species.
authors.affiliation: GlaxoSmithKline, Clinical Imaging Centre, Hammersmith Hospital, London, United Kingdom. jan.2.passchier@gsk.com
authors.forename: J
authors.initials: J
authors.lastname: Passchier
authors.forename: G
authors.initials: G
authors.lastname: Gentile
authors.forename: R
authors.initials: R
authors.lastname: Porter
authors.forename: H
authors.initials: H
authors.lastname: Herdon
authors.forename: C
authors.initials: C
authors.lastname: Salinas
authors.forename: S
authors.initials: S
authors.lastname: Jakobsen
authors.forename: H
authors.initials: H
authors.lastname: Audrain
authors.forename: M
authors.initials: M
authors.lastname: Laruelle
authors.forename: R N
authors.initials: RN
authors.lastname: Gunn
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002250:Carbon Radioisotopes; D004305:Dose-Response Relationship, Drug; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006847:Hydrocarbons, Iodinated / Q000494:pharmacology; D008024:Ligands; D008698:Mesylates / Q000494:pharmacology; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000493:pharmacokinetics; D013552:Swine; D013997:Time Factors
chemical_list: D002250:Carbon Radioisotopes; D050487:Glycine Plasma Membrane Transport Proteins; D006847:Hydrocarbons, Iodinated; D008024:Ligands; D008698:Mesylates; D019275:Radiopharmaceuticals; C078465:methyl triflate; C014055:methyl iodide