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Identification and evaluation of [ 11 C]GSK931145 as a novel ligand for imaging the type 1 glycine transporter with positron emission tomography
Author(s) -
Passchier J.,
Gentile G.,
Porter R.,
Herdon H.,
Salinas C.,
Jakobsen S.,
Audrain H.,
Laruelle M.,
Gunn R.N.
Publication year - 2010
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/syn.20760
Subject(s) - positron emission tomography , in vivo , chemistry , ligand (biochemistry) , transporter , glycine , biophysics , pharmacology , nuclear medicine , biochemistry , receptor , amino acid , medicine , biology , microbiology and biotechnology , gene
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. Synapse 64:542–549, 2010. © 2010 Wiley‐Liss, Inc.