In vivo evaluation of 11C-labeled three radioligands for glycine transporter 1 in the mouse brain

Abstract

Objective: Glycine transporter 1 (GlyT-1) is one of the most attractive therapeutic targets for schizophrenia. There is great interest in developing radioligands for in vivo imaging of GlyT-1 in the brain using positron emission tomography. Here, we report the properties of three novel non-sarcosine-based radioligands [11C]CHIBA-3007, [11C]CHIBA-3009, and [ 11C]CHIBA-3011, for GlyT-1 imaging in the mouse brain in vivo. Methods: The three radioligands were synthesized by N-[11C] methylation of the corresponding desmethyl precursor. A pharmacological characterization of these radioligands for in vivo imaging of GlyT-1 in the brain was conducted using male ddY mice. Results: [11C]CHIBA-3009 and [11C]CHIBA-3011 were scarcely incorporated into the brain, whereas [11C]CHIBA-3007 showed slight but considerable brain uptake. Regional brain uptake of [11C]CHIBA-3007 (medulla oblongata>cerebellum> cortex) wassimilar to the distribution of the GlyT-1 protein. However, pretreatment with CHIBA-3007 (1 mg/kg) or the GlyT-1 selective inhibitorALX5407 (N-[(3R)-3-([1,1′-Biphenyl]-4-yloxy)-3-(4-fluorophenyl)propyl] -N-methylglycine) (30 mg/kg) did not significantly decreasebrain uptake of [11C]CHIBA-3007, suggesting low specific binding to GlyT-1. Pretreatment with cyclosporin A significantlyincreased brain uptake of [ 11C]CHIBA-3009 and [11C]CHIBA-3011, suggesting a role for P-glycoprotein in the brain uptake ofthese ligands. All three radioligands were rapidly degraded intact forms were 3-18% in plasma and 15-74% in the brain at 15 min after injection.Conclusion: The results suggest that these three radioligands are not suitable for in vivo imaging of GlyT-1 in the brain becauseof low brain uptake and rapid metabolism. Further structural refinement is necessary to enhance brain uptake. Copyright©2012, Korean College of Neuropsychopharmacology.