Characterisation of the contribution of the GABA-benzodiazepine α1 receptor subtype to 11CRo15-4513 PET images

Abstract

This positron emission tomography (PET) study aimed to further define selectivity of 11CRo15-4513 binding to the GABARα5 relative to the GABARα1 benzodiazepine receptor subtype. The impact of zolpidem, a GABARα1-selective agonist, on 11CRo15-4513, which shows selectivity for GABARα5, and the nonselective benzodiazepine ligand 11Cflumazenil binding was assessed in humans. Compartmental modelling of the kinetics of 11CRo15-4513 time-activity curves was used to describe distribution volume (V T) differences in regions populated by different GABA receptor subtypes. Those with low α5 were best fitted by one-tissue compartment models; and those with high α5 required a more complex model. The heterogeneity between brain regions suggested spectral analysis as a more appropriate method to quantify binding as it does not a priori specify compartments. Spectral analysis revealed that zolpidem caused a significant V T decrease (∼10%) in 11Cflumazenil, but no decrease in 11CRo15-4513 binding. Further analysis of 11CRo15-4513 kinetics revealed additional frequency components present in regions containing both α1 and α5 subtypes compared with those containing only α1. Zolpidem reduced one component (mean±s.d.: 71%±41%), presumed to reflect α1-subtype binding, but not another (13%±22%), presumed to reflect α5. The proposed method for 11CRo15-4513 analysis may allow more accurate selective binding assays and estimation of drug occupancy for other nonselective ligands. © 2012 ISCBFM All rights reserved.