Characterisation of the contribution of the GABA-benzodiazepine α1 receptor subtype to [11C]Ro15-4513 PET images

This positron emission tomography (PET) study aimed to further define selectivity of [C-11]Ro15-4513 binding to the GABAR alpha 5 relative to the GABAR alpha 1 benzodiazepine receptor subtype. The impact of zolpidem, a GABAR alpha 1-selective agonist, on [C-11]Ro15-4513, which shows selectivity for GABAR alpha 5, and the nonselective benzodiazepine ligand [C-11]flumazenil binding was assessed in humans. Compartmental modelling of the kinetics of [C-11]Ro15-4513 time-activity curves was used to describe distribution volume (V-T) differences in regions populated by different GABA receptor subtypes. Those with low alpha 5 were best fitted by one-tissue compartment models; and those with high alpha 5 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 (similar to 10%) in [C-11]flumazenil, but no decrease in [C-11] Ro15-4513 binding. Further analysis of [C-11]Ro15-4513 kinetics revealed additional frequency components present in regions containing both alpha 1 and alpha 5 subtypes compared with those containing only alpha 1. Zolpidem reduced one component (mean +/- s.d.: 71%+/- 41%), presumed to reflect alpha 1-subtype binding, but not another (13%+/- 22%), presumed to reflect alpha 5. The proposed method for [C-11]Ro15-4513 analysis may allow more accurate selective binding assays and estimation of drug occupancy for other nonselective ligands. Journal of Cerebral Blood Flow & Metabolism (2012) 32, 731-744; doi:10.1038/jcbfm.2011.177; published online 4 January 2012