This positron emission tomography (PET) study aimed to further define selectivity of [(11)C]Ro15-4513 binding to the GABAR?5 relative to the GABAR?1 benzodiazepine receptor subtype. The impact of zolpidem, a GABAR?1-selective agonist, on [(11)C]Ro15-4513, which shows selectivity for GABAR?5, and the nonselective benzodiazepine ligand [(11)C]flumazenil binding was assessed in humans. Compartmental modelling of the kinetics of [(11)C]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 ?5 were best fitted by one-tissue compartment models; and those with high ?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 (~10%) in [(11)C]flumazenil, but no decrease in [(11)C]Ro15-4513 binding. Further analysis of [(11)C]Ro15-4513 kinetics revealed additional frequency components present in regions containing both ?1 and ?5 subtypes compared with those containing only ?1. Zolpidem reduced one component (mean±s.d.: 71%±41%), presumed to reflect ?1-subtype binding, but not another (13%±22%), presumed to reflect ?5. The proposed method for [(11)C]Ro15-4513 analysis may allow more accurate selective binding assays and estimation of drug occupancy for other nonselective ligands.
