Characterisation of the contribution of the GABA-benzodiazepine alpha 1 receptor subtype to [ super(11)C]Ro15-4513 PET images

This positron emission tomography (PET) study aimed to further define selectivity of [ super(11)C]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 [ super(11)C]Ro15-4513, which shows se...

Full description

Saved in:
Bibliographic Details
Published in:Journal of cerebral blood flow and metabolism 2012-04, Vol.32 (4), p.731-744
Main Authors: Myers, James FM, Rosso, Lula, Watson, Ben J, Wilson, Sue J, Kalk, Nicola J, Clementi, Nicoletta, Brooks, David J, Nutt, David J, Turkheimer, Federico E, Lingford-Hughes, Anne R
Format: Article
Language:English
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:This positron emission tomography (PET) study aimed to further define selectivity of [ super(11)C]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 [ super(11)C]Ro15-4513, which shows selectivity for GABAR alpha 5, and the nonselective benzodiazepine ligand [ super(11)C]flumazenil binding was assessed in humans. Compartmental modelling of the kinetics of [ super(11)C]Ro15-4513 time-activity curves was used to describe distribution volume (V sub(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 sub(T) decrease ( similar to 10%) in [ super(11)C]flumazenil, but no decrease in [ super(11)C]Ro15-4513 binding. Further analysis of [ super(11)C]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 [ super(11)C]Ro15-4513 analysis may allow more accurate selective binding assays and estimation of drug occupancy for other nonselective ligands.
ISSN:0271-678X
DOI:10.1038/jcbfm.2011.177