Characterisation of the contribution of the GABA-benzodiazepine α1 receptor subtype to [(11)C]Ro15-4513 PET images.
This positron emission tomography (PET) study aimed to further define selectivity of [(11)C]Ro15-4513 binding to the GABARα5 relative to the GABARα1 benzodiazepine receptor subtype. The impact of zolpidem, a GABARα1-selective agonist, on [(11)C]Ro15-4513, which shows selectivity for GABARα5, 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 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 [(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 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 [(11)C]Ro15-4513 analysis may allow more accurate selective binding assays and estimation of drug occupancy for other nonselective ligands.
Psychopharmacology Unit, University of Bristol, Bristol, UK.
James F M
JF
Myers
Lula
L
Rosso
Ben J
BJ
Watson
Sue J
SJ
Wilson
Nicola J
NJ
Kalk
Nicoletta
N
Clementi
David J
DJ
Brooks
David J
DJ
Nutt
Federico E
FE
Turkheimer
Anne R
AR
Lingford-Hughes
D000328:Adult; D000345:Affinity Labels / Q000008:administration & dosage; D001386:Azides / Q000008:administration & dosage*; D001569:Benzodiazepines / Q000008:administration & dosage*; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D004311:Double-Blind Method; D058785:GABA-A Receptor Agonists / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography; D011485:Protein Binding; D021122:Protein Subunits / Q000819:agonists / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage; D011859:Radiography; D011963:Receptors, GABA-A / Q000378:metabolism*; D000077334:Zolpidem
D000345:Affinity Labels; D001386:Azides; D058785:GABA-A Receptor Agonists; D021122:Protein Subunits; D011725:Pyridines; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D000077334:Zolpidem; C042957:Ro 15-4513