Characterisation of the Contribution of the GABA-Benzodiazepine α1 Receptor Subtype to [¹¹C]Ro15-4513 PET Images

Abstract

This positron emission tomography (PET) study aimed to further define selectivity of [11C]Ro15-4513 binding to the GABARα5 relative to the GABARα1 benzodiazepine receptor subtype. The impact of zolpidem, a GABARα1-selective agonist, on [11C]Ro15-4513, which shows selectivity for GABARα5, and the nonselective benzodiazepine ligand [11C]flumazenil binding was assessed in humans. Compartmental modelling of the kinetics of [11C]Ro15-4513 time-activity curves was used to describe distribution volume (VT) 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 VT decrease (∼10%) in [11C]flumazenil, but no decrease in [11C]Ro15-4513 binding. Further analysis of [11C]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 [11C]Ro15-4513 analysis may allow more accurate selective binding assays and estimation of drug occupancy for other nonselective ligands.

Evidence for GABA‐A receptor dysregulation in gambling disorder: correlation with impulsivity

“…In these studies, we used spectral analysis (Myers et al 2012) to show that these findings in alcohol dependence were driven by the α5 subtype rather than α1; this is consistent with the high level of α5 subtype in the hippocampus and selectivity of [ 11 C]Ro15‐4513 PET (Lingford‐Hughes et al 2016). In the current study in GD, [ 11 C]Ro15‐4513 V T in each ROI was quantified by using a 2‐tissue‐compartmental model, which we have shown to be suitable to describe the α5‐subtype‐specific signal of [ 11 C]Ro15‐4513 in most ROIs (Myers et al 2016a) though the contribution of other subtypes in regions with low GABA A α5 density, such as the cerebellum, should also be considered.…”

“…This was shown, by parsimony criteria, to describe appropriately the ligand kinetics in the range of ROIs considered (Myers et al 2016a). In this dataset, spectral analysis to partition this signal was not applied since we have shown the total V T to represent robustly α5 subtype binding (Myers et al 2016a; Myers et al 2012). All image and kinetic analysis procedures were carried out by using MIAKAT TM (Imanova Ltd, UK).…”

Spectral Analysis of Dynamic PET Studies: A Review of 20 Years of Method Developments and Applications

“…In addition to tissue kinetic quantification, SA has been used as an investigative tool to model newly introduced PET tracers or when biological systems have been explored for the first time [47–50]. In this context, SA spectra offer the possibility of determining the number of compartments present in a system as well as their types, distinguishing between equilibrating components and irreversible tracer uptake.…”

“…Most of its applications are related to the investigation of brain tissues, counting more than 100 different studies. Some meaningful examples are the applications with [ 11 C]diprenorphine [65], [ 11 C]PIB [66], [ 11 C]flumazenil [67], [ 11 C]RO15-4513 [50], [ 11 C]befloxatone [68], and [ 18 F]FIMX [69] in many different conditions including psychiatric conditions, neurodegeneration, and epilepsy. The flexibility of the algorithm allowed the extension of the method also to the analysis of nonbrain tissues, such as heart [70, 71], skeletal leg muscle [47, 72, 73], bone [74, 75], liver [76, 77], and kidney [78].…”

Selected PET Radioligands for Ion Channel Linked Neuroreceptor Imaging: Focus on GABA, NMDA and nACh Receptors

“…31 [ 11 C]Ro15-4513 was shown to have higher specificity for the GABA-α5 receptor subtype than flumazenil as demonstrated by dosage with the GABA-α1 selective agonist zolpidem. 32 …”