title: Quantification of [11C]Ro15-4513 GABAAα5 specific binding and regional selectivity in humans.
abstract: [11C]Ro15-4513 has been introduced as a positron emission tomography radioligand to image the GABAAα5 receptor subtype thought to be important in learning, memory and addiction. However, the in vivo selectivity of the ligand remains unknown and a full assessment of different analysis approaches has yet to be performed. Using human heterologous competition data, with [11C]Ro15-4513 and the highly selective GABAAα5 selective negative allosteric modulator Basmisanil (RG1662), we quantify the GABAAα5 selectivity of [11C]Ro15-4513, assess the validity of reference tissues and evaluate the performance of four different kinetic analysis methods. The results show that [11C]Ro15-4513 has high but not complete selectivity for GABAAα5, with α5 representing around 60-70% of the specific binding in α5 rich regions. Competition data indicate that the cerebellum and pons are essentially devoid of α5 signal and might be used as reference regions under certain conditions. Off-target non-selective binding to other GABAAsubtypes means that the choice of analysis method and the interpretation of outcome measures must be considered carefully. We discuss the merits of two tissue compartmental model analyses to derive both VTand VS, band-pass spectral analysis for estimation of [Formula: see text] and the simplified reference tissue model for estimation of [Formula: see text].
authors.affiliation: 1 Division of Brain Sciences, Imperial College London, London, UK.
authors.forename: Jim Fm
authors.initials: JF
authors.lastname: Myers
authors.affiliation: 2 Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Comley
authors.affiliation: 1 Division of Brain Sciences, Imperial College London, London, UK.|3 Imanova Ltd, London, UK.|4 Department of Engineering Science, University of Oxford, Oxford, UK.
authors.forename: Roger N
authors.initials: RN
authors.lastname: Gunn
mesh_terms: D001386:Azides / Q000737:chemistry*; D001569:Benzodiazepines / Q000737:chemistry*; D001667:Binding, Competitive; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods*; D011485:Protein Binding; D011869:Radioligand Assay; D011963:Receptors, GABA-A / Q000378:metabolism*; D012680:Sensitivity and Specificity
chemical_list: D001386:Azides; C527986:GABRA5 protein, human; D011963:Receptors, GABA-A; D001569:Benzodiazepines; C042957:Ro 15-4513
keywords: kinetic analysis; positron emission tomography; quantification; selectivity; γ-Aminobutyric acid