Quantification of [11C]Ro15-4513 GABAA5 specific binding and regional selectivity in humans

[C-11]Ro15-4513 has been introduced as a positron emission tomography radioligand to image the GABA(A)5 receptor subtype thought to be important in learning, memory and addiction. However, the invivo 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 [C-11]Ro15-4513 and the highly selective GABA(A)5 selective negative allosteric modulator Basmisanil (RG1662), we quantify the GABA(A)5 selectivity of [C-11]Ro15-4513, assess the validity of reference tissues and evaluate the performance of four different kinetic analysis methods. The results show that [C-11]Ro15-4513 has high but not complete selectivity for GABA(A)5, with 5 representing around 60-70% of the specific binding in 5 rich regions. Competition data indicate that the cerebellum and pons are essentially devoid of 5 signal and might be used as reference regions under certain conditions. Off-target non-selective binding to other GABA(A) subtypes 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 V-T and V-S, band-pass spectral analysis for estimation of V5 and the simplified reference tissue model for estimation of BPND.