Evaluation of the in-vivo imaging characteristics of [11C] RO0154513, a PET ligand with high affinity and moderate selectivity for GABA alpha 5 receptors

1175 Objectives [11C]RO0154513, a PET ligand with high affinity and moderate selectivity for gamma-aminobutyric acid (GABA) alpha 5 subunit containing receptors, is expected to contribute to greater understanding of neuropsychiatric disorders. A test-retest paradigm was used for model selection and accuracy estimates of distribution volume,VT and binding potential, BPND of the radioligand in non-human primates. Methods Baseline PET was performed in male papio anubis baboons (n=7) following injection of [11C]RO0154513 (17.4-19.9 mCi; mass: 0.29-1.72 micrograms). Regional V T and BPND were obtained by two-tissue compartment model (TTC, setting the K1-k2 ratio to the pons value, plasma reference graphical analysis (PRGA; Logan et al., 1990), reference tissue graphical analysis (RTGA; Logan et al., 1996), and multi-linear reference tissue method with 2 parameters (MRTM2; Ichise et al., 2002), using pons as a reference region. Results Regional VT and BPND estimates were indistinguishable among employed methods (r2>0.993; slope: 0.96-1), except for BPND of TTCM (e.g., PRGA = 0.88xTTC + 0.34; r 2=0.88). Correlations improved (judged by r2) using 90 min data, compared to 60 min data (Asai et al., 2009) in all methods. Test-retest variability estimates (TRV, as mean across animals |E - mE|x2/mE, where E and mE are estimates of VT or BPND and subject9s mean, respectively) were Conclusions [11C]RO0154513 showed high BPND in similar regions reported in rat brain (Pirker et al., 2000). RTGA without the need for arterial blood sampling appeared to be optimal for BPND, with reproducibility and robustness equal to PRGA, and superior to TTC and MRTM2. Additional studies may be required to confirm whether VT of pons is non-displaceable to use RO0154513 for drug occupancy studies with RTGA