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

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,V_T and binding potential, BP_ND 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 BP_ND 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 V_T and BP_ND estimates were indistinguishable among employed methods (r²>0.993; slope: 0.96-1), except for BP_ND 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 V_T or BP_ND and subject's mean, respectively) were <10% for V_T and BP_ND except for BP_ND of TTC (<20%). Ventral striatum, amygdala, anterior cingulate, temporal pole, and insula showed highest V_T and BP_ND.

Conclusions [¹¹C]RO0154513 showed high BP_ND in similar regions reported in rat brain (Pirker et al., 2000). RTGA without the need for arterial blood sampling appeared to be optimal for BP_ND, with reproducibility and robustness equal to PRGA, and superior to TTC and MRTM2. Additional studies may be required to confirm whether V_T of pons is non-displaceable to use RO0154513 for drug occupancy studies with RTGA