Brain translocator protein occupancy by ONO-2952 in healthy adults: A Phase 1 PET study using [¹¹ C]PBR28

ONO-2952, a novel antagonist of translocator protein 18 kDa (TSPO), binds with high affinity to TSPO in rat brain and human tumor cell line membrane preparations. This study used the TSPO-specific PET radioligand [¹¹ C]PBR28 to confirm binding of ONO-2952 to brain TSPO in human subjects, and evaluate brain TSPO occupancy and its relationship with ONO-2952 plasma concentration. Sixteen healthy subjects received a single oral dose of 200, 60, 20, or 6 mg ONO-2952 (n = 4 per dose). Two PET scans with [¹¹ C]PBR28 were conducted ≤7 days apart: at baseline and 24 h after ONO-2952 administration. [¹¹ C]PBR28 regional distribution volume (V_T ) was derived with kinetic modeling using the arterial input function and a two tissue compartment model. Nonspecific binding (V_ND ) was obtained on an individual basis for each subject using linear regression as the x-intercept of the Lassen plot. The binding potential relative to V_ND (BP_ND ) was derived as the difference between V_T in the ROI (V_T ROI) and V_ND , normalized to V_ND ; BP_ND  = (V_T ROI - V_ND )/V_ND . TSPO occupancy was calculated as the change in BP_ND (ΔBP_ND ) from individual's baseline scan to the on-medication scan to the baseline BP_ND value. TSPO occupancy by ONO-2952 was dose dependent between 20-200 mg, approaching saturation at 200 mg both in the whole brain and in 15 anatomic regions of interest (ROI). Estimated K_i values ranged from 24.1 to 72.2 nM. This open-label, single-center, single-dose study demonstrated engagement of ONO-2952 to brain TSPO. The relationship between pharmacokinetics and TSPO occupancy observed in this study support the hypothesis that ONO-2952 could potentially modulate neurosteroid production by binding to brain TSPO.