Brain translocator protein occupancy by ONO-2952 in healthy adults: A Phase 1 PET study using [ 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 [ 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 [ C]PBR28 were conducted ≤7 days apart: at baseline and 24 h after ONO-2952 administration. [ C]PBR28 regional distribution volume (V ) was derived with kinetic modeling using the arterial input function and a two tissue compartment model. Nonspecific binding (V ) 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 (BP ) was derived as the difference between V in the ROI (V ROI) and V , normalized to V ; BP  = (V ROI - V )/V . TSPO occupancy was calculated as the change in BP (ΔBP ) from individual's baseline scan to the on-medication scan to the baseline BP 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 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.