科研之友
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摘要
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 (BPND) was derived as the difference between V-T in the ROI (V-T ROI) and V-ND, normalized to V-ND; BPND=(V-T ROI - V-ND)/V-ND. TSPO occupancy was calculated as the change in BPND (BPND) from individual's baseline scan to the on-medication scan to the baseline BPND 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.
- 出版日期2017-7
