TY - JOUR T1 - Quantification of ONO-2952 Occupancy of 18-kDaTranslocator Protein in Conscious Monkey Brains using Positron Emission Tomography JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 457 LP - 465 DO - 10.1124/jpet.116.238568 VL - 360 IS - 3 AU - Katsukuni Mitsui AU - Noriko Morimoto AU - Tomohiro Niwa AU - Yoshiyuki Yamaura AU - Hiroyuki Ohba AU - Hideo Tsukada AU - Seishi Katsumata Y1 - 2017/03/01 UR - http://jpet.aspetjournals.org/content/360/3/457.abstract N2 - We have previously shown that ONO-2952, a novel 18-kDa translocator protein (TSPO) antagonist, inhibits stress-induced accumulation of neurosteroids and noradrenaline release in the rat brain and alleviates the subsequent symptomatic responses with a brain TSPO occupancy of 50% or more. In this study, we measured ONO-2952 brain TSPO occupancy in conscious rhesus monkeys using positron emission tomography (PET) with 11C-PBR28 as ligand for translational research to clinical application. PET scans were performed after single and repeated oral administration of ONO-2952 at several dose levels for each animal, with sequential arterial blood sampling. In vitro binding studies showed that ONO-2952 potently binds to brain TSPO in monkeys with an affinity equivalent to that in rats. ONO-2952, given orally before PET scans, dose dependently decreased 11C-PBR28 uptake without marked brain region specificity. Results of the quantitative analysis using arterial input function revealed that TSPO occupancy after ONO-2952 single and repeated oral administration tended to increase in parallel with its plasma concentration, reaching the highest level of 100%. These findings indicate that ONO-2952 has sufficient brain distribution in primates and that ONO-2952 TSPO occupancy in humans can also be determined using PET. ER -