Quantification of ONO-2952 Occupancy of 18-kDaTranslocator Protein in Conscious Monkey Brains using Positron Emission Tomography

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 360; no. 3; pp. 457 - 465
• Main Authors: Mitsui, Katsukuni, Morimoto, Noriko, Niwa, Tomohiro, Yamaura, Yoshiyuki, Ohba, Hiroyuki, Tsukada, Hideo, Katsumata, Seishi
• Format: Journal Article
• Language: English
• Published: United States 01.03.2017
• Subjects: Acetamides - pharmacology; Administration, Oral; Animals; Brain - diagnostic imaging; Brain - drug effects; Brain - metabolism; Carrier Proteins - antagonists & inhibitors; Carrier Proteins - metabolism; Central Nervous System Agents - pharmacology; Consciousness - drug effects; Consciousness - physiology; Cyclopropanes - pharmacology; Dose-Response Relationship, Drug; Haplorhini; Heterocyclic Compounds, 4 or More Rings - pharmacology; Positron-Emission Tomography - methods; Pyridines - pharmacology; Radiopharmaceuticals - pharmacology; Rats; Receptors, GABA-A - metabolism; Tissue Distribution
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.116.238568

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 C-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 C-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.