title: Quantification of ONO-2952 Occupancy of 18-kDaTranslocator Protein in Conscious Monkey Brains using Positron Emission Tomography.
abstract: 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) with11C-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 decreased11C-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.
authors.affiliation: Discovery Research Laboratories I (K.M., N.M., T.N., S.K.), and Pharmaceutical Technology Laboratories (Y.Y.), ONO Pharmaceutical Co., Ltd., Osaka, and Central Research Laboratory, Hamamatsu Photonics K.K., Shizuoka (H.O., H.T.), Japan.
authors.forename: Katsukuni
authors.initials: K
authors.lastname: Mitsui
authors.affiliation: Discovery Research Laboratories I (K.M., N.M., T.N., S.K.), and Pharmaceutical Technology Laboratories (Y.Y.), ONO Pharmaceutical Co., Ltd., Osaka, and Central Research Laboratory, Hamamatsu Photonics K.K., Shizuoka (H.O., H.T.), Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Morimoto
authors.affiliation: Discovery Research Laboratories I (K.M., N.M., T.N., S.K.), and Pharmaceutical Technology Laboratories (Y.Y.), ONO Pharmaceutical Co., Ltd., Osaka, and Central Research Laboratory, Hamamatsu Photonics K.K., Shizuoka (H.O., H.T.), Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Niwa
authors.affiliation: Discovery Research Laboratories I (K.M., N.M., T.N., S.K.), and Pharmaceutical Technology Laboratories (Y.Y.), ONO Pharmaceutical Co., Ltd., Osaka, and Central Research Laboratory, Hamamatsu Photonics K.K., Shizuoka (H.O., H.T.), Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Yamaura
authors.affiliation: Discovery Research Laboratories I (K.M., N.M., T.N., S.K.), and Pharmaceutical Technology Laboratories (Y.Y.), ONO Pharmaceutical Co., Ltd., Osaka, and Central Research Laboratory, Hamamatsu Photonics K.K., Shizuoka (H.O., H.T.), Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ohba
authors.affiliation: Discovery Research Laboratories I (K.M., N.M., T.N., S.K.), and Pharmaceutical Technology Laboratories (Y.Y.), ONO Pharmaceutical Co., Ltd., Osaka, and Central Research Laboratory, Hamamatsu Photonics K.K., Shizuoka (H.O., H.T.), Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Tsukada
authors.affiliation: Discovery Research Laboratories I (K.M., N.M., T.N., S.K.), and Pharmaceutical Technology Laboratories (Y.Y.), ONO Pharmaceutical Co., Ltd., Osaka, and Central Research Laboratory, Hamamatsu Photonics K.K., Shizuoka (H.O., H.T.), Japan s.katsumata@ono.co.jp.
authors.forename: Seishi
authors.initials: S
authors.lastname: Katsumata
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002491:Central Nervous System Agents / Q000494:pharmacology; D003243:Consciousness / Q000187:drug effects* / Q000502:physiology; D003521:Cyclopropanes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000882:Haplorhini; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D049268:Positron-Emission Tomography / Q000379:methods*; D011725:Pyridines / Q000494:pharmacology; D019275:Radiopharmaceuticals / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D000081:Acetamides; D002352:Carrier Proteins; D002491:Central Nervous System Agents; D003521:Cyclopropanes; D006576:Heterocyclic Compounds, 4 or More Rings; C526798:N-(2-methoxybenzyl)-N-(4-phenoxypyridin-3-yl)acetamide; C000607300:ONO-2952; D011725:Pyridines; D019275:Radiopharmaceuticals; D011963:Receptors, GABA-A; C069997:Tspo protein, rat