title: Brain translocator protein occupancy by ONO-2952 in healthy adults: A Phase 1 PET study using [11C]PBR28.
abstract: 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 [11C]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 [11C]PBR28 were conducted ≤7 days apart: at baseline and 24 h after ONO-2952 administration. [11C]PBR28 regional distribution volume (VT) was derived with kinetic modeling using the arterial input function and a two tissue compartment model. Nonspecific binding (VND) 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 VND(BPND) was derived as the difference between VTin the ROI (VTROI) and VND, normalized to VND; BPND= (VTROI - VND)/VND. TSPO occupancy was calculated as the change in BPND(ΔBPND) from individual's baseline scan to the on-medication scan to the baseline BPNDvalue. 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 Kivalues 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.
authors.affiliation: Department of Psychiatry, NYU Langone Medical Center, New York, New York.
authors.forename: W Gordon
authors.identifier: 0000-0003-0356-4197
authors.initials: WG
authors.lastname: Frankle
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.|Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Narendran
authors.affiliation: Ono Pharma Inc. USA, Lawrenceville, New Jersey, USA.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Wood
authors.affiliation: Ono Pharmaceutical Co. Ltd, Osaka, Japan.
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Suto
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Himes
authors.affiliation: Ono Pharmaceutical Co. Ltd, Osaka, Japan.
authors.forename: Michiyoshi
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: Ono Pharmaceutical Co. Ltd, Osaka, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Ohno
authors.affiliation: Ono Pharmaceutical Co. Ltd, Osaka, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Yamauchi
authors.affiliation: Ono Pharmaceutical Co. Ltd, Osaka, Japan.
authors.forename: Katsukuni
authors.initials: K
authors.lastname: Mitsui
authors.affiliation: Ono Pharma UK Ltd, London, United Kingdom.
authors.forename: Kevin
authors.initials: K
authors.lastname: Duffy
authors.affiliation: Ono Pharma UK Ltd, London, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Bruce
mesh_terms: D000081:Acetamides; D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002250:Carbon Radioisotopes; D003521:Cyclopropanes / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D018756:GABA Antagonists / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D006801:Humans; D016014:Linear Models; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography; D011725:Pyridines; D019275:Radiopharmaceuticals; D018079:Receptors, GABA / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000081:Acetamides; D002250:Carbon Radioisotopes; D003521:Cyclopropanes; D018756:GABA Antagonists; D006576:Heterocyclic Compounds, 4 or More Rings; C526798:N-(2-methoxybenzyl)-N-(4-phenoxypyridin-3-yl)acetamide; C000607300:ONO-2952; D011725:Pyridines; D019275:Radiopharmaceuticals; D018079:Receptors, GABA; C499229:TSPO protein, human
keywords: ONO-2952; [11C]PBR28; positron emission tomography; translocator protein 18 kDa