PMID- 28245513
OWN - NLM
STAT- MEDLINE
DCOM- 20180227
LR  - 20180228
IS  - 1098-2396 (Electronic)
IS  - 0887-4476 (Linking)
VI  - 71
IP  - 7
DP  - 2017 Jul
TI  - Brain translocator protein occupancy by ONO-2952 in healthy adults: A Phase 1 PET 
      study using [(11) C]PBR28.
LID - 10.1002/syn.21970 [doi]
AB  - 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) 
      (BP(ND) ) was derived as the difference between V(T) in the ROI (V(T) ROI) and 
      V(ND) , normalized to V(ND) ; BP(ND)  = (V(T) ROI - V(ND) )/V(ND) . TSPO 
      occupancy was calculated as the change in BP(ND) (DeltaBP(ND) ) from individual's 
      baseline scan to the on-medication scan to the baseline BP(ND) 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.
CI  - (c) 2017 Wiley Periodicals, Inc.
FAU - Frankle, W Gordon
AU  - Frankle WG
AUID- ORCID: 0000-0003-0356-4197
AD  - Department of Psychiatry, NYU Langone Medical Center, New York, New York.
FAU - Narendran, Rajesh
AU  - Narendran R
AD  - Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.
AD  - Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania.
FAU - Wood, Andrew T
AU  - Wood AT
AD  - Ono Pharma Inc. USA, Lawrenceville, New Jersey, USA.
FAU - Suto, Fumitaka
AU  - Suto F
AD  - Ono Pharmaceutical Co. Ltd, Osaka, Japan.
FAU - Himes, Michael L
AU  - Himes ML
AD  - Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.
FAU - Kobayashi, Michiyoshi
AU  - Kobayashi M
AD  - Ono Pharmaceutical Co. Ltd, Osaka, Japan.
FAU - Ohno, Tomoya
AU  - Ohno T
AD  - Ono Pharmaceutical Co. Ltd, Osaka, Japan.
FAU - Yamauchi, Akinori
AU  - Yamauchi A
AD  - Ono Pharmaceutical Co. Ltd, Osaka, Japan.
FAU - Mitsui, Katsukuni
AU  - Mitsui K
AD  - Ono Pharmaceutical Co. Ltd, Osaka, Japan.
FAU - Duffy, Kevin
AU  - Duffy K
AD  - Ono Pharma UK Ltd, London, United Kingdom.
FAU - Bruce, Mark
AU  - Bruce M
AD  - Ono Pharma UK Ltd, London, United Kingdom.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170311
PL  - United States
TA  - Synapse
JT  - Synapse (New York, N.Y.)
JID - 8806914
RN  - 0 (Acetamides)
RN  - 0 (Carbon Radioisotopes)
RN  - 0 (Cyclopropanes)
RN  - 0 (GABA Antagonists)
RN  - 0 (Heterocyclic Compounds, 4 or More Rings)
RN  - 0 (N-(2-methoxybenzyl)-N-(4-phenoxypyridin-3-yl)acetamide)
RN  - 0 (ONO-2952)
RN  - 0 (Pyridines)
RN  - 0 (Radiopharmaceuticals)
RN  - 0 (Receptors, GABA)
RN  - 0 (TSPO protein, human)
SB  - IM
MH  - Acetamides
MH  - Adult
MH  - Brain/*diagnostic imaging/*metabolism
MH  - Carbon Radioisotopes
MH  - Cyclopropanes/adverse effects/blood/*pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Follow-Up Studies
MH  - GABA Antagonists/adverse effects/blood/*pharmacology
MH  - Heterocyclic Compounds, 4 or More Rings/adverse effects/blood/*pharmacology
MH  - Humans
MH  - Linear Models
MH  - Magnetic Resonance Imaging
MH  - Male
MH  - Middle Aged
MH  - Positron-Emission Tomography
MH  - Pyridines
MH  - Radiopharmaceuticals
MH  - Receptors, GABA/*metabolism
MH  - Young Adult
OTO - NOTNLM
OT  - ONO-2952
OT  - [11C]PBR28
OT  - positron emission tomography
OT  - translocator protein 18 kDa
EDAT- 2017/03/01 06:00
MHDA- 2018/02/28 06:00
CRDT- 2017/03/01 06:00
PHST- 2017/01/26 00:00 [received]
PHST- 2017/02/10 00:00 [revised]
PHST- 2017/02/22 00:00 [accepted]
PHST- 2017/03/01 06:00 [pubmed]
PHST- 2018/02/28 06:00 [medline]
PHST- 2017/03/01 06:00 [entrez]
AID - 10.1002/syn.21970 [doi]
PST - ppublish
SO  - Synapse. 2017 Jul;71(7). doi: 10.1002/syn.21970. Epub 2017 Mar 11.