PMID- 29499855
OWN - NLM
STAT- In-Data-Review
LR  - 20190329
IS  - 1873-2402 (Electronic)
IS  - 0006-3223 (Linking)
VI  - 84
IP  - 6
DP  - 2018 Sep 15
TI  - Dose-Related Target Occupancy and Effects on Circuitry, Behavior, and
      Neuroplasticity of the Glycine Transporter-1 Inhibitor PF-03463275 in Healthy and
      Schizophrenia Subjects.
PG  - 413-421
LID - S0006-3223(18)30036-2 [pii]
LID - 10.1016/j.biopsych.2017.12.019 [doi]
AB  - BACKGROUND: Glycine transporter-1 (GlyT1) inhibitors may ameliorate cognitive
      impairments associated with schizophrenia. The dose-related occupancy and target 
      engagement of the GlyT1 inhibitor PF-03463275 were studied to inform optimal dose
      selection for a clinical trial for cognitive impairments associated with
      schizophrenia. METHODS: In substudy 1, the effects of PF-03463275 (10, 20, and 40
      mg twice a day) on occupancy of GlyT1 were tested using positron emission
      tomography and (18)F-MK-6577, and visual long-term potentiation (LTP) in
      schizophrenia patients (SZs) and healthy control subjects. Furthermore, the
      capacity of PF-03463275 to attenuate ketamine-induced disruption of working
      memory-related activation of a "working memory" circuit was tested only in
      healthy control subjects using functional magnetic resonance imaging.
      Subsequently, the effects of PF-03463275 (60 mg twice a day) on occupancy of
      GlyT1 and long-term potentiation were examined only in SZs (substudy 2). RESULTS:
      PF-03463275 at 10, 20, 40, and 60 mg twice a day produced approximately 44%, 61%,
      76%, and 83% GlyT1 occupancy, respectively, in SZs with higher ligand binding to 
      GlyT1 in subcortical versus cortical regions. PF-03463275 did not attenuate any
      ketamine-induced effects but did improve working memory accuracy in healthy
      control subjects. PF-03463275 increased long-term potentiation only in SZs with
      peak effects at 40 mg twice a day ( approximately 75% GlyT1 occupancy) and with a
      profile suggestive of an inverted U dose response. PF-03463275 was
      well-tolerated. CONCLUSIONS: The dose-related GlyT1 occupancy of PF-03463275 is
      linear. While PF-03463275 did not show evidence of facilitating
      N-methyl-D-aspartate receptor function in the ketamine assay, it enhanced
      neuroplasticity in SZs. These findings provide support for a clinical trial to
      test the ability of PF-03463275 to enhance cognitive remediation toward
      addressing cognitive impairments associated with schizophrenia.
CI  - Published by Elsevier Inc.
FAU - D'Souza, Deepak Cyril
AU  - D'Souza DC
AD  - Department of Psychiatry, Yale University School of Medicine, New Haven,
      Connecticut; Abraham Ribicoff Research Facilities, Connecticut Mental Health
      Center, New Haven, Connecticut; Mental Health Service Line, Veterans Affairs
      Connecticut Healthcare System, West Haven, Connecticut. Electronic address:
      deepak.dsouza@yale.edu.
FAU - Carson, Richard E
AU  - Carson RE
AD  - Department of Radiology and Biomedical Imaging, Yale University School of
      Medicine, New Haven, Connecticut; Department of Biomedical Engineering, Yale
      University, New Haven, Connecticut; Yale Positron Emission Tomography Center, New
      Haven, Connecticut.
FAU - Driesen, Naomi
AU  - Driesen N
AD  - Department of Psychiatry, Yale University School of Medicine, New Haven,
      Connecticut; Mental Health Service Line, Veterans Affairs Connecticut Healthcare 
      System, West Haven, Connecticut.
FAU - Johannesen, Jason
AU  - Johannesen J
AD  - Department of Psychiatry, Yale University School of Medicine, New Haven,
      Connecticut; Mental Health Service Line, Veterans Affairs Connecticut Healthcare 
      System, West Haven, Connecticut.
FAU - Ranganathan, Mohini
AU  - Ranganathan M
AD  - Department of Psychiatry, Yale University School of Medicine, New Haven,
      Connecticut; Abraham Ribicoff Research Facilities, Connecticut Mental Health
      Center, New Haven, Connecticut; Mental Health Service Line, Veterans Affairs
      Connecticut Healthcare System, West Haven, Connecticut.
FAU - Krystal, John H
AU  - Krystal JH
AD  - Department of Psychiatry, Yale University School of Medicine, New Haven,
      Connecticut; Department of Neurobiology, Yale University School of Medicine, New 
      Haven, Connecticut; Abraham Ribicoff Research Facilities, Connecticut Mental
      Health Center, New Haven, Connecticut; Yale-New Haven Hospital, New Haven,
      Connecticut; Mental Health Service Line, Veterans Affairs Connecticut Healthcare 
      System, West Haven, Connecticut.
CN  - Yale GlyT1 Study Group
LA  - eng
GR  - P50 AA012870/AA/NIAAA NIH HHS/United States
GR  - UH2 TR000960/TR/NCATS NIH HHS/United States
GR  - UL1 RR024139/RR/NCRR NIH HHS/United States
GR  - UL1 TR001863/TR/NCATS NIH HHS/United States
PT  - Journal Article
DEP - 20180131
PL  - United States
TA  - Biol Psychiatry
JT  - Biological psychiatry
JID - 0213264
PMC - PMC6068006
MID - NIHMS935567
OTO - NOTNLM
OT  - Cognition
OT  - Glycine transporter inhibitor
OT  - Long-term potentiation
OT  - NMDA receptor
OT  - Neuroplasticity
OT  - Positron emission tomography
OT  - Receptor occupancy
OT  - Schizophrenia
IR  - Ahn KH
FIR - Ahn, Kyung-Heup
IR  - Bielen K
FIR - Bielen, Kimberlee
IR  - Carbuto M
FIR - Carbuto, Michelle
IR  - Deaso E
FIR - Deaso, Emma
IR  - D'Souza DC
FIR - D'Souza, Deepak Cyril
IR  - Ranganathan M
FIR - Ranganathan, Mohini
IR  - Naganawa M
FIR - Naganawa, Mika
IR  - Ranganathan M
FIR - Ranganathan, Mohini
IR  - D'Souza DC
FIR - D'Souza, Deepak Cyril
IR  - Nabulsi N
FIR - Nabulsi, Nabeel
IR  - Zheng MQ
FIR - Zheng, Ming-Qiang
IR  - Lin SF
FIR - Lin, Shu-Fei
IR  - Huang Y
FIR - Huang, Yiyun
IR  - Carson RE
FIR - Carson, Richard E
IR  - Driesen N
FIR - Driesen, Naomi
IR  - Ahn KH
FIR - Ahn, Kyung-Heup
IR  - Morgan PT
FIR - Morgan, Peter T
IR  - Suckow R
FIR - Suckow, Raymond
IR  - He G
FIR - He, George
IR  - McCarthy G
FIR - McCarthy, Gregory
IR  - Krystal JH
FIR - Krystal, John H
IR  - Johannesen J
FIR - Johannesen, Jason
IR  - Kenney J
FIR - Kenney, Joshua
IR  - Gelernter J
FIR - Gelernter, Joel
IR  - Gueorguieva R
FIR - Gueorguieva, Ralitza
IR  - Pittman B
FIR - Pittman, Brian
EDAT- 2018/03/04 06:00
MHDA- 2018/03/04 06:00
CRDT- 2018/03/04 06:00
PMCR- 2019/09/15 00:00
PHST- 2017/09/08 00:00 [received]
PHST- 2017/11/14 00:00 [revised]
PHST- 2017/12/15 00:00 [accepted]
PHST- 2019/09/15 00:00 [pmc-release]
PHST- 2018/03/04 06:00 [pubmed]
PHST- 2018/03/04 06:00 [medline]
PHST- 2018/03/04 06:00 [entrez]
AID - S0006-3223(18)30036-2 [pii]
AID - 10.1016/j.biopsych.2017.12.019 [doi]
PST - ppublish
SO  - Biol Psychiatry. 2018 Sep 15;84(6):413-421. doi: 10.1016/j.biopsych.2017.12.019. 
      Epub 2018 Jan 31.