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Dose-Related Target Occupancy and Effects on Circuitry, Behavior, and Neuroplasticity of the Glycine Transporter-1 Inhibitor PF-03463275 in Healthy and Schizophrenia Subjects.
- Source :
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Biological psychiatry [Biol Psychiatry] 2018 Sep 15; Vol. 84 (6), pp. 413-421. Date of Electronic Publication: 2018 Jan 31. - Publication Year :
- 2018
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Abstract
- 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.<br />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 <superscript>18</superscript> 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).<br />Results: PF-03463275 at 10, 20, 40, and 60 mg twice a day produced ∼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 (∼75% GlyT1 occupancy) and with a profile suggestive of an inverted U dose response. PF-03463275 was well-tolerated.<br />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.<br /> (Published by Elsevier Inc.)
- Subjects :
- Adult
Brain diagnostic imaging
Cognitive Dysfunction physiopathology
Dose-Response Relationship, Drug
Double-Blind Method
Female
Humans
Ketamine administration & dosage
Long-Term Potentiation drug effects
Magnetic Resonance Imaging
Male
Memory, Short-Term drug effects
Middle Aged
Positron-Emission Tomography
Schizophrenia physiopathology
Young Adult
Azabicyclo Compounds administration & dosage
Brain metabolism
Cognitive Dysfunction drug therapy
Glycine Plasma Membrane Transport Proteins antagonists & inhibitors
Imidazoles administration & dosage
Schizophrenia drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1873-2402
- Volume :
- 84
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Biological psychiatry
- Publication Type :
- Academic Journal
- Accession number :
- 29499855
- Full Text :
- https://doi.org/10.1016/j.biopsych.2017.12.019