Dose-Related Target Occupancy and Effects on Circuitry, Behavior, and Neuroplasticity of the Glycine Transporter-1 Inhibitor PF-03463275 in Healthy and Schizophrenia Subjects

Biol Psychiatry. 2018 Sep 15;84(6):413-421. doi: 10.1016/j.biopsych.2017.12.019. Epub 2018 Jan 31.

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.

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 18F-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 ∼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.

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.

Keywords: Cognition; Glycine transporter inhibitor; Long-term potentiation; NMDA receptor; Neuroplasticity; Positron emission tomography; Receptor occupancy; Schizophrenia.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Azabicyclo Compounds / administration & dosage*
  • Brain / diagnostic imaging
  • Brain / metabolism*
  • Cognitive Dysfunction / drug therapy*
  • Cognitive Dysfunction / physiopathology
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Glycine Plasma Membrane Transport Proteins / antagonists & inhibitors*
  • Humans
  • Imidazoles / administration & dosage*
  • Ketamine / administration & dosage
  • Long-Term Potentiation / drug effects
  • Magnetic Resonance Imaging
  • Male
  • Memory, Short-Term / drug effects
  • Middle Aged
  • Positron-Emission Tomography
  • Schizophrenia / drug therapy*
  • Schizophrenia / physiopathology
  • Young Adult

Substances

  • 1-methyl-1H-imidazole-4-carboxylic acid (3-chloro-4-fluoro-benzyl)-(3-methyl-3-aza-bicyclo(3.1.0) hex-6-ylmethyl)amide
  • Azabicyclo Compounds
  • Glycine Plasma Membrane Transport Proteins
  • Imidazoles
  • Ketamine