Glycine transporter-1 (GlyT1) inhibitors may ameliorate cognitive impairments associated with schizophrenia (CIAS). 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 CIAS.
In substudy #1, the effects of PF-03463275 (10, 20, and 40 mg BID) on occupancy of GlyT1 were tested using PET and 18F-MK-6577, and visual long-term potentiation (LTP) in schizophrenia patients (SZS) and healthy subjects (HSs). 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 HSs using fMRI. Subsequently, the effects of PF-03463275 (60 mg BID) on occupancy of GlyT1 and LTP were examined only in SZs (substudy #2).
PF-03463275, 10 mg, 20 mg, 40 mg, and 60 mg BID 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 HSs. PF-03463275 increased LTP only in SZs with peak effects at 40 mg BID (∼75% GlyT1 occupancy) and with a profile suggestive of an inverted ‘U’ dose response. PF-03463275 was well-tolerated.
The dose-related GlyT1 occupancy of PF-03463275 is linear. While PF-03463275 did not show evidence of facilitating NMDA-R function in the ketamine assay, it enhanced neuroplasticity in SZs. Together, these findings provide support for a clinical trial to test the ability of PF-03463275 to enhance CR towards addressing CIAS. ClinicalTrials.gov (NCT01911676)
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