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.

中文翻译：

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健康和精神分裂症受试者中甘氨酸转运蛋白 1 抑制剂 PF-03463275 的剂量相关目标占有率和对电路、行为和神经可塑性的影响

背景甘氨酸转运蛋白-1 (GlyT1) 抑制剂可改善与精神分裂症相关的认知障碍。研究了 GlyT1 抑制剂 PF-03463275 的剂量相关占有率和靶标参与度，为与精神分裂症相关的认知障碍的临床试验提供最佳剂量选择。方法 在子研究 1 中，使用正电子发射断层扫描和 18F-MK-6577 测试了 PF-03463275（10、20 和 40 mg，每天两次）对 GlyT1 占据的影响，以及视觉长时程增强 (LTP)精神分裂症患者 (SZ) 和健康对照受试者。此外，PF-03463275 减弱氯胺酮诱导的“工作记忆”电路的工作记忆相关激活中断的能力仅在健康对照受试者中使用功能磁共振成像进行了测试。随后，PF-03463275（60 毫克，每天两次）对 GlyT1 占据和长时程增强的影响仅在 SZ 中进行了检查（子研究 2）。结果 PF-03463275 每天两次 10、20、40 和 60 毫克，在皮质下区域与皮质区域与 GlyT1 的配体结合更高的 SZ 中，GlyT1 占据率分别为约 44%、61%、76% 和 83%。PF-03463275 不会减弱任何氯胺酮诱导的作用，但确实提高了健康对照受试者的工作记忆准确性。PF-03463275 仅在 SZ 中增加长期增强作用，峰值效应为每天 2 次 40 毫克（~75% GlyT1 占有率），并且具有提示倒 U 剂量反应的特征。PF-03463275 耐受性良好。结论 PF-03463275 的剂量相关 GlyT1 占有率是线性的。虽然 PF-03463275 在氯胺酮试验中没有显示促进 N-甲基-D-天冬氨酸受体功能的证据，但它增强了 SZ 的神经可塑性。这些发现为一项临床试验提供了支持，以测试 PF-03463275 增强认知修复能力以解决与精神分裂症相关的认知障碍的能力。