Translational Neuroscience Optimization of GlyT1 Inhibitor

描述(申请人提供)：背景：认知障碍是导致精神分裂症患者功能障碍的重要原因，目前尚无有效的治疗方法。此应用程序的目标是使用翻译神经科学方法来开发一种治疗与精神分裂症(CIAS)相关的认知障碍的方法。NMDAR功能缺陷参与了CIAS的发生，因此，促进NMDAR功能的发挥是治疗CIAS的一种潜在途径。甘氨酸转运蛋白抑制剂(GlyT1Is)可以通过提高突触甘氨酸水平和刺激NMDAR的GlycineB联合激动剂位点来增强NMDAR相关的可塑性。临床前数据支持GlyT1is作为CIAS治疗的潜力。PF-03463275是一种Glyt1I抑制剂，尚未经过治疗CIAS的测试。包括PF-03463275在内的较高剂量的Glyt1is可能具有平缓和/或恶化的效应，暗示着倒U形剂量反应。因此，确定GlyT1Is的最佳治疗剂量范围至关重要。UH2：UH2的目标是确定PF-03463275的最佳剂量。我们将使用正电子发射断层扫描成像来确定F-03463275与剂量相关的占有率，以确定它是否达到预期目标并产生足够的占有率以使其有效。同时，我们将使用功能磁共振成像作为与剂量相关的GlyT1I促进NMDAR功能的分析；我们将确定PF-03463275是否对与工作记忆相关的氯胺酮诱导的前额叶皮质BOLD激活的中断产生剂量相关的减弱。UH2方法：24名健康受试者将接受安慰剂或两次有效剂量的PF-03463275 Bid，每次为期一周，在此期间，他们将接受正电子发射计算机断层扫描、长期增强治疗和氯胺酮-功能磁共振成像挑战研究。UH3：在这一阶段(UH3)，我们将在一项新的概念证明、双盲、安慰剂对照的组间研究中测试PF-03463275对CIAS的疗效。在患者生活的典型贫困认知环境中，药物对可塑性的增强可能不足以补救长期存在的认知功能障碍。因此，就像体育锻炼可能会优化合成类固醇的效果一样，这项试验将结合认知补救和PF-03463275治疗。UH3方法：服用利培酮或阿立哌唑的精神分裂症患者(n=76)将随机接受安慰剂或主动PF-03463275 BID，除认知治疗外。CAI的变化将使用Matrics Consensus Cognitive Battery综合分数进行评估。我们还将使用视觉长时程增强(LTP)，一种体内测量依赖NMDAR的突触可塑性的指标，作为PF-03463275作用机制的新生物标记物。使用这种方法，我们建议识别PF-03463275对LTP指数的可塑性的影响，并评估PF-03463275在精神分裂症患者中恢复这种形式的神经可塑性的能力，因为在精神分裂症患者中它是缺陷的。

DESCRIPTION (provided by applicant): Background: Cognitive impairments, for which there are no effective treatments, contribute significantly to functional disability in schizophrenia. Th goal of this application is to use a translational neuroscience approach to develop a treatment for the cognitive impairments associated with schizophrenia (CIAS). Deficits in NMDA receptor (NMDAR) function contribute to the CIAS and therefore, facilitation of NMDA-R function is one potential treatment approach for CIAS. Glycine transporter inhibitors (GlyT1Is) can enhance NMDAR related plasticity by raising synaptic glycine levels and stimulating the GlycineB co-agonist site of NMDARs. Preclinical data support the potential of GlyT1Is as treatments for the CIAS. PF-03463275 is a Glyt1I inhibitor that has not been tested for treatment of the CIAS. Higher doses of Glyt1Is including PF-03463275 may have a plateauing and/or worsening of effects suggestive of an inverted 'U' dose response. Therefore, it is critical for the optimal therapeutic dose range of GlyT1Is. UH2: The goal of the UH2 is to determine the best dose of PF-03463275. We will use positron emission tomography (PET) imaging to determine the dose-related occupancy of F-03463275 in order to determine whether it reaches its intended target and produces sufficient occupancy to be effective. In parallel, we will use fMRI as an assay of the dose-related GlyT1I facilitation of NMDAR function; we will determine whether PF-03463275 produces dose-related attenuation of the ketamine-induced disruption in prefrontal cortical BOLD activation related to working memory. UH2 Approach: 24 healthy subjects will receive placebo or two active doses of PF-03463275 BID for one week each during each of which, they will undergo a PET scan, long-term potentiation (LTP) session and a Ketamine-fMRI challenge study. UH3: In this phase (UH3), we will test the efficacy of PF-03463275 for CIAS in a novel proof of concept, double-blind, placebo-controlled, between-group study. Pharmacological enhancement of plasticity may not be sufficient to remediate long-standing cognitive dysfunction in the presence of the typical impoverished cognitive environment that patients live in. Therefore, just as physical exercise might optimize the effects of anabolic steroids, this trial wil combine cognitive remediation with PF-03463275 treatment. UH3 Approach: Schizophrenia subjects (n=76) taking risperidone or aripiprazole will be randomized to receive either placebo or active PF-03463275 BID in addition to cognitive remediation. Change in CAIS will be assessed using the Matrics Consensus Cognitive Battery composite score. We will also use visual Long Term Potentiation (LTP), an in vivo measure of NMDA-R-dependent synaptic plasticity, as a novel biomarker of the mechanism of action of PF-03463275. Using this approach, we propose to identify PF-03463275 effects on plasticity as indexed by LTP and to evaluate the capacity of PF- 03463275 to restore this form of neuroplasticity in schizophrenia patients, in whom it is deficient.