Translational Neuroscience Optimization of GlyT1 Inhibitor

背景：认知障碍是导致精神分裂症患者功能障碍的重要因素，目前尚无有效的治疗方法。本应用程序的目标是使用转化神经科学方法开发与精神分裂症（CIAS）相关的认知障碍的治疗方法。NMDA受体（NMDAR）功能的缺陷有助于CIAS，因此，促进NMDA- r功能是CIAS的一种潜在治疗方法。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NMDARs的GlycineB共激动剂位点来增强NMDAR相关的可塑性。临床前数据支持glyt1 - is治疗CIAS的潜力。PF-03463275是一种Glyt1I抑制剂，尚未被测试用于治疗CIAS。较高剂量的Glyt1Is（包括PF-03463275）可能会出现稳定和/或效应恶化，提示倒“U”型剂量反应。因此，确定glyt1 - is的最佳治疗剂量范围至关重要。UH2: UH2的目的是确定PF-03463275的最佳剂量。我们将使用正电子发射断层扫描（PET）成像来确定F-03463275的剂量相关占位率，以确定它是否达到预定目标并产生足够的有效占位率。同时，我们将使用fMRI作为NMDAR功能的剂量相关GlyT1I促进的分析；我们将确定PF-03463275是否对氯胺酮诱导的与工作记忆相关的前额皮质BOLD激活的破坏产生剂量相关的衰减。UH2方法：24名健康受试者将接受安慰剂或两种活性剂量的PF-03463275 BID，各为期一周，在每次治疗期间，他们将接受PET扫描、长期增强（LTP）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验证、双盲、安慰剂对照、组间研究中测试PF-03463275对CIAS的疗效。在患者所处的典型认知环境贫乏的情况下，药物增强可塑性可能不足以修复长期存在的认知功能障碍。因此，正如体育锻炼可以优化合成代谢类固醇的效果一样，该试验将认知修复与PF-03463275治疗相结合。UH3方法：服用利培酮或阿立哌唑的精神分裂症受试者（n=76）将随机接受安慰剂或活性PF-03463275 BID以及认知修复。CAIS的变化将使用matrix Consensus Cognitive Battery综合评分进行评估。我们还将使用视觉长时程增强（LTP）作为nf -03463275作用机制的新生物标志物，LTP是一种体内测量nmda - r依赖性突触可塑性的方法。使用这种方法，我们建议确定PF-03463275对LTP指标的可塑性的影响，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。

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.