Translational Neuroscience Optimization of GlyT1 Inhibitor

GlyT1 抑制剂的转化神经科学优化

• 批准号: 8599140
• 负责人: John H. Krystal
• 金额: $ 180.8万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-18 至 2014-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8599140
• 关键词: Affinity; Agonist; Anabolic steroids; Animals; Antipsychotic Agents; Attention; Binding; Biological Assay; Biological Markers; Blood drug level result; Brain; Brain imaging; Chemicals; Chronic; Clinical Research; Clinical Trials; Cognitive; Cognitive deficits; Cognitive remediation; Consensus; Data; Dose; Double-Blind Method; Environment; Event-Related Potentials; Exercise; Functional Magnetic Resonance Imaging; GLYT1; Glycine; Goals; Human; Image; Impaired cognition; Infusion procedures; Inhibitory Concentration 50; Ketamine; Life; Ligands; Long-Term Potentiation; Measures; Memory; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neuronal Plasticity; Outcome Measure; Patients; Pharmaceutical Preparations; Phase; Placebo Control; Placebos; Plasma; Positron-Emission Tomography; Randomized; Regulation; Risperidone; Schizophrenia; Short-Term Memory; Site; Synapses; Synaptic plasticity; System; Testing; Therapeutic; Treatment Efficacy; Visual; aripiprazole; attenuation; cognitive function; disability; effective therapy; efficacy testing; functional disability; glycine transporter; in vivo; indexing; inhibitor/antagonist; innovation; novel; novel therapeutics; pre-clinical; preclinical study; public health relevance; receptor function; response; translational neuroscience; treatment response

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.

描述（由申请人提供）：背景：认知障碍，没有有效的治疗方法，有助于显着精神分裂症的功能障碍。本申请的目的是使用转化神经科学方法来开发与精神分裂症相关的认知障碍（CIAS）的治疗。NMDA受体（NMDAR）功能缺陷导致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（GlyT 1 Is）可通过提高突触甘氨酸水平和刺激NMDAR的甘氨酸B共激动剂位点来增强NMDAR相关的可塑性。临床前数据支持GlyT 1 Is作为CIAS治疗的潜力。PF-03463275是一种Glyt 1 I抑制剂，尚未进行治疗CIAS的试验。较高剂量的Glyt 1 Is（包括PF-03463275）可能会出现效应稳定期和/或恶化，提示呈倒“U”型剂量反应。因此，GlyT 1 Is的最佳治疗剂量范围至关重要。 UH 2：UH 2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（PET）成像来确定F-03463275的剂量相关占用率，以确定其是否达到预期目标并产生足够的占用率以有效。同时，我们将使用fMRI作为剂量相关GlyT 1 I促进NMDAR功能的试验;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叶皮质BOLD激活中断产生剂量相关衰减。UH 2方法：24例健康受试者将接受安慰剂或两种活性剂量的PF-03463275 BID，每次持续1周，在此期间，他们将接受PET扫描、长时程增强（LTP）治疗和氯胺酮-fMRI激发研究。 UH3：在本阶段（UH 3），我们将在一项新的概念验证、双盲、安慰剂对照、组间研究中检测PF-03463275对CIAS的疗效。可塑性的药理学增强可能不足以补救长期存在的认知功能障碍的患者生活在典型的贫困的认知环境中。因此，正如体育锻炼可能优化合成代谢类固醇的作用一样，本试验将联合收割机认知补救与PF-03463275治疗相结合。UH 3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联合认知补救治疗。将使用矩阵共识认知成套测验综合评分评估CAIS的变化。 我们还将使用视觉长期增强（LTP）（一种NMDA-R依赖性突触可塑性的体内测量方法）作为PF-03463275作用机制的新型生物标志物。使用这种方法，我们建议确定PF-03463275对可塑性的影响，以LTP为指标，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。