A Translational and Neurocomputational Evaluation of a D1R Partial Agonist for Schizophrenia

项目总结 此UO1应用程序是对NIMH计划公告的回应，该计划旨在加快HIGH 通过在生物标志物上建立与剂量相关的药效学效应来优先治疗药物，这些生物标志物旨在为患者提供信息 QUTE临床开发。多巴胺D1受体(D1R)激动剂是最优先考虑的辅助治疗之一 精神分裂症的机制。目前，所有的D1R激动剂也都是D5R激动剂。D1R/D5R激动剂具有前认知功能 以及临床前研究中的抗精神病药样作用，反映了它们稳定额叶前皮质网络活动的能力 通过增强抑制调节来提高空间工作记忆的精确度。 前额叶皮质(PFC)功能连接(FC)。然而，D1R/D5R激动剂在患者中的剂量相关益处不能 在先前的试点研究中得到了证明。这一应用表明，D1R/D5R激动剂的测试需要更多的 直接翻译/计算神经科学框架(即最合适的生物标记物)和精确医学 策略(即适当的患者亚群)。为了加快最佳剂量的选择，我们提出了一种多个 中心研究密集映射D1R/D5R部分激动剂PF-06412562即刻释放(IR)的剂量相关效应， 作为主要观察指标的三种信息性翻译功能神经成像(FMRI)生物标记物的研究：i)SWM相关 研究内容包括：1)激活；2)基于任务的功能障碍；3)早期精神分裂症患者的静息态功能障碍。主要目标1将应用MUL- 对这三个结果度量(SWM相关的激活、基于任务的FC和静息状态FC)的多变量分析策略 测试PF-06412562是否产生剂量相关效应。这种多变量翻译神经标记物的设计和供电 告知关于继续进行全面临床试验的明确的通过/不通过决定。如果出现以下情况，将显示GO决定 通过任务诱发的多变量组合测量的神经信号具有显著的剂量相关药物效应。 在swm任务期间激活和fc，在休息期间fc。相反，如果存在以下情况，将做出不去的决定 对多变量指数没有剂量相关的影响。次要目标2将量化与剂量相关的药物对SWM的影响 基于在功能磁共振期间收集的行为数据的精确度。探索性目标3将模拟PF的生物物理性质- 06412562在能够模拟SWM模拟的皮质回路模型中，该模型将模拟假设的分子机制 治理有利于认知的PF-06412562对SWM的影响。接下来，我们将测试PF-06412562的剂量相关模式 由Allen衍生的人类D1R和D5R受体转录图谱对患者静息FC的影响 人脑图谱。最后，探索性目标4将研究PF-06412562效应的潜在临床预测因子和调节因子。 对神经成像生物标记物有影响。总的来说，这项翻译生物标记物研究为最优先的实验提供了信息 NIMH Matrics Initiative使用精准医学战略确定了治疗机制，该战略针对特定的 可能对D1R/D5R激动剂有认知反应的早期精神分裂症患者亚群。

PROJECT SUMMARY This UO1 application is a response to the NIMH Program Announcement intended to accelerate the development of a high priority therapeutic agent by establishing its dose-related pharmacodynamic effects on biomarkers designed to inform subse- quent clinical development. Dopamine D1 receptor (D1R) agonism is among the most highly prioritized adjunctive treatment mechanisms for schizophrenia. Currently, all D1R agonists are also D5R agonists. D1R/D5R agonists have pro-cognitive and antipsychotic-like effects in preclinical studies, reflecting their ability to stabilize prefrontal cortical network activity in the face of distractors, and to enhance the precision of spatial working memory (sWM) by enhancing inhibitory tuning of prefrontal cortical (PFC) functional connectivity (FC). Yet, dose-related benefits of D1R/D5R agonism in patients could not be demonstrated in prior pilot studies. This application proposes that the testing of D1R/D5R agonists requires both a more direct translational/computational neuroscience framework (i.e., the most appropriate biomarkers) and a precision medicine strategy (i.e., the appropriate subpopulation of patients). To accelerate the selection of an optimal dose, we propose a multi- center study that densely maps the dose-related effects of the D1R/D5R partial agonist, PF-06412562 immediate release (IR), on three informative translational functional neuroimaging (fMRI) biomarkers as primary outcome measures: i) sWM-related activation; ii) task-based FC; and iii) resting-state FC in early course schizophrenia patients. Primary Aim 1 will apply a mul- tivariate analytic strategy to these three outcome measures (sWM-related activation, task-based FC and resting-state FC) to test if PF-06412562 produces a dose-related effect. This multivariate translational neural marker is designed and powered to inform a clear Go/No-Go decision with regards to proceeding to a full-scale clinical trial. A Go decision will be indicated if there is a significant dose-related drug effect on the neural signal measured via the multivariate combination of task-evoked activation and FC during the sWM task and FC during rest. Conversely, a No-Go decision will be reached if there is an absence of a dose-related effect on the multivariate index. Secondary Aim 2 will quantify dose-related drug effects on sWM precision based on behavioral data collected during fMRI. Exploratory Aim 3 will model the biophysical properties of PF- 06412562 in a cortical circuit model capable of sWM simulations, which will simulate hypothesized molecular mechanisms governing pro-cognitive PF-06412562 effects on sWM. In turn, we will will test if the dose-related pattern of PF-06412562 effects on resting FC in patients maps onto D1R and D5R receptor transcriptomic profiles in humans derived from from Allen Human Brain Atlas. Finally, Exploratory Aim 4 will study potential clinical predictors and moderators of PF-06412562 ef- fects on neuroimaging biomarkers. Collectively, this translational biomarker study informs the highest priority experimental treatment mechanism identified by the NIMH MATRICS Initiative using a precision medicine strategy that targets a specific subpopulation of early course schizophrenia patients who may pro-cognitively respond to D1R/D5R agonism.