Novel imaging agents of oxidative stress in the pathophysiology of the central nervous system

摘要： 活性氧自由基(ROS)在多种疾病的发病和加重中起重要作用。 疾病，包括脑外伤、肌萎缩侧索硬化症、抑郁症、双相情感障碍、成瘾和中风。目前，ROS 在生命系统中直接在中枢神经系统内测量需要终止受试者；因此，非侵入性 支持纵向研究的工具，例如识别CNS的相关二级生物标记物 疾病、监测疾病进展和预测症状的出现，将彻底改变当前的战略和 以大脑中氧化应激为目标的检测。这项研究旨在开发一种临床可翻译的小说 正电子发射断层扫描(PET)显像剂，能够特异性地识别大脑中的ROS。 这一提议具有很高的创新性，因为它试图开发出第一个临床可翻译的氧化应激 麻醉剂；本质上，用于检测和分级大脑内氧化应激的同一分子将 用于治疗特定中枢神经系统疾病中的氧化应激。这将产生巨大的临床影响，因为 例如，Radicava™(依达拉奉注射剂)最近被fda批准用于治疗肌萎缩侧索硬化。 硬化症(ALS)，这是FDA批准的第一种治疗这种疗法-饥饿，虚弱的疾病在近 30年了。不幸的是，只有一小部分肌萎缩侧索硬化症患者对Radicava™疗法有实际反应，这是 考虑到医生无法确定哪些患者会真正做出反应，这是有问题的。此外， Ridicava™的价格为17,000美元/剂，患者的治疗计划极其繁重(Ridicava™是 每天给药超过60分钟，连续14天，然后休息14天，然后进行额外的周期 (如订明的)。我们认为，这个例子突出了抗氧化剂现状的一个关键挑战-- 以治疗策略为基础。在这项提案中，我们将开发一种依达拉奉的PET类似物。我们已经这么做了 进行了18F-依达拉奉类似物的首次放射合成，并表征了 依达拉奉对小鼠中风模型的治疗。我们将从研究两种合成方法开始 其他依达拉奉PET类似物，并表征它们在溶液中的ROS反应性分布和在 体外试验(特异性目标1)。由于依达拉奉PET类似物都是新的化学实体，我们还将 量化每种药物在正常小鼠体内的生物分布(特定目标2A)。展望未来，收集到的数据 特定的目标1和2A将提供一种先导依达拉奉PET试剂，用于在我们的 小鼠中风模型。然后我们将通过量化中风模型中的铅显像剂来验证 中风后氧化应激导致脑组织中依达拉奉蓄积量的测定 显像剂对大脑中氧化应激的敏感性(特定目标2B)。我们的目标是快速临床 翻译先导依达拉奉类似物作为潜在的治疗药物，因此，我们将优先考虑 开发FDA批准所需的强大的放射合成技术。

ABSTRACT: Reactive oxygen species (ROS) play significant roles in the pathogenesis and exacerbation of various diseases, including TBI, ALS, depression, bipolar disorder, addiction, and stroke. Currently, ROS measurement directly within the CNS in living systems requires termination of the subject; thus, a non-invasive tool that would enable longitudinal studies such as identifying relevant secondary biomarkers of the CNS disease, monitor disease progression, and predict symptom onset, would revolutionize current strategies and assays targeting oxidative stress in the brain. This investigation seeks to develop a clinically-translatable novel positron emission tomography (PET) imaging agent capable of specifically identifying ROS within the brain. This proposal is highly innovative as it seeks to develop the first clinically-translatable oxidative stress theranostic agent; in essence, the same molecule used to detect and stage oxidative stress within the brain will be used to treat oxidative stress within the given CNS disease. This will have an enormous clinical impact as for example, Radicava™ (edaravone injection) was recently approved by the FDA to treat amyotrophic lateral sclerosis (ALS), which is the first FDA-approved therapy for this therapy-starved, debilitating disease in nearly 30 years. Unfortunately, only a subset of ALS patients will actually respond to Radicava™ therapy, which is problematic given physicians have no way of identifying which patients will actually respond. Furthermore, Radicava™ costs $17,000/dose and the treatment plan for patients is extremely burdensome (Radicava™ is administered over 60 minutes every day for 14 straight days, then 14 day break, followed by additional cycles as prescribed). We believe that this example highlights a key challenge of the current status of antioxidant- based therapeutic strategies. In this proposal, we will develop a PET analogue of edaravone. We have already performed the first radiosynthesis of an 18F-edaravone analogue and have characterized the efficacy of edaravone therapy in a stroke model of mice. We will start by investigating synthetic methodologies for two additional edaravone PET analogues, and characterize their ROS reactivity profiles in solution and using in vitro assays (Specific Aim 1). As the edaravone PET analogues are all new chemical entities, we will also quantify each agents biodistribution in normal mice (Specific Aim 2A). Moving forward, the data gathered in Specific Aim 1 and 2A will provide a lead edaravone PET agent to pursue imaging oxidative stress in our mouse stroke model. We will then validate the lead imaging agent in our stroke model by quantifying the amount of edaravone accumulated within brain as a result of oxidative stress from stroke and determine sensitivity of the imaging agent to oxidative stress in the brain (Specific Aim 2B). Our goal is rapid clinical translation of the lead edaravone analog for use as a potential theranostic agent, thus, we will prioritize developing robust radiosynthetic techniques needed for FDA approval.