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

中枢神经系统病理生理学氧化应激的新型显像剂

• 批准号: 10705491
• 负责人: Kiel Neumann
• 金额: $ 133.2万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-16 至 2024-09-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10705491
• 关键词: Novel; imaging; agents; oxidative; stress

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.

摘要： 活性氧（ROS）在各种肿瘤的发病和加重中起重要作用。 疾病，包括TBI、ALS、抑郁症、双相情感障碍、成瘾和中风。目前，ROS 直接在生命系统中的CNS内进行测量需要终止受试者;因此， 一种能够进行纵向研究的工具，例如确定CNS的相关次要生物标志物 疾病，监测疾病进展，并预测症状发作，将彻底改变目前的战略， 针对脑中氧化应激的测定。本研究旨在开发一个临床翻译小说 正电子发射断层扫描（PET）成像剂，其能够特异性地识别脑内的ROS。 这项建议是高度创新的，因为它试图开发第一个临床翻译的氧化应激 治疗诊断剂;本质上，用于检测和分期脑内氧化应激的相同分子将 用于治疗给定CNS疾病中的氧化应激。这将产生巨大的临床影响， 例如，Radicava™（依达拉奉注射液）最近被FDA批准用于治疗肌萎缩侧索硬化症。 硬化症（ALS），这是第一个FDA批准的治疗这种治疗饥饿，衰弱的疾病，在近 30年不幸的是，只有一部分ALS患者对Radicava™治疗有反应， 问题是，医生没有办法确定哪些患者实际上会有反应。此外，委员会认为， Radicava™的价格为17，000美元/剂，患者的治疗计划极其繁重（Radicava™是 每天给药60分钟以上，连续给药14天，然后停药14天，随后进行额外的周期 按规定）。我们认为，这个例子突出了抗氧化剂现状的一个关键挑战- 基于治疗策略。在本提案中，我们将开发依达拉奉的PET类似物。我们已经 进行了18F-依达拉奉类似物的首次放射合成，并表征了 依达拉奉治疗小鼠中风模型。我们将从研究两种合成方法开始， 其他依达拉奉PET类似物，并表征其在溶液中的ROS反应性特征和在 体外试验（特定目标1）。由于依达拉奉PET类似物都是新的化学实体，我们还将 定量每种药剂在正常小鼠中的生物分布（特定目标2A）。接下来，收集到的数据 特定目标1和2A将提供一种领先的依达拉奉PET试剂，以在我们的研究中进行氧化应激成像 小鼠中风模型。然后，我们将通过量化脑卒中模型中的 脑内依达拉奉蓄积量作为中风氧化应激的结果，并确定 成像剂对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 翻译的铅依达拉奉类似物作为一个潜在的治疗诊断剂，因此，我们将优先 开发FDA批准所需的强大的放射合成技术。