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

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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.