OBJECTIVE: Identify, design, synthesize and characterize PET/SPECT radiotracers for imaging of tauopathies. Tauopathies are associated with abnormally phosphorylated or folded Tau protein in response to TBI or concussion. Small molecules which bind pathological Tau species are sought. DESCRIPTION: Traumatic Brain Injury (TBI) is a suspected risk factor for neurodegenerative diseases such as Alzheimer"s (1) and Chronic Traumatic Encephalopathies (CTEs) (2). CTEs are associated with concussion/sports injuries. Single Photon Emission Computed Tomography (SPECT) or Positron Emission Tomography (PET) radiotracers are under consideration for routine use in the clinic for diagnosing neurodegenerative disease. Indeed, the PET imaging agent, Fluorbetapir (Amyvid) is now FDA approved for assessing brain neuritic plaques (3) for Alzheimer"s disease. Until Fluorbetapir was approved, confirmation of molecular-level neurodegenerative change in the clinic was limited to a handful of agents or autopsy. Of these agents, none of them are intended to assay specific changes related to TBI. Based on reports which link Tau protein with TBIs and CTEs (4), this topic seeks proposals that will develop small molecules that specifically bind Tau or its pathogenic species. It is anticipated that Phase I will encompass the identification, design, synthesis and characterization of candidate molecules for Tau binding. Successful proposals will identify a specified tau pathological target in the proposal. Candidate molecules may be identified via literature, but a sound plan demonstrating how the agent would be synthesized, characterized and radiolabeled must be included as part of the proposal. Phase II should provide validation of the lead agent (e.g. Phase I Clinical Trials) ahead of FDA approval and commercialization. The successful candidate agent could be used to 1) detect and diagnose tauopathies at their earliest stages, 2) monitor treatment/injury, 3) aid researchers in distinguishing the differences between neurological disease and injury. Proposals should indicate how the marker will impact 1 or more of these research goals. PHASE I: Proposals should contain a rationale for the appropriateness of the lead compound. The proposal should also describe the synthetic chemistry strategy (or equivalent), and provide a plan for radiolabeling the compound(s). It is expected that at the end of Phase I, several candidate radiolabeled agents will be made available for phase 2 funding under an approved IND. A structural validation strategy using analytical chemistry methods (e.g. NMR, UV/VIS, Mass Spectrometry) should be included. No animal/human research will be done as part of Phase I. PHASE II: Phase II funding is expected to characterize several candidate radiolabeled agents in pre-clinical and/or Phase I human studies. The characterization work will validate any lead agent(s) for Phase III SBIR research. Evidence that GMP/GLP manufacturing practices will be enforced should be included as part of the proposal. Studies into the distribution, metabolism and pharmacokinetics of these agents are encouraged, along with a robust plan for assessing safety and efficacy as part of the workplan. The Phase II plan should also include a plan for commercialization and FDA approval. Suggested elements of the proposal narrative concerning commercialization include considering and detailing the anticipated costs and design of Phase II/III Clinical Trials. The Phase II/III Clinical Trials should feature robust neurological endpoints which would illustrate the efficacy of these agents. PHASE III: Sports Injuries, Alzheimer"s disease, and TBIs share tauopathies as a common pathological feature. There is an absence of reliable, quantifiable, non-invasive markers for Tau. This marker could be used to 1) detect and diagnose tauopathies at their earliest stages, 2) monitor treatment/injury, and 3) aid researchers in distinguishing the differences between neurological disease and brain injury. For example, a marker such as this may help in making determinations regarding return to duty (or the practice field) for individuals that have suffered from concussions. Other imaging strategies such as CT and MRI do not currently provide the functional resolution to assess brain injuries over time. SPECT/CT agents are uniquely positioned to longitudinally study brain injuries and response to therapies because they require a chemical tracer to specifically bind to pathological species in the brain. This research could have a large impact on how we understand, diagnose and treat concussion, both domestically and within the military.