(300 WORDS MAX)This is a follow-on study to develop radiotracers for differentially diagnosing and staging Alzheimer's disease (AD) through whole brain imaging. Our strategy targets the neurofibrillary lesions composed of tau protein instead of beta-amyloid lesions because the former appear early in the course of disease and correlate well with neurodegeneration as disease progresses. For these reasons, assessment of neurofibrillary pathology is the current gold standard for post-mortem diagnosis and staging of AD. Our project seeks to port this approach to living people. Past support from ADDF/Elan Pharmaceuticals allowed us to conduct a preliminary characterization of binding sites on synthetic tau aggregates, to prepare a new mathematical model of radiotracer pharmacokinetics capable of guiding the discovery process, and to complete a preliminary structure activity relationship for benzothiazole-aryl and oxindole derivatives. Most importantly, it allowed us to address the issue of relative binding selectivity for aggregates composed of tau over beta-amyloid, which is the crucial roadblock that must be overcome in the development of tau-based radiotracers. Results from these studies indicate that synthetic tau aggregates have a greater tolerance for certain ligand substituents relative to beta-amyloid aggregates, and therefore that tau selectivity can be generated by "dialing down" affinity for beta-amyloid. The goal of the current application is to extend these results to radiotracer concentrations, and to build a quantitative structure activity relationship suitable for lead optimization. Successfully completed, this study will reveal the final affinity and selectivity characteristics needed for success, and take us to the key go/no-go decision point of whether to initiate lead optimization. Over the long-term, when combined with emerging therapies for AD, direct premortem detection of tau aggregates has the potential to change the standard of care for this deadly disease.