This is a follow-on funding request for project 281205, which seeks to discover candidate radiotracers for premortem diagnosis and staging of Alzheimer's disease (AD) pathology. The proposed agents differ from the current generation of imaging agents by targeting neurofibrillary tangles and other manifestations of tau pathology rather than beta-amyloid (Abeta) plaques. The strategy has the potential to detect disease early in its course and to bring the gold standard of post-mortem diagnosis and staging to the neurology clinic. During the first period of ADDF funding we identified key barriers to progress and established clear target criteria for tau binding affinity, site density, and selectivity relative to Abeta aggregates. In the second period of funding, we conducted a thorough quantitative structure activity relationship analysis of two "hits" that we previously identified by high throughput screening (corresponding to benzothiazole and oxindole scaffolds). This approach allowed us to rigorously quantify the relationship between compound structure and its affinity for tau relative to Abeta aggregates. Most importantly, it identified the structural features that should be optimized to foster high binding potential, and established priorities for in vivo testing. We now request resources to synthesize promising new analogs and to test pharmacokinetic performance in mice. Successfully completed, the proposed experiments should clarify the utility of our compound series, and provide the necessary preliminary data to attract the major resources needed to advance the project.