Ligand polarizability contributes to tau fibril binding affinity

Whole brain imaging of tau-bearing neurofibrillary lesions has the potential to improve the premortem diagnosis and staging of Alzheimer's disease. Diverse compounds with high affinity for tau aggregates have been reported from high-throughput screens, but the affinity driving features common among them have not been determined. To identify these features, analogs of compounds discovered by high-throughput screening, including phenothiazine, triarylmethine, benzothiazole, and oxindole derivatives, were tested for their ability to displace fluorescent thioflavin dyes from filaments made from recombinant tau protein or authentic paired helical filaments purified from Alzheimer's disease tissue. When representative members of all scaffolds were assayed, the rank order of binding affinity determined for synthetic and authentic filaments correlated strongly, indicating that synthetic filaments have predictive utility for ligand development. Within individual scaffold families, binding affinity was found to correlate with compound polarizability, consistent with a role for dispersion forces in mediating ligand binding. Overall, the data indicate that polarizability is an important commonality among structurally diverse tau binding ligands, and that affinity for tau aggregates can be maximized by integrating formal assessment of this parameter into ligand discovery efforts. (C) 2011 Elsevier Ltd. All rights reserved.