Positron Emission Tomography (PET) ligands have advanced Alzheimer's disease (AD) diagnosis and treatment. Using autoradiography and cryo-EM, we identified AD brain tissue with elevated tau burden, purified filaments, and determined the structure of second-generation high avidity PET ligand MK-6240 at 2.31 Å resolution, which bound at a 1:1 ratio within the cleft of tau paired-helical filament (PHF), engaging with glutamine 351, lysine K353, and isoleucine 360. This information elucidates the basis of MK-6240 PET in quantifying PHF deposits in AD and may facilitate the structure-based design of superior ligands against tau amyloids.
Keywords: Alzheimer’s disease (AD); Cryo-electron microscopy (cryo-EM); Neurofibrillary tangles (NFTs); Positron emission tomography (PET); Tau; [18F]MK-6240 PET tracer; atomic resolution; autoradiography; binding affinity; binding agents; in vivo PET imaging; pi-pi aromatic stacking.