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Depositions of fibrillary tau protein aggregates are implicated in diverse tauopathies, including Alzheimers disease (AD) and frontotemporal lobar degeneration (FTLD). A panel of radiochemicals has enabled in-vivo positron emission tomography (PET) of AD tau pathologies composed of all six tau isoforms, while sensitive detection of FTLD tau inclusions, mostly consisting of tau isoforms with three or four repeat domains only, has been unsuccessful. Here, we generated an imaging probe, PM-PBB3, for capturing tau deposits with all isoform composites. In-vitro assays demonstrated the reactivity of this compound with tau pathologies in AD, four-repeat tauopathies such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), and three-repeat tauopathies represented by Picks disease (PiD). We could also utilize PM-PBB3 for bimodal, multiscale optical/PET imaging of a living murine tauopathy model. A subsequent clinical PET study revealed increased binding of radiolabeled 18F-PM-PBB3 in diseased patients, reflecting cortical-dominant AD and subcortical-dominant PSP tau topologies. Notably, the in-vivo reactivity of 18F-PM-PBB3 with three- and four-repeat tau lesions was strongly supported by neuropathological examinations of autopsied and biopsied brains derived from PiD, PSP and CBD patients who underwent PET scans. Finally, visual inspection of 18F-PM-PBB3-PET images was indicated to facilitate individually based identification of the neuropathological basis, composed of PSP, CBD and PiD, underlying the diverse clinical phenotypes of FTLD. Taking these findings together, we propose the new tau probe as a powerful tool for etiological, diagnostic and therapeutic PET assessments of the tau pathogenesis in AD and FTLD spectra at nonclinical and clinical levels. One Sentence SummaryWe developed a positron emission tomography probe for tau fibrils in an animal model and patients with Alzheimers disease and non-Alzheimers disease tauopathies with high contrast, enabling translational assessments of the tau pathogenesis and diagnostic evaluations of disease-specific and stage-dependent tau topologies on an individual basis.

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