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Purpose Tau deposition is a key pathological feature of Alzheimer’s disease (AD) and other neurodegenerative disorders. The spreading of tau neurofibrillary tangles across defined brain regions corresponds to the observed level of cognitive decline in AD. Positron-emission tomography (PET) has proved to be an important tool for the detection of amyloid-beta (Aβ) aggregates in the brain, and is currently being explored for detection of pathological misfolded tau in AD and other non-AD tauopathies. Several PET tracers targeting tau deposits have been discovered and tested in humans. Limitations have been reported, especially regarding their selectivity. Methods In our screening campaign we identified pyrrolo[2,3- b :4,5- c ’]dipyridine core structures with high affinity for aggregated tau. Further characterization showed that compounds containing this moiety had significantly reduced monoamine oxidase A (MAO-A) binding compared to pyrido[4,3- b ]indole derivatives such as AV-1451. Results Here we present preclinical data of all ten fluoropyridine regioisomers attached to the pyrrolo[2,3- b :4,5- c ’]dipyridine scaffold, revealing compounds 4 and 7 with superior properties. The lead candidate [ 18 F]PI-2620 (compound 7 ) displayed high affinity for tau deposits in AD brain homogenate competition assays. Specific binding to pathological misfolded tau was further demonstrated by autoradiography on AD brain sections (Braak I-VI), Pick’s disease and progressive supranuclear palsy (PSP) pathology, whereas no specific tracer binding was detected on brain slices from non-demented donors. In addition to its high affinity binding to tau aggregates, the compound showed excellent selectivity with no off-target binding to Aβ or MAO-A/B. Good brain uptake and fast washout were observed in healthy mice and non-human primates. Conclusions Therefore, [ 18 F]PI-2620 was selected for clinical validation. Electronic supplementary material The online version of this article (10.1007/s00259-019-04397-2) contains supplementary material, which is available to authorized users.

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