Discovery of 2-(4-(2-fluoroethoxy)piperidin-1-yl)-9-methyl-9H-pyrrolo[2,3-b:4,5-c']dipyridine ([18F]PI-2014) as PET tracer for the detection of pathological aggregated tau in Alzheimer's disease and other tauopathies.

The compound screening was initiated with a direct staining assay to identify compounds binding to Tau aggregates and not Abeta plaques using human brain sections derived from late stage Alzheimer's disease donors. The binding of Tau aggregate selective compounds was then quantitatively assessed with human brain derived paired helical filaments utilizing the label-free Back Scattering Interferometry assay. In vivo biodistribution experiments of selected fluorine-18 labeled compounds were performed in mice to assess brain uptake, brain washout, and defluorination. Compound 11 emerged as the most promising candidate, displaying high in vitro binding affinity and selectivity to neurofibrillary tangles. Fluorine-18 labeled compound 11 showed high brain uptake and rapid washout from the mouse brain with no observed bone uptake. Furthermore, compound 11 was able to detect Tau aggregates in tauopathy brain sections from corticobasal degeneration, progressive supranuclear palsy, and Pick's disease donors. Thus, 2-(4-(2-fluoroethoxy)piperidin-1-yl)-9-methyl-9H-pyrrolo[2,3-b:4,5-c']dipyridine (PI-2014, compound 11) was selected for characterization in a first-in-human study.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Emanuele Gabellieri, Heiko Kroth, Francesca Capotosti, Jerome Molette, Nampally Sreenivasachary, Tanja Juergens, Yvan Varisco, David Hickman, Andrea Pfeifer are employees of AC Immune SA. Andre Mueller, Mathias Berndt, Felix Oden, Heribert Schmitt-Willich, Ludger Dinkelborg, Andrew Stephens are employees of Life Molecular Imaging GmbH. Hanno Schieferstein was an employee of Piramal Imaging GmbH (currently at Merck KGaA).
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