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European Journal of Nuclear Medicine and Molecular Imaging
Published in: European Journal of Nuclear Medicine and Molecular Imaging 10/2019

Open Access 01-09-2019 | Frontotemporal Dementia | Original Article

Discovery and preclinical characterization of [18F]PI-2620, a next-generation tau PET tracer for the assessment of tau pathology in Alzheimer’s disease and other tauopathies

Authors: Heiko Kroth, Felix Oden, Jerome Molette, Hanno Schieferstein, Francesca Capotosti, Andre Mueller, Mathias Berndt, Heribert Schmitt-Willich, Vincent Darmency, Emanuele Gabellieri, Cédric Boudou, Tanja Juergens, Yvan Varisco, Efthymia Vokali, David T. Hickman, Gilles Tamagnan, Andrea Pfeifer, Ludger Dinkelborg, Andreas Muhs, Andrew Stephens

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 10/2019

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Abstract

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 [18F]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, [18F]PI-2620 was selected for clinical validation.
Appendix
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Metadata
Title
Discovery and preclinical characterization of [18F]PI-2620, a next-generation tau PET tracer for the assessment of tau pathology in Alzheimer’s disease and other tauopathies
Authors
Heiko Kroth
Felix Oden
Jerome Molette
Hanno Schieferstein
Francesca Capotosti
Andre Mueller
Mathias Berndt
Heribert Schmitt-Willich
Vincent Darmency
Emanuele Gabellieri
Cédric Boudou
Tanja Juergens
Yvan Varisco
Efthymia Vokali
David T. Hickman
Gilles Tamagnan
Andrea Pfeifer
Ludger Dinkelborg
Andreas Muhs
Andrew Stephens
Publication date
01-09-2019
Publisher
Springer Berlin Heidelberg
Published in
European Journal of Nuclear Medicine and Molecular Imaging / Issue 10/2019
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI
https://doi.org/10.1007/s00259-019-04397-2

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