PI-2620 Lead Optimization Highlights
the Importance of Off-Target Assays to Develop a PET Tracer for the
Detection of Pathological Aggregated Tau in Alzheimer’s Disease
and Other Tauopathies
posted on 2021-08-29, 19:29authored byHeiko Kroth, Felix Oden, Jerome Molette, Hanno Schieferstein, Emanuele Gabellieri, Andre Mueller, Mathias Berndt, Nampally Sreenivasachary, Andreia Monica Serra, Francesca Capotosti, Heribert Schmitt-Willich, David Hickman, Andrea Pfeifer, Ludger Dinkelborg, Andrew Stephens
The first candidate PI-2014 was tested in healthy
controls and subjects with Alzheimer’s disease (AD). As PI-2014 displayed off-target binding to monoamine oxidase
A (MAO-A), a new lead with improved binding to Tau and decreased MAO-A
binding was required. For compound optimization, Tau binding assays
based on both human AD brain homogenate and Tau-paired helical filaments
were employed. Furthermore, two MAO-A screening assays based on (1)
human-recombinant MAO-A and (2) displacement of 2-fluoro-ethyl-harmine
from mouse brain homogenate were employed. Removing the N-methyl group from the tricyclic core resulted in compounds displaying
improved Tau binding. For the final round of optimization, the cyclic
amine substituents were replaced by pyridine derivatives. PI-2620 (2-(2-fluoropyridin-4-yl)-9H-pyrrolo[2,3-b:4,5-c′]dipyridine) emerged as
a best candidate displaying high Tau binding, low MAO-A binding, high
brain uptake, and fast and complete brain washout. Furthermore, PI-2620 showed Tau binding on brain sections from corticobasal
degeneration, progressive supranuclear palsy, and Pick’s disease.