Design, Syntheses, and in Vitro Evaluation of New Fluorine-18 Radiolabeled Tau-Labeling Molecular Probes

Deposition
of aggregates of hyperphosphorylated tau protein is
a hallmark of tauopathies like Alzheimer and many other neurodegenerative
diseases. A sensitive and selective method of in vivo detection of
tau-aggregate presence and distribution could provide the means of
an early diagnosis of tau-associated diseases. Furthermore, the use
of selective molecular probes that enable histochemical differentiation
of protein aggregates post-mortem would be advantageous for the insight
into the properties of tau protein aggregates. We chose to design
new molecular probes based on the structure of 2-(1-(6-((2-[18F]­f​luoroethyl)­(methyl)­amino)-2-naphthyl)­ethylidene)­malononitrile
to investigate their likelihood of fitting into VQIVYK tau protein
binding channel model. In a modular approach, using cross-coupling
reactions, we synthesized a series of candidates, radiolabeled them
with fluorine-18 radioisotope, and determined their physicochemical
and in vitro binding properties. Herein we report the synthesis of
a series of molecular probes capable of detection of tau protein deposits
in vitro.