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

摘要

src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jmcmar/2017/jmcmar.2017.60.issue-21/acs.jmedchem.7b00764/20171103/images/medium/jm-2017-00764x_0011.gif">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]fluoroethyl)(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.