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Synthesis and selective 2H-, 13C-, and 15N-labeling of the Tau protein binder THK-523

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A new synthetic route to the Tau binder, THK-523, is disclosed herein, which can easily be adapted to 13C- and D-isotope labeling. The synthesis proceeds via two key reactions, namely, a Pd-catalyzed carbonylative Sonogashira coupling and a reductive ring-closing step with hydrogen or deuterium gas. By carrying out these reactions in a 2-chamber reactor we reported previously, ex situ-generated carbon monoxide and hydrogen/deuterium can be applied in stoichiometric quantities, thereby facilitating isotope labeling of this Tau-binding compound. Iridium-catalyzed hydrogen isotope exchange (HIE) reactions were performed on THK-523 and its 13C-labeled analog providing access to 4 additional analogues labeled with deuterium as well. Finally, by applying a Buchwald-Hartwig coupling, we were able to prepare a 15N-THK-523 variant with the isotope label in the quinoline ring system.

Original languageEnglish
JournalJournal of Labelled Compounds and Radiopharmaceuticals
Pages (from-to)30-35
Publication statusPublished - Jan 2017

    Research areas

  • Alzheimer disease, Buchwald-Hartwig coupling, Carbonylative sonogashira coupling, Hydrogen isotope exchange, Isotope labeling, Tau binder

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