Synthesis and Initial Characterization of a Selective, Pseudo‐irreversible Inhibitor of Human Butyrylcholinesterase as PET Tracer

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  • Christian Gentzsch
    Pharmaceutical and Medicinal Chemistry Institute of Pharmacy and Food Chemistry Julius-Maximilians-University of Würzburg Am Hubland 97074 Würzburg Germany
  • Matthias Hoffmann
    Pharmaceutical and Medicinal Chemistry Institute of Pharmacy and Food Chemistry Julius-Maximilians-University of Würzburg Am Hubland 97074 Würzburg Germany
  • Yasuhiro Ohshima
    Comprehensive Heart Failure Center University Hospital of Würzburg Am Schwarzenberg 15 97078 Würzburg Germany
  • Naoko Nose
    Graduate School of Medicine Dentistry and Pharmaceutical Sciences Okayama University 2-5-1 Shikata-cho, Kita-ku Okayama Japan
  • Xinyu Chen
    Department of Nuclear Medicine University Hospital of Augsburg Stenglinstraße 2 86156 Augsburg Germany
  • Takahiro Higuchi
    Comprehensive Heart Failure Center University Hospital of Würzburg Am Schwarzenberg 15 97078 Würzburg Germany
  • Michael Decker
    Pharmaceutical and Medicinal Chemistry Institute of Pharmacy and Food Chemistry Julius-Maximilians-University of Würzburg Am Hubland 97074 Würzburg Germany

抄録

<jats:title>Abstract</jats:title><jats:p>The enzyme butyrylcholinesterase (BChE) represents a promising target for imaging probes to potentially enable early diagnosis of neurodegenerative diseases like Alzheimer's disease (AD) and to monitor disease progression in some forms of cancer. In this study, we present the design, facile synthesis, <jats:italic>in vitro</jats:italic> and preliminary <jats:italic>ex vivo</jats:italic> and <jats:italic>in vivo</jats:italic> evaluation of a morpholine‐based, selective inhibitor of human BChE as a positron emission tomography (PET) tracer with a pseudo‐irreversible binding mode. We demonstrate a novel protecting group strategy for <jats:sup>18</jats:sup>F radiolabeling of carbamate precursors and show that the inhibitory potency as well as kinetic properties of our unlabeled reference compound were retained in comparison to the parent compound. In particular, the prolonged duration of enzyme inhibition of such a morpholinocarbamate motivated us to design a PET tracer, possibly enabling a precise mapping of BChE distribution.</jats:p>

収録刊行物

  • ChemMedChem

    ChemMedChem 16 (9), 1427-1437, 2021-03

    Wiley

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