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Synthesis and Initial Characterization of a Selective,Pseudo-irreversible Inhibitor of Human Butyrylcholinesterase as PET Tracer |
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| Authors: | Christian Gentzsch Dr. Matthias Hoffmann Dr. Yasuhiro Ohshima Naoko Nose Dr. Xinyu Chen Prof. Dr. Takahiro Higuchi Prof. Dr. Michael Decker |
| Affiliation: | 1. Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, Julius-Maximilians-University of Würzburg, Am Hubland, 97074 Würzburg, Germany These authors contributed equally to this work.;2. Comprehensive Heart Failure Center, University Hospital of Würzburg, Am Schwarzenberg 15, 97078 Würzburg, Germany Department of Nuclear Medicine, University Hospital of Würzburg, Oberdürrbacher Straße 6, 97080 Würzburg, Germany;3. Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama, Japan;4. Department of Nuclear Medicine, University Hospital of Augsburg, Stenglinstraße 2, 86156 Augsburg, Germany Comprehensive Heart Failure Center, University Hospital of Würzburg, Am Schwarzenberg 15, 97078 Würzburg, Germany Department of Nuclear Medicine, University Hospital of Würzburg, Oberdürrbacher Straße 6, 97080 Würzburg, Germany;5. Comprehensive Heart Failure Center, University Hospital of Würzburg, Am Schwarzenberg 15, 97078 Würzburg, Germany;6. Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, Julius-Maximilians-University of Würzburg, Am Hubland, 97074 Würzburg, Germany |
| Abstract: | 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, in vitro and preliminary ex vivo and in vivo 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 18F 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. |
| Keywords: | carbamate enzyme kinetics fluorine-18 positron emission tomography radiotracers |