Synthesis and Initial Characterization of a Selective, Pseudo‐irreversible Inhibitor of Human Butyrylcholinesterase as PET Tracer. (1st March 2021)

• Record Type: Journal Article
• Authors: Gentzsch, Christian; Hoffmann, Matthias; Ohshima, Yasuhiro; Nose, Naoko; Chen, Xinyu; Higuchi, Takahiro; Decker, Michael
• Is Part Of: ChemMedChem. Volume 16:Number 9(2021)
• Page Start: 1427
• Page End: 1437
• Publication Date: 2021-03-01
• Subjects: carbamate -- enzyme kinetics -- fluorine-18 -- positron emission tomography -- radiotracers; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202000942
• Languages: English
• ISSNs: 1860-7179

Abstract

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 18 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. Abstract : PET tracer : A pseudo‐irreversible butyrylcholinesterase inhibitor with prolonged duration of action, high inhibitory potency and pronounced selectivity was used to design an 18 F‐labeled radiotracer for positron emission tomography. Syntheses and a new protecting group strategy for radiolabeling carbamates are presented, binding and kinetics are investigated, and the radiotracer is tested in ex vivo autoradiography and in vivo microPET studies.