title: A Novel Way To Radiolabel Human Butyrylcholinesterase for Positron Emission Tomography through Irreversible Transfer of the Radiolabeled Moiety.
abstract: The enzyme butyrylcholinesterase (BChE) is known to be involved in the detoxification of xenobiotics in blood plasma and is associated with the progress of neurodegenerative disorders, diabetes type 2, obesity, and diseases of the cardiovascular system. In the present study, we developed carbamate-based inhibitors serving as positron emission tomography (PET) radiotracers with (18) F and (11) C as radioisotopes to visualize BChE distribution. These inhibitors are radiolabeled at the carbamate site and transfer this moiety onto BChE, which thus results in covalent and permanent radiolabeling of the enzyme. There are no comparable radiotracers for cholinesterases described to date. By ex vivo autoradiography experiments on mice brain slices and kinetic investigations, selective and covalent transfer of the radiolabeled carbamate moiety onto BChE was proven. These tracers might provide high resolution of BChE distribution in vivo to enable investigations into the pathophysiological mechanisms of diseases associated with alterations in BChE occurrence.
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, Julius Maximilian University Würzburg, Am Hubland, 97074, Würzburg, Germany.
authors.forename: Edgar
authors.initials: E
authors.lastname: Sawatzky
authors.affiliation: Experimental Nuclear Medicine, Center of Inner Medicine, University Hospital Würzburg, OberdürrbacherStrasse 6, 97080, Würzburg, Germany.
authors.forename: Ehab
authors.initials: E
authors.lastname: Al-Momani
authors.affiliation: Experimental Nuclear Medicine, Center of Inner Medicine, University Hospital Würzburg, OberdürrbacherStrasse 6, 97080, Würzburg, Germany.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Kobayashi
authors.affiliation: Experimental Nuclear Medicine, Center of Inner Medicine, University Hospital Würzburg, OberdürrbacherStrasse 6, 97080, Würzburg, Germany.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Higuchi
authors.affiliation: Experimental Nuclear Medicine, Center of Inner Medicine, University Hospital Würzburg, OberdürrbacherStrasse 6, 97080, Würzburg, Germany.
authors.forename: Samuel
authors.initials: S
authors.lastname: Samnick
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, Julius Maximilian University Würzburg, Am Hubland, 97074, Würzburg, Germany. Michael.Decker@uni-wuerzburg.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Decker
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000201:enzymology; D002091:Butyrylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D002250:Carbon Radioisotopes; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D005462:Fluorine Radioisotopes; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D051379:Mice; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
chemical_list: C000622562:13-methyl-5,8,13,13a-tetrahydro-6H-isoquinolino(1,2-b)quinazolin-10-yl (7-fluoroheptyl)carbamate; D002219:Carbamates; D002250:Carbon Radioisotopes; D002800:Cholinesterase Inhibitors; D005462:Fluorine Radioisotopes; D006576:Heterocyclic Compounds, 4 or More Rings; D019275:Radiopharmaceuticals; C000622563:tetrahydro-13-methyl-5H-isoquinolino(1,2-b)quinazolin-10-yl heptylcarbamate; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: carbamates; inhibitors; irreversible labeling; isotopic labeling; radiopharmaceuticals