title: In Vivo Metabolic Trapping Radiotracers for Imaging Monoamine Oxidase-A and -B Enzymatic Activity.
abstract: The isozymes of monoamine oxidase (MAO-A and MAO-B) are important enzymes involved in the metabolism of numerous biogenic amines, including the neurotransmitters serotonin, dopamine, and norepinephrine. Recently, changes in concentrations of MAO-B have been proposed to be an in vivo marker of neuroinflammation associated with Alzheimer's disease. Previous developments of in vivo radiotracers for imaging changes in MAO enzyme expression or activity have utilized the irreversible propargylamine-based suicide inhibitors or high-affinity reversibly binding inhibitors. As an alternative approach, we have investigated 1-[(11)C]methyl-4-aryloxy-1,2,3,6-tetrahydropyridines as metabolic trapping agents for the monoamine oxidases. MAO-mediated oxidation and spontaneous hydrolysis yield 1-[(11)C]methyl-2,3-dihydro-4-pyridinone as a hydrophilic metabolite that is trapped within brain tissues. Radiotracers with phenyl, biphenyl, and 7-coumarinyl ethers were evaluated using microPET imaging in rat and primate brains. No isozyme selectivity for radiotracer trapping was observed in the rat brain for any compound, but in the monkey brain, the phenyl ether demonstrated MAO-A selectivity and the coumarinyl ether showed MAO-B selectivity. These are lead compounds for further development of 1-[(11)C]methyl-4-aryloxy-1,2,3,6-tetrahydropyridines with optimized brain pharmacokinetics and isozyme selectivity.
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, ‡The Interdepartmental Program in Medicinal Chemistry, University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors.forename: Allen F
authors.initials: AF
authors.lastname: Brooks
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, ‡The Interdepartmental Program in Medicinal Chemistry, University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors.forename: Xia
authors.initials: X
authors.lastname: Shao
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, ‡The Interdepartmental Program in Medicinal Chemistry, University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors.forename: Carole A
authors.initials: CA
authors.lastname: Quesada
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, ‡The Interdepartmental Program in Medicinal Chemistry, University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors.forename: Phillip
authors.initials: P
authors.lastname: Sherman
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, ‡The Interdepartmental Program in Medicinal Chemistry, University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors.forename: Peter J H
authors.initials: PJ
authors.lastname: Scott
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, ‡The Interdepartmental Program in Medicinal Chemistry, University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Kilbourn
mesh_terms: D000818:Animals; D002247:Carbon Isotopes / Q000494:pharmacology; D003952:Diagnostic Imaging; D006801:Humans; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D011854:Radiochemistry
chemical_list: D002247:Carbon Isotopes; D008996:Monoamine Oxidase Inhibitors; D008995:Monoamine Oxidase; C579458:monoamine oxidase A, human
keywords: Alzheimer’s disease; carbon-11; monoamine oxidase; neuroimaging; positron emission tomography