Journal
ACS CHEMICAL NEUROSCIENCE
Volume 6, Issue 12, Pages 1965-1971Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.5b00223
Keywords
Alzheimer's disease; neuroimaging; positron emission tomography; carbon-11; monoamine oxidase
Funding
- National Institutes of Health (National Institute of Neurological Diseases and Stroke) [1R21 NS075553]
- National Institutes of Health (National Institute of Biomedical Imaging and Bioengineering) [T32-EB005172]
- Alzheimer's Association [NIRP-14-305669]
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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-[C-11]methyl-4-aryloxy-1,2,3,6-tetrahydropyridines as metabolic trapping agents for the monoamine oxidases. MAO-mediated oxidation and spontaneous hydrolysis yield 1-[C-11]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-[C-11]methyl-4-aryloxy-1,2,3,6-tetrahydropyridines with optimized brain pharmacokinetics and isozyme selectivity.
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