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.