Positron emission tomography measurement of brain MAO-B inhibition in patients with Alzheimer's disease and elderly controls after oral administration of sembragiline

Stefan Sturm, Anton Forsberg, Stephane Nave, Per Stenkrona, Nicholas Seneca, Andrea Varrone, Robert A. Comley, Patrik Fazio, Candice Jamois, Ryuji Nakao, Zbigniew Ejduk, Nabil Al-Tawil (+4 others)
2016 European Journal of Nuclear Medicine and Molecular Imaging  
Purpose In Alzheimer's disease (AD), increased metabolism of monoamines by monoamine oxidase type B (MAO-B) leads to the production of toxic reactive oxygen species (ROS), which are thought to contribute to disease pathogenesis. Inhibition of the MAO-B enzyme may restore brain levels of monoaminergic neurotransmitters, reduce the formation of toxic ROS and reduce neuroinflammation (reactive astrocytosis), potentially leading to neuroprotection. Sembragiline (also referred as RO4602522, RG1577
more » ... d EVT 302 in previous communications) is a potent, selective and reversible inhibitor of MAO-B developed as a potential treatment for AD. Methods This study assessed the relationship between plasma concentration of sembragiline and brain MAO-B inhibition in patients with AD and in healthy elderly control (EC) subjects. Positron emission tomography (PET) scans using [ 11 C]-L -deprenyl-D 2 radiotracer were performed in ten patients with AD and six EC subjects, who received sembragiline each day for 6-15 days. Results At steady state, the relationship between sembragiline plasma concentration and MAO-B inhibition resulted in an E max of ∼80-90 % across brain regions of interest and in an EC 50 of 1-2 ng/mL. Data in patients with AD and EC subjects showed that near-maximal inhibition of brain MAO-B was achieved with 1 mg sembragiline daily, regardless of the population, whereas lower doses resulted in lower and variable brain MAO-B inhibition. Conclusions This PET study confirmed that daily treatment of at least 1 mg sembragiline resulted in near-maximal inhibition of brain MAO-B enzyme in patients with AD.
doi:10.1007/s00259-016-3510-6 pmid:27633250 pmcid:PMC5281649 fatcat:lieuojdjy5fzje2uee5egzdiwu