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

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 and 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00259-016-3510-6) contains supplementary material, which is available to authorized users.