Monoamine oxidase: radiotracer chemistry and human studies

Abstract

Monoamine oxidase (MAO) oxidizes amines from both endogenous and exogenous sources thereby regulating the concentration of neurotransmitter amines such as serotonin, norepinephrine, and dopamine as well as many xenobiotics. MAO inhibitor drugs are used in the treatment of Parkinson's disease and in depression stimulating the development of radiotracer tools to probe the role of MAO in normal human biology and in disease. Over the past 30 years since the first radiotracers were developed and the first positron emission tomography (PET) images of MAO in humans were carried out, PET studies of brain MAO in healthy volunteers and in patients have identified different variables that have contributed to different MAO levels in brain and in peripheral organs. MAO radiotracers and PET have also been used to study the current and developing MAO inhibitor drugs including the selection of doses for clinical trials. In this article, we describe the following: (1) the development of MAO radiotracers; (2) human studies including the relationship of brain MAO levels to genotype, personality, neurological, and psychiatric disorders; and (3) examples of the use of MAO radiotracers in drug research and development. We will conclude with outstanding needs to improve the radiotracers that are currently used and possible new applications.

Molecular aspects of monoamine oxidase B

“…In order to see elevation of brain amines in humans, more than 90% inhibition of MAO is required (Fowler et al, 2015). The altered amine balance as a result of MAO inhibition then initiates a process of change in the CNS, with a lag of around three weeks before effects on mood are detected.…”

“…Conversely, most of the MAO inhibitors in common use are irreversible inhibitors so recovery from inhibition is slow (Fowler et al, 1996, Zajecka andZajecka, 2014). It should be noted that, although PET scans are the method of choice for measuring the levels of active MAO in the brain, the method does not measure changes in the brain amines (Fowler et al, 2015).…”

“…Multiple ligands for MAO A or for MAO B are now available and the pharmacokinetics are well understood, as reviewed in (Fowler et al, 2015) . An irreversible ligand such as deprenyl requires active MAO B to form the adduct, so serves as an in vivo measurement of both protein and activity; reversible ligands measure only protein levels.…”

“…For the best pharmacological effect, MAO B must be more than 90% inhibited (Fowler et al, 2005). The recovery of MAO B in human brain was followed using PET, revealing a recovery period of about 40 days (Fowler et al, 2005, Fowler et al, 2015. enzyme is added to the substrate and inhibitor at the same time.…”

“…The interest in drug design to increase monoamine levels is reflected in a constant stream of reviews. Several reviews in the last 5 years provide the wider background to MAO (Bortolato and Shih, 2011, Youdim and Reiderer, 2011, Ramsay, 2012, Song et al, 2013, Fowler et al, 2015 This review will include key references for the established facts but focus on examples of recent research on the expression, activity and inhibition of MAO B.…”