Radiochemistry devoted to the production of monoamine oxidase (MAO‐A and MAO‐B) ligands for brain imaging with positron emission tomography

Abstract

Monoamine oxidase (MAO) belongs to a family of flavin-containing integral enzymes that are present in the outer mitochondrial membrane in neurons and glial cells in the central nervous system. These enzymes catalyze the oxidative deamination of various neurotransmitters, biogenic amines, and xenobiotics, thereby influencing their availability and physiological activity in brain and body. Over the past decades, many potential positron emission tomography tracers have been put forward to visualize MAO in the brain with varying success, and recent publications on the topic illustrate the continuing interest in the field. The present review gives an overview of the compounds that have been put forward as possible MAO tracers in the brain and focuses on the radiochemical procedures that have been developed to produce them up till now. Relevant radioligands are grouped by the main radiochemical strategies that have been employed to synthesize them, and some interesting details and findings that are crucial to the radiosyntheses are provided.

11C- and 18F-Radiotracers for In Vivo Imaging of the Dopamine System: Past, Present and Future

“…Although MAO inhibitors are valuable therapeutic agents for disorders such as Parkinson’s disease, they are not candidates for specific dopaminergic imaging agents due to this widespread distribution. Nevertheless, they are an important component of the dopamine system, and have been the target for in vivo PET radiotracer development [ 68 , 69 ]. There have been three approaches to MAO radioligands for PET: suicide inhibitors, reversible antagonists, and metabolic substrates.…”

“…The suicide inhibitors deprenyl and chlorgylline were synthesized in carbon-11 form and demonstrated to be trapped in human brain in proportion to MAO levels, with [ 11 C]deprenyl showing MAO-B selectivity and [ 11 C]chlorgylline MAO-A selectivity [ 70 ]. Improved pharmacokinetics and sensitivity were achieved by selective deuteration of [ 11 C]deprenyl, and 18 F-labeled analogs (e.g., [ 18 F]fluorodeprenyl and [ 18 F]rasagaline), were synthesized in subsequent years [ 68 ]. [ 11 C]Deprenyl and its deuterated form have remained the most utilized MAO radiotracers.…”

“…The extensive medicinal chemistry efforts in MAO inhibitors intended for therapeutic use provided many additional options for new PET radiotracer development, resulting in the preparation of carbon-11 and fluorine-18 labeled radiotracers that function as reversible inhibitors (rather than the suicide inhibitors like deprenyl). Several of these have been successfully introduced into human studies, among them [ 11 C]harmine and [ 11 C]befloxatone [ 68 ].…”

Alternative approaches for PET radiotracer development in Alzheimer's disease: imaging beyond plaque

“…Consequently, MAO‐B has been suggested as a potential therapeutic target and PET biomarker of neuroinflammation and neurodegeneration in AD . Many radiotracers have been developed for imaging MAO‐B by several groups . Established agents for imaging MAO‐B in the clinic include the suicide substrate [ 11 C]‐deprenyl and the deuterated analog [ 11 C]‐deprenyl‐D 2 .…”

Monoamine oxidase: radiotracer chemistry and human studies

“…In this article, we will highlight 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) MAO and drug research. We note that there are earlier reviews on MAO radiotracers and positron emission tomography (PET) and recent reviews of MAO‐A and MAO‐B substrates and radiotracers …”