Abstract
Monoamine oxidase B (MAO-B) is an important enzyme regulating the levels of monoaminergic neurotransmitters. Selective MAO-B inhibitors have been labeled with carbon-11 or fluorine-18 to visualize the localization of MAO-B in vivo by positron emission tomography (PET) and thereby have been useful for studying neurodegenerative diseases. The aim of this study was to develop promising fluorine-18 labeled reversible MAO-B PET radioligands and their biological evaluation in vitro by autoradiography. Radiolabeling was achieved by classical one-step fluorine-18 nucleophilic substitution reaction. The stability and radiochemical yield was analyzed with HPLC. All five fluorine-18 labeled compounds were tested in human whole hemisphere autoradiography experiments. Five compounds (GEH200439, GEH200448, GEH200449, GEH200431A, and GEH200431B) were successfully radiolabeled with fluorine-18, and the incorporation yield of the fluorination reactions varied from 10 to 45% depending on the compound. The radiochemical purity was higher than 99% for all at the end of synthesis. Radioligands were found to be stable, with a radiochemical purity of >99% in a sterile phosphate buffered saline (pH = 7.4) over the duration of the study. The ARG binding density of only 18F-GEH200449 was consistent with known MAO-B expression in the human brain. Radiolabeling of five new fluorine-18 MAO-B reversible inhibitors was successfully accomplished. Compound 18F-GEH200449 binds specifically to MAO-B in vitro postmortem brain and could be a potential candidate for in vivo PET investigation.
Highlights
Monoamine oxidase is an intracellular enzyme mounted in the outer membrane of mitochondria in neuronal and nonneuronal cells in the brain and in most cell types of peripheral organs.[1]
monoamine oxidase (MAO) Type B” (MAO-B) is predominantly expressed in various parts of the CNS and has been estimated to constitute up to ∼70% of total brain MAO activity.[2]
Because of the enzymes’ central role in the neurotransmitter metabolism, MAO-B has since long been established as a target in the pharmacological therapy of psychiatric disorders such as depression[5] and social anxiety[6] as well as in Parkinson’s disease (PD).[7]
Summary
Monoamine oxidase is an intracellular enzyme mounted in the outer membrane of mitochondria in neuronal and nonneuronal cells in the brain and in most cell types of peripheral organs.[1]. The ARG binding density of only 18F-GEH200449 was consistent with known MAO-B expression in the human brain. Compound 18F-GEH200449 binds to MAO-B in vitro postmortem brain and could be a potential candidate for in vivo
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