Design, Synthesis, and Evaluation of (2-Aminocyclopropyl)phenyl Derivatives as Novel Positron Emission Tomography Imaging Agents for Lysine-Specific Demethylase 1 in the Brain

Dysregulation of
histone H3 lysine 4 (H3K4) methylation is implicated
in the pathogenesis of neurodevelopmental disorders. Lysine-specific
demethylase 1 (LSD1) determines the methylation status of H3K4 through
flavin adenine dinucleotide (FAD)-mediated histone demethylation.
Therefore, LSD1 inhibition in the brain can be a novel therapeutic
option for treating these disorders. Positron emission tomography
(PET) imaging of LSD1 allows for investigating LSD1 expression levels
under normal and disease conditions and validating target engagement
of therapeutic LSD1 inhibitors. This study designed and synthesized
(2-aminocyclopropyl)­phenyl derivatives with irreversible binding to
LSD1 as PET imaging agents for LSD1 in the brain. We optimized lipophilicity
of the lead compound to minimize the risk of nonspecific binding and
identified 1e with high selectivity over monoamine oxidase
A and B, which are a family of FAD-dependent enzymes homologous to
LSD1. PET imaging in a monkey showed a high uptake of [18F]1e to regions enriched with LSD1, indicating its specific
binding to LSD1.