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

J Med Chem. 2021 Apr 8;64(7):3780-3793. doi: 10.1021/acs.jmedchem.0c01937. Epub 2021 Mar 17.

Abstract

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.

MeSH terms

  • Animals
  • Brain / metabolism*
  • Cell Line
  • Contrast Media / chemical synthesis
  • Contrast Media / metabolism*
  • Cyclopropanes / chemical synthesis
  • Cyclopropanes / metabolism*
  • Drug Design
  • Histone Demethylases / metabolism*
  • Humans
  • Macaca mulatta
  • Male
  • Positron-Emission Tomography
  • Protein Binding
  • Rats
  • Swine

Substances

  • Contrast Media
  • Cyclopropanes
  • Histone Demethylases