Design and radiosynthesis of class-IIa HDAC inhibitor with high molar activity via repositioning the 18F-radiolabel

Sci Rep. 2024 Jul 2;14(1):15100. doi: 10.1038/s41598-024-65668-z.

Abstract

The design and radiosynthesis of [18F]NT376, a high potency inhibitor of class-IIa histone deacetylases (HDAC) is reported. We utilized a three-step radiochemical approach that led to the radiosynthesis of [18F]NT376 in a good radiochemical yield, (17.0 ± 3%, decay corrected), high radiochemical purity (> 97%) and relatively high molar activity of 185.0 GBq/µmol (> 5.0 Ci/µmol). The repositioning of the 18F-radiolabel into a phenyl ring (18F-Fluoro-aryl) of the class-IIa HDAC inhibitor avoided the shortcomings of the direct radiolabeling of the 5-trifluoromethyl-1,2,4-oxadiazole moiety that was reported by us previously and was associated with low molar activity (0.74-1.51 GBq/µmol, 20-41 mCi/µmol). This radiochemical approach could find a wider application for radiolabeling similar molecules with good radiochemical yield and high molar activity.

MeSH terms

  • Drug Design
  • Fluorine Radioisotopes* / chemistry
  • Histone Deacetylase Inhibitors* / chemical synthesis
  • Histone Deacetylase Inhibitors* / chemistry
  • Histone Deacetylase Inhibitors* / pharmacology
  • Humans
  • Oxadiazoles / chemical synthesis
  • Oxadiazoles / chemistry
  • Radiochemistry / methods
  • Radiopharmaceuticals* / chemical synthesis
  • Radiopharmaceuticals* / chemistry

Substances

  • Histone Deacetylase Inhibitors
  • Fluorine Radioisotopes
  • Radiopharmaceuticals
  • Fluorine-18
  • Oxadiazoles