High-yielding, automated radiosynthesis of [¹¹ C]martinostat using [¹¹ C]methyl triflate

Histone deacetylases (HDACs) mediate epigenetic mechanisms implicated in a broad range of central nervous system dysfunction, including neurodegenerative diseases and neuropsychiatric disorders. [¹¹ C]Martinostat allows in vivo quantification of class I/IIb HDACs and may be useful for the quantification of drug-occupancy relationship, facilitating drug development for disease modifying therapies. The present study reports a radiosynthesis of [¹¹ C]martinostat using [¹¹ C]methyl triflate in ethanol, as opposed to the originally described synthesis using [¹¹ C]methyl iodide and DMSO. [¹¹ C]Methyl triflate is trapped in a solution of 2 mg of precursor 1 dissolved in anhydrous ethanol (400 μl), reacted at ambient temperature for 5 min and purified by high-performance liquid chromatography; 1.5-1.8 GBq (41-48 mCi; n = 3) of formulated [¹¹ C]martinostat was obtained from solid-phase extraction using a hydrophilic-lipophilic cartridge in a radiochemical yield of 11.4% ± 1.1% (nondecay corrected to trapped [¹¹ C]MeI), with a molar activity of 369 ± 53 GBq/μmol (9.97 ± 1.3 Ci/μmol) at the end of synthesis (40 min) and validated for human use. This methodology was used at our production site to produce [¹¹ C]martinostat in sufficient quantities of activity to scan humans, including losses incurred from decay during pre-release quality control testing.