Radiosynthesis of ¹¹C-phenytoin Using a DEGDEE Solvent for Clinical PET Studies

Phenytoin is an antiepileptic drug that is used worldwide. The whole-body pharmacokinetics of this drug have been extensively studied using ¹¹C-phenytoin in small animals. However, because of the limited production amounts that are presently available, clinical ¹¹C-phenytoin PET studies to examine the pharmacokinetics of phenytoin in humans have not yet been performed. We aimed to establish a new synthesis method to produce large amounts of ¹¹C-phenytoin to conduct human studies.

[¹¹C] methane was produced using an in-house cyclotron by the ¹⁴N (p, α) ¹¹C nuclear reaction of 5 % of hydrogen containing 95 % of nitrogen gas. About 30 GBq of ¹¹C-methane was then transferred to a homogenization cell containing Fe₂O₃ powder mixed with Fe granules heated at 320 ⁰C to yield ¹¹C-phosgene. Xylene, 1,4-dioxane, and diethylene glycol diethyl ether (DEGDEE) were investigated as possible reaction solvents.

The ratio of ¹¹C-phenytoin radioactivity to the total ¹¹C radioactivity in the reaction vessel (reaction efficiency) was 7.5% for xylene, 11% for 1,4-dioxane, and 37% for DEGDEE. The synthesis time was within 45 min from the end of bombardment until obtaining the final product. The radioactivity produced was more than 4.1 GBq in 10 mL of saline at the end of synthesis. The specific activity of the product ranged from 1.7 to 2.2 GBq/μmol. The quality of the [¹¹C] phenytoin injection passed all criteria required for clinical use.

The use of DEGDEE as a solvent enabled the production of a large amount of ¹¹C-phenytoin sufficient to enable PET studies examining the human pharmacokinetics of phenytoin.