Simple and Highly Efficient Synthesis of 3’-deoxy-3’-[18F]fluorothymidine by Nucleophilic Fluorination Catalyzed by Protic Solvent

Abstract

The aim of this study was to develop a method for the radiochemical synthesis of 3’-deoxy-3’-[18F]fluorothymidine ([18F]FLT) by nucleophilic substitution catalyzed by protic solvent. We introduced t-butanol (t-BuOH) as a new reaction solvent for the nucleophilic [18F]fluorination with [18F]fluoride using (5'-O-DMTr-2'-deoxy-3'-O-nosyl-ß-D-threo-pentofuranosyl)-3-N-BOC-thymine as a precursor to synthesis [18F]FLT. [18F]F- was eluted by 1) elution with tetrabutylammoniumbicarbonate (TBAHCO3), or 2) Cs2CO3 and kryptofix 2.2.2. (K222) after trapping of [18F]F- on ion exchange cartridge, or 3) addition of tetrabutylammonium hydroxide (TBAOH) and [18F]F- to the reactor without trapping of [18F]F- on ion exchange cartridge. We optimized the reaction conditions, and then applied them to automatic synthesis using commercially available radiochemistry modules (TracerLab MX and FX, GE Healthcare). We achieved a high radiochemical yield of 85.3±3.5% after hydrolysis on the radioTLC with TBAHCO3 as an elution solvent and 20 mg of precursor at 100oC. (n=4) With the same labeling condition, use of Cs2CO3 and K222 with t-BuOH and TBAOH with t-BuOH showed radiochemical yields of 57.1±22.5% and 55.0±18.8% on the radioTLC, respectively. (n=3 for each condition) Automated synthesis with TBAHCO3 as an elution solvent, and 20 mg of precursor at 120oC for 10 min [18F]fluorination showed radiochemical yields of 65.5±5.4% and 60.2±5.2% after HPLC purification with FX and MX modules, respectively. (n=10 for each condition) Synthesized [18F]FLT showed good stability for 6 hours. [18F]FLT was synthesized with high radiochemical yield by nucleophilic substitution catalyzed by protic solvent with mild reaction conditions and short preparation time.