Simple and highly efficient synthesis of 3′-deoxy-3′-[¹⁸F]fluorothymidine using nucleophilic fluorination catalyzed by protic solvent

Abstract

Purpose

The aim of this study was to develop a method of radiochemical synthesis of 3′-deoxy-3′-[¹⁸F]fluorothymidine ([¹⁸F]FLT) with an improved radiochemical yield using nucleophilic substitution catalyzed by protic solvent.

Methods

We introduced t-butanol (t-BuOH) as a new reaction solvent for nucleophilic [¹⁸F]fluorination with [¹⁸F]fluoride using (5′-O-DMTr-2′-deoxy-3′-O-nosyl-β-D-threo-pentofuranosyl)-3-N-BOC-thymine to synthesize [¹⁸F]FLT. [¹⁸F]F⁻ was eluted with (1) tetrabutylammonium bicarbonate (TBAHCO₃), (2) Cs₂CO₃ and kryptofix 2.2.2 (K₂₂₂) after trapping of [¹⁸F]F⁻ on an ion exchange cartridge, or (3) addition of tetrabutylammonium hydroxide (TBAOH) and [¹⁸F]F⁻ to the reactor without trapping [¹⁸F]F⁻ on an ion exchange cartridge. We optimized [¹⁸F]fluorination conditions with t-butanol and then applied them to automatic synthesis using commercially available radiochemistry modules (TracerLab MX, GE Healthcare).

Results

We achieved a high radiochemical yield of 85.3 ± 3.5% by radio-TLC with TBAHCO₃ as an elution solvent and 20 mg of precursor at 100°C (n = 4). With the same labeling conditions, use of Cs₂CO₃ and K₂₂₂ with t-BuOH and TBAOH with t-BuOH generated radiochemical yields of 57.1 ± 22.5% and 55.0 ± 18.8% by radio-TLC, respectively (n = 3 for each condition). Automated synthesis with TBAHCO₃ and 20 mg of precursor at 120°C for 10 min of [¹⁸F]fluorination led to radiochemical yields of 60.2 ± 5.2% after HPLC purification with an MX module (n = 10). Synthesized [¹⁸F]FLT was stable for 6 h.

Conclusion

[¹⁸F]FLT was synthesized with a significantly improved radiochemical yield by nucleophilic substitution catalyzed by protic solvent with mild reaction conditions and a short preparation time.