Microfluidic synthesis of [¹⁸F]FLT

Objectives We report here the automated production of 3’-deoxy-3’-[F-18]fluoro-thymidine using a flow-based microfluidic chemistry system.

Methods The NanoTek LF is a modular flow-based microreactor assembly. Using the ABX Boc-dimethoxytrityl-nosyl-thymidine precursor in the “Discovery Mode” of the NanoTek LF software, the incorporation of the fluoride was optimized for temperature and flow rates through the reactor. The optimum flow rate used in the radiosynthesis was 200 µl/min with a reaction temperature of 170° C on a 100 µm i.d. X 2 m reactor and resulted in an incorporation yield of fluoride of 82 ± 3% (n=20) as determined by radio-TLC. The product from the microreactor was then hydrolyzed, followed by neutralization and purified by semi-prep HPLC, using PBS with 8% ethanol (v:v).

Results Starting with 500 mCi of [¹⁸F]-fluoride (recycled O-18 water), the radiochemical yield of [¹⁸F]FLT was 18-25% (uncorr.) after semi-prep HPLC, with a reaction time of 65 minutes, specific activity of 2 Ci/µmol and rad. purity of >99%. The material was then used for imaging pulmonary tumors in C57Bl/6 mice that had been injected with 50,000 B16F10 tumor cells in 0.2 mL of PBS in the lateral tail vein. After a 21-day period of tumor growth the animals received ~ 220 µCi (8.1 MBq) of [¹⁸F]FLT and were left for 1 h before being imaged by PET/CT using an energy window of 350-650 keV. The data were reconstructed onto a 256 × 256 × 159 matrix (0.22 × 0.22 × 0.80 mm voxel dimensions) using a maximium a posteriori (MAP) algorithm with zoom set at 2 and a β value of 0.001.

Conclusions This work has demonstrated the use of microfluidics to rapidly radiolabel and purify 3’-deoxy-3’-[¹⁸F]fluoro-thymidine (FLT) in sufficient quantity, purity and specific activities for small animal imaging.

Research Support University of Tennessee Physician's Medical Education and Research Fund (PMERF