Microfluidic synthesis of [¹⁸F]FMISO

Objectives The automated production of 1-[¹⁸F]fluoro-3-(2-nitro-imidazol-1-yl)-propan-2-ol ([¹⁸F]FMISO) utilizing a flow-based microfluidic chemistry system is described.

Methods The NanoTek LF is a modular flow-based microreactor assembly. The nucleophilic substitution of 1-(2’-nitro-1’-imidazolyl)-2-O-tetrahydropyranyl-3-O-p-toluenesulfonyl propanediol (NITTP; ABX Advanced Biochemical Compounds) with Kryptofix [¹⁸F]fluoride was optimized for temperature and flow rates through the reactor in the “Discovery Mode”. The optimum flow rate and temperature used for the radiosynthesis in a 100 µm i.d. X 4 m reactor were found to be 200 µl/min and 170°C respectively. This resulted in an incorporation yield of fluoride of 85 ± 3% (n= 6) as determined by radio-TLC. The intermediate THP ether obtained from the microreactor was hydrolyzed with 1 N HCl, followed by neutralization using 1 N NaOH. Final purification was performed by reverse phase semi-prep HPLC, using 4% ethanol in water (v:v).

Results 500 mCi of [¹⁸F]-Fluoride (recycled O-18 water) produced [¹⁸F]FMISO in a radiochemical yield of 40-45% (uncorr.). The total synthesis time including semi-prep HPLC purification was 50 min. The specific activity was observed to be 2 Ci/µmol with a radiochemical purity of >97%.

Conclusions Using microfluidics technology, a convenient and rapid synthesis of 1-[¹⁸F]fluoro-3-(2’-nitro-imidazol-1’-yl)-propan-2-ol was accomplished in an adequate quantity, excellent purity and high specific activity for small animal imaging studies.

Research Support The Molecular Imaging and Translational Research Progra