Synthesis of [(18)F]FMISO in a flow-through microfluidic reactor: Development and clinical application

The PET radiotracer [(18)F]FMISO has been used in the clinic to image hypoxia in tumors. The aim of the present study was to optimize the radiochemical parameters for the preparation of [(18)F]FMISO using a microfluidic reaction system. The main parameters evaluated were (1) precursor concentration, (2) reaction temperature, and (3) flow rate through the microfluidic reactor. Optimized conditions were then applied to the batch production of [(18)F]FMISO for clinical research use.

For the determination of optimal reaction conditions within a flow-through microreactor synthesizer, 5-400 μL the precursor and dried [(18)F]fluoride solutions in acetonitrile were simultaneously pushed through the temperature-controlled reactor (60-180 °C) with defined flow rates (20-120 μL/min). Radiochemical incorporation yields to form the intermediate species were determined using radio-TLC. Hydrolysis to remove the protecting group was performed following standard vial chemistry to afford [(18)F]FMISO.

Optimum reaction parameters for the microfluidic set-up were determined as follows: 4 mg/mL of precursor, 170 °C, and 100 μL/min pump rate per reactant (200 μL/min reaction overall flow rate) to prepare the radiolabeled intermediate. The optimum hydrolysis condition was determined to be 2N HCl for 5 min at 100 °C. Large-scale batch production using the optimized conditions gave the final, ready for human injection [(18)F]FMISO product in 28.4 ± 3.0% radiochemical yield, specific activity of 119 ± 26 GBq/μmol, and >99% radiochemical and chemical purity at the end of synthesis (n = 4).

By using the NanoTek microfluidic synthesis system, [(18)F]FMISO was successfully prepared with good specific activity and high radiochemical purity for human use. The product generated from large-scale batch production using flow chemistry is currently being used in clinical research.