Synthesis of [18F]FAZA using micro-fluidic technology

Objectives [18F]FAZA is a frequently used radiotracer for PET imaging of hypoxia. Current automated synthesis of [18F]FAZA involves a 5 min [18F]fluoride incorporation on 1-(2,3-di-O-acetyl-5-O-tosyl-a-D-arabinofuranosyl)-2-nitroimidazole followed by a 2 min hydrolysis step. However, the overall radiochemical yield (RCY) is reported to be low. Microfluidic technology is a rapidly evolving novel technique enabling micro-scale chemical reactions. This technology allows fast reactions in a simple experimental set-up, while using only very low amounts of starting material. The present study describes radiosynthesis of [18F]FAZA by means of micro-fluidic technology.

Methods Radiosynthesis in a microfluidic apparatus was optimized through varying various reaction parameters like temperature (80°C to 140°C), flow rate (8 uL x min-1 to 40 uL x min-1), reaction time (using different length of reactor), solvent (DMSO or CH3CN), and precursor concentration (2.5 mg x mL-1 to 5 mg x mL-1).

Results Optimal reaction conditions for [18F]fluoride incorporation were developed for small scale (0.1 MBq to 100 MBq) and large scale preparations (400 Mq to 2 GBq). Best reaction conditions at small scale include a reaction temperature of 120°C, a flow rate of 18 uL x min-1 for 5 min 20 sec, DMSO as solvent, and a precursor concentration of 2.5 mg x mL-1. These conditions afforded purified [18F]FAZA in 72% RCY. Large scale synthesis of [18F]FAZA employed a reaction temperature of 120°C, a flow rate of 28 uL x min-1 for 4 min 10 sec, DMSO as the solvent, and a precursor concentration of 5 mg x mL-1. These conditions gave HPLC-purified [18F]FAZA in 29 % RCY. Subsequent radiopharmacological evaluation of [18F]FAZA involved dynamic small animal PET studies in EMT-6 tumor bearing mice.

Conclusions Application of microfluidic technology significantly improved radiochemical yields of [18F]FAZA. Microfluidic technology represents an interesting alternative for the synthesis of clinically relevant PET radiotracers like [18F]FAZA. Future work is focused on the use of larger starting activities of [18F]fluoride (>5 GBq)