Microfluidic devices for electrode trapping of [¹⁸F]fluoride from [¹⁸O]water and continuous flow radiosynthesis of [¹⁸F]FLT

Objectives: [¹⁸F]FLT uptake in tissues reflects the activity of the thymidine salvage pathway, the mechanism to provide DNA precursors from the extracellular environment to dividing cells.¹ [¹⁸F]FLT-PET has been used in many preclinical and clinical research studies, especially in oncology and other highly proliferative tissue.² Classically, production of [¹⁸F]FLT is achieved in modest yields, it has a slow and inconvenient azeotropic evaporation step for drying ¹⁸F followed by time consuming HPLC purification step, hence it is only available at high cost and with limited availability from specialized production laboratories.³ Despite the well characterized nature of his tracer there is still a critical need to develop new, cost effective and reliable radiosynthetic and validation methodologies.⁴ We report here a microfluidic based system for [¹⁸F]FLT synthesis in which a combination of a microfluidic electrochemical cell and a capillary is used for the separation of [¹⁸F]fluoride from [¹⁸O]water followed by the radiolabeling reaction.

Methods: The microfluidic system comprises a microfluidic electrochemical cell⁵ and a capillary reactor. [¹⁸F]fluoride was first trapped from [¹⁸O]water by the electrochemical cell and then released into dry MeCN solution (0.3 mL) containing KHCO₃ and K222. This solution was mixed with precursor 3’-N-Boc-5’-dimethoxytrityl-3’-O-nosyl-thymidine (10-15 mg) and passed through a capillary heated at 100^oC over 5 min followed acidic hydrolysis at room temperature for 5 min.

Results: [¹⁸F]fluoride activity of 95-99% (initial activity 370 MBq-2.01 GBq) was efficiently trapped and up to 90% of [¹⁸F]fluoride was released into 0.15 mL of MeCN-K222-KHCO₃ solution within 5 min, which subsequently was reacted with FLT precursors, giving 50-75% labeling yields. The protecting groups were removed quantitatively by HCl (2N) hydrolysis. The obtained [¹⁸F]FLT was used for an investigation of [¹⁸F]FLT uptake in an SKGT4 tumor, showing [¹⁸F]FLT uptake and bio-distribution as expected for the SKGT4 xenograft model in nude mice.

Conclusion: A microfluidic system combining a microfluidic electrochemical cell and a capillary can simply and reproducibly synthesize [¹⁸F]FLT within 30 min in high yield for preclinical studies. This flow system prototype is compact and efficient for standard radiotracer synthesis and can be developed for other nucleophilic substitution labelling processes with ¹⁸F. Research Support: This work was part funded by the Daisy Appeal (grant no. DAhull2011).

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