Efficient Radiosynthesis of 3′-Deoxy-3′-18F-Fluorothymidine Using Electrowetting-on-Dielectric Digital Microfluidic Chip

Journal of Nuclear Medicine

Chang-Jin “CJ” Kim¹  Johannes Czernin¹  Liu Wei¹  R. Michael van Dam¹  Muhammad Rashed Javed¹  Pei Yuin Keng¹  Hee-Kwon Kim¹  Supin Chen¹ 

关键词: ¹⁸F-FLT;    microfluidic chip;    radiosynthesis;    high specific activity;   

DOI  :  10.2967/jnumed.113.121053

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

Access to diverse PET tracers for preclinical and clinical research remains a major obstacle to research in cancer and other disease research. The prohibitive cost and limited availability of tracers could be alleviated by microfluidic radiosynthesis technologies combined with a high-yield microscale radiosynthetic method. In this report, we demonstrate the multistep synthesis of 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) with high yield on an electrowetting-on-dielectric (EWOD) microfluidic radiosynthesizer, previously developed in our group. We have identified and established several parameters that are most critical in the microscale radiosynthesis, such as the reaction time, reagent concentration, and molar ratios, to successfully synthesize 18F-FLT in this compact platform. Methods: 18F-FLT was synthesized from the 3-N-Boc-1-[5-O-(4,4′-dimethoxytrityl)-3-O-nosyl-2-deoxy-β-d-lyxofuranosyl] thymine precursor on the EWOD chip starting from the first solvent exchange and 18F-fluoride ion activation step to the final deprotection step. The fluorination reaction was performed in a mixture of thexyl alcohol and dimethyl sulfoxide. The crude product after deprotection was collected from the chip and purified on a custom-made solid-phase extraction cartridge and subjected to quality control testing. The purified 18F-FLT was suitable for small-animal PET studies in multiple nude mice xenografted with the A431 carcinoma cell line. Results: 18F-FLT was successfully synthesized on the EWOD microdevice coupled with an off-chip solid-phase extraction purification with a decayed-corrected radiochemical yield of 63% ± 5% (n = 5) and passed all of the quality control tests required by the U.S. Pharmacopeia for radiotracers to be injected into humans. We have successfully demonstrated the synthesis of several batches of 18F-FLT on EWOD, starting with approximately 333 MBq of radioactivity and obtained up to 52 MBq (non–decay-corrected) of 18F-FLT on cartridge purification. The specific activity of 2 representative preparations of 18F-FLT synthesized on the EWOD chip were measured to be 1,800 and 2,400 GBq/μmol. Conclusion: The EWOD microchip and optimized synthesis method in combination represent an effective platform for synthesizing 18F-FLT with high yield and of good quality for imaging. This compact platform, with configurable synthesis steps, could potentially form the basis of a stand-alone system that decouples PET probe production from the cyclotron and specialized radiochemistry facilities and increases diversity and flexibility in probe production.

【 授权许可】

Unknown