Custom-built automated radiosynthesis platform for Al[18F]F radiochemistry and its application for clinical production

Abstract

The construction of fully automated Al[18F]F radiochemistry can enhance the reproducibility and reliability of Al[18F]F-based radiopharmaceuticals while promoting translation from preclinical to clinical studies. However, commercially available automated radiosynthesizers possess several disadvantages pertaining to the performance of Al[18F]F radiochelation, including the presence of unsuitable sealed-heating for microvolume reactions, imprecise liquid handling and lack of a validated kit formulation for automatic production. In order to address these limitations, this study attempted to design, assemble and validate a custom-built radiosynthesizer for the production of clinical-grade Al[18F]F tracers. Due to the special design of the proposed interlinked sealed-heating, the microvolume solution of the reaction mixture was able to be heated above the boiling point without incurring significant volume change. Moreover, high efficiency for [18F]fluoride concentration was achieved with only 150 µL saline as the eluent with use of the syringe pump, allowing the replication of accurate liquid handling and finally minimizing the volume of the reaction mixture. A validated kit formulation was then developed to bolster the reproducibility and robustness of Al[18F]F chelation. Benefiting from the consumable kit formulation and automated processes optimization, the isolated radiochemical yield for the Al[18F]F tracer was found to be generally higher than those of the reported synthesizer. Furthermore, to demonstrate proof-of-concept, 18F-Alfatide II was then synthesized in large scale (up to 8.31 GBq) with high radiochemical purity (>99 %) and molar activity of 10.6–83.2 GBq/μmol. 18F-Alfatide II exhibited favorable pharmacokinetics in lung cancer patients for clinical trials, demonstrating high and specific accumulation in tumor tissues.