Optimization, automation and validation of the large-scale radiosynthesis of Al18F tracers in a custom-made automatic platform for high yield

Abstract

Al¹⁸F radiochemistry is a convenient ¹⁸F-labeling strategy with favorable characteristics, such as rapid chelation without complex chemistry, simple solid-phase purification and production of scalable doses. However, the commercially available synthesizers are preferred for ¹⁸F nucleophilic fluorination at milliliter-scale reaction volumes rather than radiochelation in aqueous solution. To address the problem, we have designed and assembled a custom-made automatic platform that is suitable for reliable Al¹⁸F radiochelation under conditions like small reaction volumes, heating under sealed conditions, and SPE-based purification. The automated platform, in general, works by four unit operations: (1) ¹⁸F trapping and elution, (2) radiolabeling in a small-volume reactor, (3) SPE purification, and (4) formulation and sterilization by terminal filtration. After the optimization of each unit operation, three representative Al¹⁸F tracers were produced in large scale in the range of 6.8–18.5 GBq at the end of synthesis (EOS) < 30 min, yielding isolated products with the decay-corrected radiochemical yields of 52 ± 6% for [¹⁸F]-Alfatide II, 67 ± 6% for [¹⁸F]-PSMA-11 and 45 ± 5% for [¹⁸F]-NOTA-Octreotide. The isolated RCYs were generally higher than those of the protocols operated in commercially available platforms and comparable to those of the processes implemented manually. All quality control tests met the criteria of the 2015 edition of the Chinese pharmacopoeia. Besides these three tracers, the production of other Al¹⁸F radiotracers in large radioactive batches would be convenient for multi-patient doses and off-site transportation, which would increase the potential for the clinical translation of Al¹⁸F tracers.