Fully Automated [¹⁸F]AlF Radiolabeling Using a Microdroplet Reactor Platform

The preparation of ¹⁸F-labeled biomolecules for PET imaging is often challenging due to complex synthesis protocols and the short half-life of F-18 (109.8 min). The aluminum-[¹⁸F]fluoride ([¹⁸F]AlF) method offers a straightforward, efficient route for radiofluorinating biomolecules, with demonstrated utility in both preclinical and clinical imaging. However, one technique's flaw is the mismatch between the typical microvolume conditions required for high-yield [¹⁸F]AlF chelation and the milliliter-scale operation of commercial automated radiosynthesizers. To address this shortcoming, we leverage microscale radiochemistry techniques and report the first fully-automated, droplet-based production of [¹⁸F]AlF-labeled compounds using a compact and cost-effective platform. The optimized process was first achieved using a NODA analogue (NODA-Tz) as a model substrate at a 15 μL reaction scale, and was subsequently applied to the fully automated synthesis of the clinically-relevant PET probe [¹⁸F]AlF-FAPI-74 which targets fibroblast activation protein expressed in most cancers. [¹⁸F]AlF-FAPI-74 (n = 3) was obtained with high radiochemical yield (RCY, 75 ± 5%), radiochemical purity (RCP, >99%), activity yield (67 ± 4%), and apparent molar activity (A _m , 358-482 GBq/μmol). Starting from 2.6-3.5 GBq of [¹⁸F]fluoride, the final product quantity (1.8-2.4 GBq) was sufficient for multiple patient doses. Compared to the conventional vial-based methods, the microdroplet approach showed significant improvements including reduced synthesis time (19 ± 1 min vs. 31 min), higher yield, and reduced precursor consumption (5 nmol vs. 80 nmol). This work demonstrates the feasibility and advantages of translating [¹⁸F]AlF chemistry to a microdroplet platform, enabling more efficient radiotracer production and broader clinical accessibility.