Droplet-Based Radiosynthesis and High-Throughput Optimization of Vinyl Sulfone Prosthetic Group ([18F]FVSB) and Peptide Bioconjugation

Fluorine-18 is often considered an ideal positron emitter owing to its excellent chemical, physiological, and nuclear properties. Consequently, the development of rapid, simple, and reliable 18F-labeling strategies remains critically important for synthesizing new radiopharmaceuticals for PET molecular imaging. A common approach involves the synthesis of 18F-labeled prosthetic groups that subsequently undergo bioconjugation with peptides or other biomolecules to generate 18F-labeled imaging probes. However, conventional synthetic methods for these prosthetic groups are often lengthy, require large quantities of precursor and solvent, and typically rely on elevated reaction temperatures. Herein, we report a droplet-based microscale synthetic methodology for the preparation of the [18F]FVSB prosthetic group that minimizes precursor and solvent usage, proceeds rapidly, and operates at relatively low temperatures. Conditions were optimized using a platform for performing droplet reactions in parallel, enabling high-throughput study of multiple reaction parameters within a short period of time. Additionally, we introduce a simple micro-cartridge purification technique that affords purified [18F]FVSB in small volumes. Furthermore, we describe an efficient bioconjugation that requires substantially lower reagent amounts than the previously reported macroscale method. The microscale process we report could facilitate wider use of this 18F-labeling strategy and can be extended to label other thiol-bearing peptides or biomolecules.