Simplified one-pot ¹⁸F-labeling of biomolecules with in situ generated fluorothiophosphate synthons in high molar activity

Conventional F-labeling methods that demand substrate pre-modification or lengthy radiosynthesis procedures have impeded the visualization and translation of numerous biomolecules, as biomarkers or ligands, using modern positron emission tomography techniques . Moreover, F-labeled biomolecules in high molar activity (A) that are indispensable for sensitive imaging could be only achieved under strict labeling conditions. Herein, F-labeled fluorothiophosphate (FTP) synthons in high A have been generated rapidly in reaction solutions with < 5% water nucleophilic substitution by wet [F]F, which required minimal processing from cyclotron target water. Various F-labeled FTP synthons have been prepared in 30 sec at room temperature with high radiochemical yields > 75% (isolated, non-decay-corrected). FTP synthons with unsaturated hydrocarbon or activated ester group can conjugate with typical small molecules, peptides, proteins, and metallic nanoparticles. 337-517 GBq μmol A has been achieved for F-labeled c(RGDyK) peptide using an automatic module with 37-74 GBq initial activity. The combination of high F-fluorination efficiency of FTP synthons and following mild conjugation condition provides a universal simplified one-pot F-labeling method for broad unmodified biomolecular substrates.