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

Rationale: Conventional ¹⁸F-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 in vivo. Moreover, ¹⁸F-labeled biomolecules in high molar activity (A_m) that are indispensable for sensitive imaging could be only achieved under strict labeling conditions. Methods: Herein, ¹⁸F-labeled fluorothiophosphate (FTP) synthons in high A_m have been generated rapidly in situ in reaction solutions with < 5% water via nucleophilic substitution by wet [¹⁸F]F^-, which required minimal processing from cyclotron target water. Results: Various ¹⁸F-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^-1 A_m has been achieved for ¹⁸F-labeled c(RGDyK) peptide using an automatic module with 37-74 GBq initial activity. Conclusion: The combination of high ¹⁸F-fluorination efficiency of FTP synthons and following mild conjugation condition provides a universal simplified one-pot ¹⁸F-labeling method for broad unmodified biomolecular substrates.