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

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