We describe a high radiochemical
yield late-stage direct 18F-labeling of bare biomolecules
containing common active groups.
Spontaneity and site-selectivity are attributed to the remarkably
higher rates of nucleophilic substitution reactions on phosphonates
than on other electrophiles by F– at various hydrogen
bond forms. Rapid access to many medicinally significant 18F-labeled biomolecules is achieved at 21–68% radiochemical
yields and 35.9–55.1 GBq μmol–1 molar
activities both manually or automatically.
18 F-Labeling methods for the preparation of 18 F-labeled molecular probes can be classified into electrophilic fluorination, nucleophilic fluorination, metal-F coordination, and 18 F/ 19 F isotope exchange. Isotope exchange-based 18 F-labeling methods demonstrate mild conditions featuring water resistance and facile high-performance liquid chromatography-free purification in direct 18 F-labeling of substrates. This paper systematically reviews isotope exchange-based 18 F-labeling methods sorted by the adjacent atom bonding with F, i.e., carbon and noncarbon atoms (Si, B, P, S, Ga, Fe, etc.). The respective isotope exchange mechanism, radiolabeling condition, radiochemical yield, molar activity, and stability of the 18 F-product are mainly discussed for each isotope exchange-based 18 F-labeling method as well as the cuttingedge application of the corresponding 18 F-labeled molecular probes.
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 (Am) that are indispensable for sensitive imaging could be only achieved under strict labeling conditions. Methods: Herein, 18 F-labeled fluorothiophosphate (FTP) synthons in high Am 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 Am 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.
Scheme 21. 18 F-Labeling of dialkyl phosphine fluoride via 18 F/ 19 F isotope exchange. (a) A PET image of 18 F-DBPOF-c(RGDyk) in U87MG nude mice at 23 min post-injection. (b) A PET image from a 60 min dynamic scan with 18 F-DBPOF-HSA in healthy female Wistar rats. Adapted with permission from Ref. [93].
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