Mechanistic investigation of the substituent effects on Si–F bond reactivity in phenyl silicon-fluoride acceptors (SiFA)

Silicon-fluoride acceptors (SiFA) have emerged as a transformative technology for the development of novel peptide-based PET tracers and theranostic radiopharmaceuticals, offering a rapid, high-yielding, robust, and operationally simple method for incorporating fluorine-18 through isotope exchange on silicon. The di-tert-butylfluoro(phenyl)silane core of SiFA is typically conjugated to biomolecules via a functional group positioned either meta- or para- to the silicon center on the phenyl ring. Although a variety of such substituents have been employed, their impact on the efficiency of 18F-labeling and the hydrolytic stability of the Si–F bond has not been systematically evaluated. In this study, we investigate the electronic effects of commonly used meta and para substituents on the kinetics of these reactions. A Hammett analysis was employed to further elucidate the mechanisms of Si–F bond hydrolysis and to quantify the substituent effect. Furthermore, in light of the growing application of bifunctional SiFAs for incorporation into peptide chains or as linkers between peptides and chelators in radiotheranostics, we synthesized a series of 3,5-disubstituted SiFAs and characterized their physicochemical properties. Our findings provide a foundation for the rational design of novel 18F-labeled radiopharmaceuticals based upon SiFA technology.