N-Aryl sulfamoyl fluorides (ArSAFs) are hydrolytically stable motifs widely used in drug design, yet their suitability for radiotracer development has not been explored. Here, we report the efficient radiosynthesis of 18FArSAFs by base-free sulfur(VI) fluoride exchange (SuFEx), affording high molar activities from nanomolar precursor amounts. The resulting compounds exhibited excellent in vitro stability across a wide pH range and in human plasma. In vivo studies in mice confirmed high metabolic stability for selected N-alkyl-N-aryl derivatives. Additionally, several Nin-18FSAF-substituted tryptophan analogues showed up to 2–3-fold higher cellular uptake than the current gold standard 18FFET in U87 MG glioblastoma cells, and their accumulation was sensitive to inhibition of amino acid transporters. However, Nin-18FSAF-substituted indole derivatives exhibited rapid in vivo defluorination, independent of substitution pattern. In contrast, 18FSAF-substituted dihydrotryptophan and 4-(MeNH)Phe derivatives showed high in vivo stability. These findings establish N-alkyl-N-aryl sulfamoyl 18Ffluorides as robust and accessible scaffolds for radiotracer development.
Bertram et al. (Thu,) studied this question.