Aryl Sulfamoyl [¹⁸F]Fluorides: Preparation via Base-Free SuFEx ¹⁸F-Fluorination and Assessment of Their Applicability...

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 [¹⁸F]ArSAFs 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 N_in-[¹⁸F]SAF-substituted tryptophan analogues showed up to 2-3-fold higher cellular uptake than the current gold standard [¹⁸F]FET in U87 MG glioblastoma cells, and their accumulation was sensitive to inhibition of amino acid transporters. However, N_in-[¹⁸F]SAF-substituted indole derivatives exhibited rapid in vivo defluorination, independent of substitution pattern. In contrast, [¹⁸F]SAF-substituted dihydrotryptophan and 4-(MeNH)Phe derivatives showed high in vivo stability. These findings establish N-alkyl-N-aryl sulfamoyl [¹⁸F]fluorides as robust and accessible scaffolds for radiotracer development.