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

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 Nin[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, Nin-[18F]SAFsubstituted indole derivatives exhibited rapid in vivo defluorination, independent of substitution pattern. In contrast, [18F]SAFsubstituted 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.