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

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