Development of Heteroaromatic Silicon Fluoride Acceptors (HetSiFAs) for ¹⁸F-Labeled Radiopharmaceuticals

Silicon Fluoride Acceptors (SiFAs) enable ¹⁸F-labeling of complex peptides via isotope exchange under exceptionally mild conditions. SiFA radiopharmaceuticals have been clinically validated for diagnosing and treating cancers as tracers for positron emission tomography (PET) and radiotwin theranostics. Despite these advances, conventional phenyl SiFAs (PhSiFAs) require complex substrate engineering to mask their lipophilicity, which complicates the design of new tracers. Here, we report a new and diverse class of heteroaromatic SiFA derivatives (HetSiFAs) that are significantly less lipophilic than classical PhSiFAs. We show that HetSiFAs retain suitable stability without compromising labeling kinetics. We highlight the performance of a pyrazole-HetSiFA for rapid and efficient ¹⁸F-labeling within a model TATE-peptide and show that the resulting PET tracer clears through the kidneys with minimal defluorination in mice. Novel radiopharmaceuticals incorporating HetSiFAs can capitalize on the improved and flexible pharmacokinetic parameters and excellent ¹⁸F-fluorination efficiency offered by these scaffolds.