"AquaF" Building Blocks for Water-Compatible S_N2 ¹⁸F-Fluorination of Small-Molecule Radiotracers

Despite the widespread use of hydrophilic building blocks to incorporate ¹⁸F and improve tracer pharmacokinetics, achieving effective leaving group-mediated nucleophilic ¹⁸F-fluorination in water (excluding ¹⁸F/¹⁹F-exchange) remains a formidable challenge. Here, we present a water-compatible S_N2 leaving group-mediated ¹⁸F-fluorination method employing preconjugated "AquaF" (phosphonamidic fluorides) building blocks. Among 19 compact tetracoordinated pentavalent P(V)-F candidates, the "AquaF" building blocks exhibit superior water solubility, sufficient capacity for ¹⁸F-fluorination in water, and excellent in vivo metabolic properties. Two nitropyridinol leaving groups, identified from a pool of leaving group candidates that further enhance the precursor water solubility, enable ¹⁸F-fluorination in water with a 10^-2 M^-1 s^-1 level reaction rate constant (surpassing the ¹⁸F/¹⁹F-exchange) at room temperature. With the exergonic concerted S_N2 ¹⁸F-fluorination mechanism confirmed, this ¹⁸F-fluorination method achieves ∼90% radiochemical conversions and reaches a molar activity of 175 ± 40 GBq/μmol (using 12.2 GBq initial activity) in saline for 12 "AquaF"-modified proof-of-concept functional substrates and small-molecule ¹⁸F-tracers. [¹⁸F]AquaF-Flurpiridaz demonstrates significantly improved radiochemical yield and molar activity compared to ¹⁸F-Flurpiridaz, alongside enhanced cardiac uptake and heart/liver ratio in targeted myocardial perfusion imaging, providing a comprehensive illustration of "AquaF" building blocks-assisted water-compatible S_N2 ¹⁸F-fluorination of small-molecule radiotracers.