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

Despite the widespread use of hydrophilic building blocks to incorporate F-18 and improve tracer pharmacokinetics, achieving effective leaving group-mediated nucleophilic F-18-fluorination in water (excluding F-18/F-19-exchange) remains a formidable challenge. Here, we present a water-compatible S(N)2 leaving group-mediated F-18-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 F-18-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 F-18-fluorination in water with a 10(-2) M-1 s(-1) level reaction rate constant (surpassing the F-18/F-19-exchange) at room temperature. With the exergonic concerted S(N)2 F-18-fluorination mechanism confirmed, this F-18-fluorination method achieves similar to 90% radiochemical conversions and reaches a molar activity of 175 +/- 40 GBq/mu mol (using 12.2 GBq initial activity) in saline for 12 "AquaF"-modified proof-of-concept functional substrates and small-molecule F-18-tracers. [F-18]AquaF-Flurpiridaz demonstrates significantly improved radiochemical yield and molar activity compared to F-18-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(N)2 F-18-fluorination of small-molecule radiotracers.