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

Despite the widespread use of hydrophilic building blocks to incorporate 18 F and improve tracer pharmacokinetics, achieving effective leaving group-mediated nucleophilic 18 F-fluorination in water (excluding 18 F/ 19 F-exchange) remains a formidable challenge. Here, we present a water-compatible S N 2 leaving group-mediated 18 F-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 18 F-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 18 F-fluorination in water with a 10 –2 M –1 s –1 level reaction rate constant (surpassing the 18 F/ 19 F-exchange) at room temperature. With the exergonic concerted S N 2 18 F-fluorination mechanism confirmed, this 18 F-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 18 F-tracers. [ 18 F]AquaF-Flurpiridaz demonstrates significantly improved radiochemical yield and molar activity compared to 18 F-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 18 F-fluorination of small-molecule radiotracers.

Перевод пока недоступен