“AquaF” Building Blocks for Water-Compatible S<sub>N</sub>2 <sup>18</sup>F-Fluorination of Small-Molecule Radiotracers
Zhaobiao Mou, Yiwei Zhu, Lei Zhang, Mengting Ma, Zhongjing Li, Zhongjing Li, Yiming Guo, Jiamei Zheng, Zixiao Zhao, Kaiqiang Zhang, Xiaoyuan Chen, Zijing Li, Zijing Li
Abstract
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.