| Summary: | Background: Temperature-sensitive radiopharmaceutical precursors require lower reaction temperatures (<100 °C) during nucleophilic radiofluorination in order to avoid compound thermolysis, often resulting in sub-optimal radiochemical yields (RCYs). To facilitate nucleophilic aromatic substitution (S<sub>N</sub>Ar) of nucleofuges commonly used in radiofluorination (e.g., nitro group), we explored the use of Lewis acids as nucleophilic activators to accelerate [<sup>18</sup>F]fluoride incorporation at lower temperatures, and thereby increasing RCYs for thermolabile activated precursors. Lewis acid-assisted radiofluorination was exemplified on the temperature-sensitive compound 1-(4-(4-morpholino-7-neopentyl-7<i>H</i>-pyrrolo[2,3-d]pyrimidin-2-yl)phenyl)-3-(6-nitropyridin-3-yl)urea (MN3PU, compound 3) targeting leucine-rich repeat kinase 2 (LRRK2), an important target in the study of Parkinson’s disease and various cancers. Methods: To a vessel containing dried K[<sup>18</sup>F]F-K222 complex, a solution of precursor MN3PU ((3), 1 mg; 1.8 μmol) and Lewis acid (6 μL of 0.2 μmol: chromium II chloride (A), ferric nitrite (B) or titanocene dichloride (C)) in 500 μL of <i>N,N</i>-dimethylformamide (DMF) (with 10% <i>t</i>-BuOH for B) were added. Reactions were stirred for 25 min at 90 °C. In parallel, reactions were conducted without the addition of Lewis acids for baseline comparison. After purification via preconditioned Sep-Pak C18 plus cartridges, aliquots were analyzed by analytical radio-HPLC. Results: Non-decay corrected radiochemical yields (ndc RCYs) for [<sup>18</sup>F]FMN3PU (7) were improved from 1.7 ± 0.7% (no addition of Lewis acids) to 41 ± 1% using Cr(II) and 37 ± 0.7% using Ti(II)-based Lewis acids, with radiochemical purities of ≥96% and molar activities (A<sub>m</sub>) of up to 3.23 ± 1.7 Ci/μmol (120 ± 1.7 GBq/μmol). Conclusion: RCYs of [<sup>18</sup>F]FMN3PU (7) improved from ~5% using conventional nucleophilic radiofluorination, up to 41 ± 1% using Lewis-acid supported S<sub>N</sub>Ar.
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