Photocatalytic nucleophilic 18F-deoxyfluorination of catechol derivatives for facile automated synthesis of high-molar-activity [18F]FDOPA

The nucleophilic aryl ¹⁸ F-fluorination of catechol derivatives has long presented a challenge due to the repulsion of the high electron density aromatic ring against the attack of ¹⁸ F-fluoride, which has limited the development and production of PET tracers. Here, we report a photocatalyzed aryl ¹⁸ F-deoxyfluorination strategy for the efficient ¹⁸ F-labeling of the catechol moiety, facilitating the synthesis of the PET tracer [ ¹⁸ F]FDOPA. The challenging direct nucleophilic ¹⁸ F-fluorination was ultimately achieved by fine-tuning the electronic properties of the aromatic ring with different O -derived leaving groups to align with the photocatalysis system. Various precursors were rapidly prepared and investigated under azeotropic drying-free photolabeling conditions, with several precursors showing notable potential for the synthesis of [ ¹⁸ F]FDOPA. The substrate 3i , which bears a 4,5-dicyano-2-fluorophenoxy leaving group and demonstrates excellent ¹⁸ F-deoxyfluorination efficiency, was selected for further optimization towards scale-up synthesis. The [ ¹⁸ F]FDOPA was successfully produced in 16.5% - 21.2% (n = 5) non-decay corrected RCY within 80 minutes with 6.45 ± 2.39 Ci/μmol molar activity on a commercial radiosynthesis module using an innovative RFTA photocatalyst. The readily available and stable precursor makes this transition-metal-free approach an attractive routine for the daily production of [ ¹⁸ F]FDOPA with high molar activity, which also paves the way for the nucleophilic ¹⁸ F-fluorination of other catechol derivatives.