Copper-Mediated Aromatic Radiofluorination Revisited: Efficient Production of PET Tracers on a Preparative Scale

Graphical Abstract

Less is more: Copper-mediated nucleophilic aromatic radiofluorination under “low base” and “minimalist” conditions affords radiolabeled arenes in reasonable to excellent yields on a preparative scale. In particular, the “minimalist” approach circumvents time-consuming azeotropic drying, avoids the application of base and other additives, and enables efficient production of clinical doses of positron emission tomography (PET) tracers, such as [¹⁸F]FDA, 4-[¹⁸F]FPhe and [¹⁸F]DAA1106 (RCY=radiochemical yield).

Abstract

Two novel methods for copper-mediated aromatic nucleophilic radiofluorination were recently reported. Evaluation of these methods reveals that, although both are efficient in small-scale experiments, they are inoperative for the production of positron emission tomography (PET) tracers. Since high base content turned out to be responsible for low radiochemical conversions, a “low base” protocol has been developed which affords ¹⁸F-labeled arenes from diaryliodonium salts and aryl pinacol boronates in reasonable yields. Furthermore, implementation of our “minimalist” approach to the copper-mediated [¹⁸F]-fluorination of (mesityl)(aryl)iodonium salts allows the preparation of ¹⁸F-labeled arenes in excellent RCCs. The novel radiofluorination method circumvents time-consuming azeotropic drying and avoids the utilization of base and other additives, such as cryptands. Furthermore, this procedure enables the production of clinically relevant PET tracers; [¹⁸F]FDA, 4-[¹⁸F]FPhe, and [¹⁸F]DAA1106 are obtained in good isolated radiochemical yields. Additionally, [¹⁸F]DAA1106 has been evaluated in a rat stroke model and demonstrates excellent potential for visualization of translocator protein 18 kDa overexpression associated with neuroinflammation after ischemic stroke.