Positron Emission Tomography (PET) is a high precision non-invasive imaging technique for time resolved in vivo molecular imaging, especially useful for early disease diagnosis and treatment efficacy monitoring. A continuous demand for new imaging agents and the absence of practical, robust, selective methods for their synthesis calls for expanding the existing radiochemistry technologies. Fluorine-18 is preferred for its favorable positron emission properties and longer half-life (t1/2 = 110 min), so imaging agents can be produced remotely and distributed to hospitals. Traditional radiofluorination of complex molecules by late-stage functional group interconversion is limited by challenging synthesis of each precursor. Alternative direct approaches are at their nascent stages, exhibiting low radiochemichal yields (RCY) and innate substrate control of the fluorination sites, which can be restrictive to target binding. The prosthetic group approach can be favored as it offers perfect fluorine site selectivity despite requiring an extra step. We report a new blueprint for fluorine-18 incorporation, enabled by visible light induced C–C coupling. Readily available terminal alkenes are rapidly iodofluorinated to form several new aromatic prosthetic groups bearing a benzylic fluoride and synthetically valuable primary iodide. Subsequent visible light induced alkyl Heck-type reaction with a second terminal alkene yields a diverse scope of compounds with interchangeable aromatic groups, all bearing the desired fluorine tag at the linker. The protocol was translated to fluorination with 18F on an automated radiosynthesis module, by which radioactive homoallylic fluorides were obtained in good radiochemical yields and reasonable molar activity. The potential utility of this approach for molecular imaging probe development was demonstrated by incorporation of 18F into biologically relevant molecules. Further validation of this strategy is ongoing, guided by molecular modeling, to synthesize potential radiotracers for positron emission tomography imaging of upregulated cancer markers, such as stearoyl-CoA desaturase-1.

Homoallylic radiofluorination toward practical approaches for the synthesis and application of imaging agents

ACS Spring 2022

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