Despite ag rowing interest in CHF 2 in medicinal chemistry,there is alackofefficient methods for the insertion of CHF 18 Fi nto druglike compounds.H erein described is ap hotoredoxf lowr eaction for 18 F-difluoromethylation of Nheteroaromatics that are widely used in medicinal chemistry. Following the two-step synthesis for anew 18 F-difluoromethylation reagent, the photoredoxreaction is completed within two minutes and proceeds by CÀHa ctivation, circumventing the need for pre-functionalizationo ft he substrate.T he method is operationally simple and affords straightforwarda ccess to radiolabeled N-heteroaromatics with high molar activity suitable for biological in vivo studies and clinical application.
We recently reported a new method for the 18 F-difluoromethylation of N-heteroaromatics for PET imaging. The method involves the synthesis of a new 18 F-difluoromethylating reagent 2-[ 18 F]((difluoromethyl)sulfonyl)benzo[d]thiazole and a flow photoredox 18 Fdifluoromethylation. For preclinical development and human Positron Emission Tomography (PET) studies with new radiotracers, an automation of the process is mandatory, mostly to avoid radioprotection issues, due to the use of high amounts of radioactivity and to ensure a better reliability of the production. We hereby describe the automation of this 18 Fdifluoromethylation method, on a model substrate, Acyclovir, on a commercially available AllinOne (AIO) synthesizer from Trasis. The whole process is completed in 95 minutes and provides radiolabeled Acyclovir with a molar activity of 35 GBq/µmol. This automated protocol can be implemented for the 18 F-difluoromethylation of a wide range of Nheteroaromatics compounds typically found in medicinal chemistry.
The 18 F-labeling of CF 2 H groups has been recently studied in radiopharmaceutical chemistry owing to the favorable nuclear and physical characteristics of the radioisotope 18 F for positron emission tomography (PET). Following up on the reported efficiency of the [ 18 F]difluoromethyl benzothiazolyl-sulfone ([ 18 F]1) as a 18 F-difluoromethylating reagent, we investigated the influence of structurally-related [ 18 F]difluoromethyl heteroaryl-sulfones in the reactivity toward the photoredox C-H 18 F-difluoromethylation of heteroarenes under continuous-flow conditions. In the present work, six new [ 18 F]difluoromethyl heteroaryl-sulfones [ 18 F]5a-[ 18 F]5f were prepared and, based on the overall radiochemical yields (RCYs), three of these reagents ([ 18 F]5a, [ 18 F]5c, and [ 18 F]5f) were selected for the fully automated radiosynthesis on a FASTlab TM synthesizer (GE Healthcare) at high level of starting radioactivity. Subsequently, their efficiency as 18 F-difluoromethylating reagents was evaluated using the antiherpetic drug acyclovir as a model substrate. Our results showed that the introduction of molecular modifications in the structure of [ 18 F]1 influenced the amount of fac-Ir III (ppy) 3 and the residence time needed to ensure a complete C-H 18 F-difluoromethylation process. The photocatalytic C-H 18 F-difluoromethylation reaction with the reagents [ 18 F]5a, [ 18 F]5c, and [ 18 F]5f was extended to other heteroarenes. Radical-trapping experiments demonstrated the likely involvement of radical species in the C-H 18 F-difluoromethylation process.
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