10.1002/chem.201904132
Chemistry - A European Journal
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provided an aqueous solution of [18F]AgF. The [18F]AgF was then
azeoptropically dried, and MeCN was added followed by the
thionoester. The reaction mixture was then heated to 80 C for 20
min, filtered and examined by HPLC. These operationally simple
reactions were exceptionally clean and exhibited good to
excellent radiochemical conversion (RCC) to the corresponding
18F-difluoroalkyl ethers [18F]27, [18F]31 and [18F]44 (Figure 3). For
these proof-of-concept studies, AgF carrier was added. Thus, in
its present form this radiosynthesis of 18F-difluoroalkyl ethers may
not be suitable for some imaging applications. However,
decreasing the amount of [19F]AgF or omitting [19F]AgF altogether
should enable production of radiotracers with clinically relevant
specific activities and will be the subject of further examination.
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Figure 3. Synthesis of 18F-labelled difluoroethers using [18F]AgF. General
conditions: a solution containing [18F]AgF (70-250 MBq), [19F]AgF (3 equiv), and
thionoester in MeCN (0.6 mL) was heated to 80 C for 20 min. RCC was
calculated by % integrated area of the 18F product versus [18F]fluoride in a radio-
HPLC trace.
In summary, we have developed a new method for the
synthesis of difluoroalkyl ethers that involves the direct
fluorodesulfurization of thionoesters with Ag(I)F at room
temperature. This mild and rapid reaction tolerates a wide range
of functional groups and water, clearly differentiating it from the
many existing syntheses of difluoroalkyl ethers that generally rely
on toxic and/or dangerous reagents. These qualities also make
this process useful for the production of radiotracers using
[18F]AgF, which we demonstrated in three examples including the
preparation of an 18F-labelled analogue of sarmazenil, a partial
inverse agonist of benzodiazepine receptors. The ready access
to difluoroalkyl ethers enabled by this convenient strategy should
enable the further study of this functional group for materials and
medicinal chemistry, and inspire new applications in
radiochemistry.
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Acknowledgements
This work was supported by an NSERC Discovery CRD grant for
R.B. and C.F., a MSFHR Career Investigator Award (R.B.), a
Hoffmann-La Roche Fellowship (M.B.N.). The authors thank the
TRIUMF TR13 cyclotron team. TRIUMF receives federal funding
via a contribution agreement with the National Research Council
of Canada.
Keywords: difluoroether • fluorodesulfurization • silver(I)fluoride •
18F-labelling • radiotracer
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