A copper-mediated
radiofluorination of aryl- and vinylboronic acids
with K18F is described. This method exhibits high functional
group tolerance and is effective for the radiofluorination of a range
of electron-deficient, -neutral, and -rich aryl-, heteroaryl-, and
vinylboronic acids. This method has been applied to the synthesis
of [18F]FPEB, a PET radiotracer for quantifying metabotropic
glutamate 5 receptors.
A copper-mediated nucleophilic radiofluorination
of aryl- and vinylstannanes
with [18F]KF is described. This method is fast, uses commercially
available reagents, and is compatible with both electron-rich and
electron-deficient arene substrates. This method has been applied
to the manual synthesis of a variety of clinically relevant radiotracers
including protected [18F]F-phenylalanine and [18F]F-DOPA. In addition, an automated synthesis of [18F]MPPF
is demonstrated that delivers a clinically validated dose of 200 ±
20 mCi with a high specific activity of 2400 ± 900 Ci/mmol.
In a relatively short period of time, transition metal-mediated radiofluorination reactions have changed the PET radiochemistry landscape. These reactions have enabled the radiofluorination of a wide range of substrates, facilitating access to radiopharmaceuticals that were challenging to synthesize using traditional fluorine-18 radiochemistry. However, the process of adapting these new reactions for automated radiopharmaceutical production has revealed limitations in fitting them into the confines of traditional radiochemistry systems. In particular, the presence of bases (e.g. K2CO3) and/or phase transfer catalysts (PTC) (e.g. kryptofix 2.2.2) associated with fluorine-18 preparation has been found to be detrimental to reaction yields. We hypothesized that these limitations could be addressed through the development of alternate techniques for preparing [18F]fluoride. This approach also opens the possibility that an eluent can be individually tailored to meet the specific needs of a metal-catalyzed reaction of interest. In this communication, we demonstrate that various solutions of copper salts, bases, and ancillary ligands can be utilized to elute [18F]fluoride from ion exchange cartridges. The new procedures are effective for fluorine-18 radiochemistry and, as proof of concept, have been used to optimize an otherwise base-sensitive copper-mediated radiofluorination reaction.
A copper-mediated method for the transformation of diverse arylboron compounds and arylstannanes to aryl-[C]-nitriles is reported. This method is operationally simple, uses commercially available reagents, and is compatible with a wide variety of substituted aryl- and heteroaryl substrates. This method is applied to the automated synthesis of high specific activity [C]perampanel in 10% nondecay-corrected radiochemical yield (RCY).
[18F]-labeled aryl fluorides are widely used as radiotracers
for positron emission tomography (PET) imaging. Aryl halides (ArX)
are particularly attractive precursors to these radiotracers, as they
are readily available, inexpensive, and stable. However, to date,
the direct preparation of [18F]-aryl fluorides from aryl
halides remains limited to SNAr reactions between highly
activated ArX substrates and K18F. This report describes
an aryl halide radiofluorination reaction in which the C(sp
2
)–18F bond is formed
via a copper-mediated pathway. Copper N-heterocyclic
carbene complexes serve as mediators for this transformation, using
aryl halide substrates with directing groups at the ortho position. This reaction is applied to the radiofluorination of electronically
diverse aryl halide derivatives, including the bioactive molecules
vismodegib and PH089.
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