About one year ago, a report from the Gouverneur lab in Oxford reported the use of fluorous sulfonates as precursors to 18F imaging agents. Nucleophilic displacement of the fluorous sulfonate by 18F anion provided the desired compounds as shown below. In these types of reactions, the 18F is obviously far more valuable than the precursor, so in general a large excess of the alkylating agent is used. The removal of the excess alkylating agent and their by-products using a simple, fast, and automatable method is desirable to provide the purest imaging agent possible. Hhhhmmm. Simple and fast. Perfect for fluorous methods, which is what they found using a fluorous solid phase extraction (FSPE) purification to remove the excess fluorous sulfonate. Their report earned them an Angewandte Chemie cover.
Now comes a report from Prof. Bengt Langstrom’s group at Uppsala where they essentially use a similar strategy for 18F substitution. They report yields, however, that are not quite as good as Prof. Gouverneur’s using the same fluorous sulfonate. They claim better results using a pentafluorophenyl sulfonate rather than a perfluoroalkyl sulfonate. They then utilized pentafluorophenyl modified silica gel for the solid phase extraction. In the test reaction below they report a 77% radiochemical purity after SPE using the pentafluorophenyl sulfonate as opposed to a 50% yield using the perfluoroalkyl sulfonate pictured. For the SPE using the pentafluorophenyl sulfonate the authors used a pentafluorophenyl modified silica gel as the soilid phase.
Langstrom and co-workers report that with the pentafluorophenyl sulfonate they do not observe loss of radioactivity which was observed with the perfluoroalkyl sulfonate. This loss with the perfluoroalkyl sulfonate they ascribe to fluorine scrambling with the 19F atoms of the perfluoroalkyl chain, which the Gouverneur group also observed as a loss of specific activity.
The work provides an potential alternative approach to using a fluorinated sulfonate as a leaving group for 18F substitution. It does, however, remain to be seen how this method compares to the perfluoroalkyl approach in the preparation of actual agents such as FDG, FMISO, and others. The pentafluorophenyl based SPE doesn’t seem as discriminating as the traditional FSPE. The authors collected several fluorophobic fractions with the third being the purest. I would anticipate that the separation could get even more difficult for molecules such as 18F-L-thymidine.
With that caveat, however, the work is another demonstration that a fluorinated or fluorous sulfonate in conjunction with SPE may be an attractive alternative to current methods in nucleophilic 18F substitutions. There are still some issues to be sorted out, but it is an area where fluorous could make a big impact.