Nucleophilic 18F Substitution for Radiotracer Synthesis

Suddenly within the last month or so, several papers have appeared in the literature using fluorous methods for the synthesis of radioimaging agents.  These molecules are used in diagnostic  medicine and clinical research.  We have already summarized some of them and you can find these earlier posts in the Isotope Chemistry category.  Just published online is a new paper from Prof. Véronique Gouverneur at Oxford along with scientists at AstraZeneca and Siemens Molecular Imaging, describing her group’s work in developing methodology for the nucleophilic substitution of 18F using fluorous tagged leaving groups.

18F labeled probes are the most popular radionuclide used in positron emission tomography (PET) imaging. PET imaging is particularly useful in the treatment of cancer patients, where 2-fluoro-deoxyglucose (FDG) can be used to visualize tumors.  One of the limitations of PET is that a cyclotron is required to produce 18F, which then needs to be incorporated into the desired radiotracer.   The requirement of a cyclotron and on-site chemical synthesis of the probes limits the number of facilities that can produce these agents, therefore, the radiotracers are usually synthesized in a central facility which supplies hospitals.  This is a primary reason why 18F is preferred over other nuclei such as 11C, since it’s half-life, 110 minutes, is relatively long.

110 minutes is not that long, however, so each minute counts in the preparation of a radiotracer.  In addition, due to the cost of the radionuclide, the precursor to fluorine substitution is often used in high excess.  This then requires some sort of purification, especially if the precursor can compete with the radiotracer for the intended target.  Several methods are used including HPLC, but these can be slow resulting in loss of activity.  Solid-phase techniques have been used, but these often result in unfavorable reaction kinetics due to the heterogeneous conditions.  Not to mention, solid-phase techniques usually require the use of excess reagents in solution.  If you are using K[18F] as your fluorine source, that’s actually opposite of want you want to do.  Sounds like a job for fluorous!

Nucleophilic substitution followed by fluorous solid phase extraction (FSPE)

Prof. Gouverneur and co-workers have done is to use a fluorous sulfonate as a leaving group.  By reacting an excess of a fluorous sulfonate molecule with K[18F]-Kryptofix 2.2.2. they could effect the nucleophilic substitution of fluorine into various molecules which were then used to produce radiotracers.  The large excess remaining fluorous sulfonate could be separated from the fluorine substituted product by fluorous solid phase extraction (FSPE) resulting in pure compound with excellent radiochemical yield.  They then went on to prepare several radiotracers used in PET imaging.

Synthesis of PET imaging Radiotracers with Fluorous Solid Phase Extraction (FSPE) purification

There are several interesting aspects in the paper.  First was that the sulfonate they made contained a carbon spacer between the fluorous domain and the sulfonate functionality.  They found that without the spacer they observed substitution at the sulfur and not at the carbon.  Next was the use of DMSO as a fluorophobic additive for the fluorophobic wash instead of water due to the aqueous sensitivity of one of the molecules.  Finally, was the observation that some leaching of “cold” fluorine seems to be occurring during the fluorination.

Overall, a very nice communication which really demonstrates the value of fluorous techniques.

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