Two improved routes to ¹¹C PET imaging agents

When you get a positron emission tomography (PET) scan, the medical procedure begins minutes beforehand when a chemist prepares a radioactive imaging agent starting from a simple isotope-labeled compound created in a cyclotron. Radiation given off by the imaging agent, which is typically a sugar, peptide, or other so-called reporter biomolecule, can be tracked as the agent travels through your body, allowing for the assessment of drug distribution, protein expression, and metabolism to diagnose disease and monitor your health.

During the past few years, chemists have reported a number of synthetic breakthroughs making ¹⁸F-labeled compounds. Fluorine can improve the performance of imaging agents by helping the compounds reach their targets. And ¹⁸F has a half-life of about 110 minutes, versus only about 20 minutes for ¹¹C, the other commonly used PET isotope, providing more time to prepare the imaging agent.

Two research groups have now devised synthetic strategies that offer more flexible routes to ¹¹C-labeled compounds.

Mohammad B. Haskali and Victor W. Pike of the U.S. National Institute of Mental Health’s Medical Imaging Branch have developed the first method for preparing ¹¹C-labeled fluoroform, ¹¹CHF₃, and used the reagent to incorporate labeled trifluoromethyl groups into imaging agents (Chem. Eur. J. 2017, DOI: 10.1002/chem.201701701).

Haskali and Pike found that cobalt trifluoride readily fluorinates ¹¹CH₄ to ¹¹CHF₃, which the researchers then used to prepare a copper transfer reagent for incorporating ¹¹CF₃ groups into model compounds such as benzophenone and known drugs such as the antidepressant fluoxetine (Prozac). Start to finish, the synthesis takes less than 20 minutes and achieves a higher level of radioactivity, and therefore potentially better PET image quality, than is possible by starting with ¹⁸F-labeled fluoroform.

Chemists have focused on generating ¹⁸F-labeled CF₃ groups, but due to the quirks of ¹⁸F chemistry, only modest radioactivity in imaging agents has been achieved, notes PET radiochemist Philip Miller of Imperial College London. “This paper describes a really novel workaround to the molar activity issue by using ¹¹C-labeled fluoroform,” Miller says. “This will be a real boon for those needing to develop PET probes with CF₃ groups, and demonstrates the versatility of ¹¹C as an isotope for PET tracers.”

In a second achievement, a team led by MIT synthetic chemist Stephen L. Buchwald and Harvard Medical School radiochemist Jacob M. Hooker have devised a palladium-mediated cross-coupling reaction that uses ¹¹C-labeled hydrogen cyanide, H¹¹CN, as a reagent. The team directly labeled nanomolar amounts of unmodified peptides with ¹¹C cyano groups in less than 15 minutes under mild conditions (J. Am. Chem. Soc. 2017, DOI: 10.1021/jacs.7b02761).

The approach demonstrates “some very clever” ¹¹C coupling chemistry that opens up new possibilities for peptide labeling, Miller says. Carbon-11 is not commonly used for peptide labeling because of the chemical and time challenges, Miller adds. “Not only are these new ¹¹C-labeling reactions fast and selective on the peptide, the team has also proved that the labeling system is workable under high-activity synthesis.”