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Electrophilic Fluorinating Agent Offers Practical Access To Radiolabeled Compounds

Catch-and-release compound is made from fluoride rather than fluorine gas

by Bethany Halford
November 7, 2011 | A version of this story appeared in Volume 89, Issue 45

Pd-18F complex electrophilically fluorinates an aryl-Pd complex (bottom). This PET image (top) of a rat was made using a 18F-fluorinated compound prepared with a new Pd-18F complex.

Radiochemists can now expand their toolbox of molecular probes for positron emission tomography (PET), thanks to a new electrophilic fluorinating reagent. The palladium-based compound is made with 18F-fluoride, rather than 18F-fluorine gas, so it’s more practical to prepare than previously reported electrophilic fluorinating agents (Science, DOI: 10.1126/science.1212625).

PET imaging is a powerful, noninvasive tool for observing biological functions, particularly when spying on cancer cells or on the brain. The technique relies on compounds labeled with radioactive atoms, of which 18F is the most popular, thanks to its 110-minute half-life.

But the short half-life that makes 18F a good radionuclide also means the atom must be added to the molecular probe toward the end of its synthesis. That chemistry is typically done at or near the site where the PET scan will be performed using nucleophilic 18F-fluorinating compounds.

This limits the scope of the molecular probes that can be prepared, since there are plenty of molecules that resist nucleophilic fluorination. So researchers led by Harvard University’s Tobias Ritter and Harvard Medical School’s Jacob M. Hooker sought to make an electrophilic 18F-fluorinating compound. Such reagents have been reported before, but they have been synthesized with 18F-fluorine gas, a chemical that’s difficult to make and difficult to handle.

“If you want to have an impact in PET, the reaction has to be as simple as possible and as practical as possible,” Ritter says. So his group came up with a palladium-fluoride complex that’s made with the more commonly used 18F-fluoride. The complex can capture 18F-fluoride as a nucleophile but release 18F as an electrophile, Ritter explains. They designed this catch-and-release compound by blocking access to the electrophilic Pd center, making nucleophilic attack at fluoride more likely.

The complex fluorinates electron-rich palladium-arene complexes, tolerates a range of functional groups, and can be used to create complex aromatic PET-imaging probes quickly. It’s also fairly stable to water and heat, Ritter notes. The researchers have already used the reagent to create probes for PET imaging in animals.

Because the fluorination reaction makes use of Pd reagents, the issue of removing the metal prior to injecting the tracer into patients remains. But the researchers report that because only small amounts of the molecular probes are needed, purification with high-performance liquid chromatography was sufficient to remove all but 5 ppb of Pd residue, well within the 1,000-ppb limit set by U.S. Pharmacopeia.

“The development of a high-specific-activity electrophilic fluorination reagent from 18F-fluoride has been on the PET chemist’s wish list for decades,” says Joanna S. Fowler, an expert in PET radiotracers at Brookhaven National Laboratory. “This work is a gift to the field, opening up a whole new world of high-specific -activity 18F-labeled molecules which were not previously accessible.”

“This Pd-mediated fluorination reaction is highly innovative and could significantly improve 18F-labeling reactions at a high specificity leading to radiopharmaceutical products suitable for clinical application,” adds Hank F. Kung, a radiopharmaceutical expert at the University of Pennsylvania.


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