No more mirrors: a new way of making molecules for tracking disease

Abigail Doyle

Abigail Doyle, associate professor of chemistry (Photo by C. Todd Reichart)

RADIOACTIVITY IS USUALLY ASSOCIATED with nuclear fallout or comic-book spider bites, but in very small amounts it can be a useful tool for diagnosing diseases.

Small molecules containing a radioactive isotope of fluorine, called 18F, allow doctors to track tumors using a scanning procedure known as positron emission tomography (PET). But existing methods of making 18F radiotracers tend to produce molecules that are identical in every way but one — the molecules are oppositely oriented, like a person’s right and left hand, or like mirror images. Due to their distinct 3-D structures, only one of the mirror images — known as enantiomers — is useful for tracking tumors.

Now, researchers at Princeton University led by Abigail Doyle, an associate professor of chemistry, report a route that can selectively produce just one type of enantiomer — either right-handed or left-handed — which could aid researchers in making more potent radiotracers. The work was published online in March 2014 in the Journal of the American Chemical Society.

“We know that in biology, small-molecule interactions with enzymes often depend on the 3-D properties of the molecule,” Doyle said. “Being able to prepare the enantiomers of a given tracer, in order to optimize which tracer has the best binding and imaging properties, could be really useful.”


Molecules such as the one pictured can occur as two varieties that are identical in every way but one — they are mirror images of each other. Due to their distinct 3-D structures, these mirror images, known as enantiomers, interact with the body differently. Abigail Doyle’s group report a route that can selectively produce just one type of enantiomer, a result that could help researchers make more potent radiotracers for use in disease diagnosis.

Doyle’s research team developed a cobalt fluoride catalyst that causes radioactive fluoride to react with epoxides — triangleshaped molecules that contain an oxygen atom. The researchers’ method demonstrated excellent ability to select single enantiomers for 11 substrates, five of which are known pre-clinical PET tracers.

With this new method, researchers can test single enantiomers of existing or new PET radiotracers and evaluate if these compounds offer any advantage over the enantiomeric mixtures. Ultimately, the goal is to use this chemistry to identify a completely novel PET radiotracer for imaging.

Currently, there are only four FDA-approved 18F radiotracers. One of the major limitations to discovering PET tracers is the source of 18F. Existing 18F sources are strongly basic and, during the process of making the 18F radiotracer, can cause the elimination of alcohol and amine groups and rearrange the groups into mixtures of enantiomers in a process called racemization.

Under Doyle’s less basic reaction conditions, however, even alcohols and secondary amines are tolerated and no racemization is observed. The research was supported by the National Institutes of Health, the National Science Foundation and the Pennsylvania Department of Health.

First author Thomas Graham, who earned his Ph.D. in spring 2014, and graduate student Frederick Lambert commuted to the University of Pennsylvania, where they conducted the radiolabeling experiments in the laboratory of collaborator Hank Kung, an emeritus professor of radiology.

“We demonstrated that the radioactivity is high enough that we could actually use it for imaging. That’s an exciting next step,” Doyle said.

–By Tien Nguyen