Metabolic tracking: NMR and radiolabels

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  • Published: Feb 1, 2016
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: Metabolic tracking: NMR and radiolabels

Systematic signals

A new method for labeling molecules with radioactive elements could let chemists more easily track how drugs under development are metabolized in the body. Renyuan Pony Yu Courtesy of Princeton

Unexpected systematic signals in the proton NMR spectra of an iron catalyst have serendipitously led to a new way to radiolabel compounds and track how drugs are metabolized in the body.

Chemical space is vast and drug discovery a tough call for those searching without a map. Moreover, the journey is not simply about finding the path of least resistance from A to B there are metabolic detours and bioavailability forks in the road. Now, researchers at Princeton University and pharmaceutical company Merck writing in the journal Nature have a new tool to help them navigate chemical space more effectively. They have demonstrated how they can selectively replace hydrogen atoms in their lead compounds with tritium in a single step to allow them to leave a "breadcrumb trail" in the form of radiolabelled compounds. The process can be done in a single step without interfering with the biological properties of the original compound.

Princeton's Paul Chirik and colleagues point out that state of the art techniques are reliable but they only work with specific solvents and often those solvents cannot dissolve the drug compound of interest. The team's new work with an iron-based catalyst that is tolerant to a much wider range of solvents allows them to radiolabel their molecules with much more control.

Access all areas

"The fact that you can access other positions is what makes this reaction really special," explains Chirik. Earlier methods were only able to incorporate radioactive tritium atoms into the molecule directly next to an atom or a group of atoms called a directing group. The new iron-catalyzed method does not require a directing group, and instead places tritium at whatever positions in the molecules are the least crowded. Merck's David Hesk adds that, "Radiolabelled compounds help medicinal chemists get a better picture of what actually happens to the drug by showing how the drug is metabolized and cleared." The ability to navigate the metabolic route early cuts the journey time from discovery to pharmaceutical market. "Having another labelling reaction is very powerful because it gives radiochemists another tool in the toolbox," he says.

The new tool was discovered almost by accident when Chirik's graduate student Renyuan Pony Yu was working with an iron catalyst for an entirely different purpose in collaboration with Merck. Yu was using NMR spectroscopy to deduce the positions of hydrogen atoms, as you do. "We started seeing this beautiful, very systematic pattern of signals in the NMR, but we didn’t really know what they were," explains Yu. Particularly puzzling was the fact that the pattern of signals would disappear over time. The team turned to Istvan Pelczer, Director of the NMR Facility at Princeton, for help. He developed a technique to analyze the signals with much greater confidence and the researchers homed in on the origins of the puzzling pattern: the iron catalyst was interacting with the deuterium-rich solvent used to dissolve the NMR sample and swapping out hydrogen atoms for heavy hydrogen.

Yu presented the findings to Matt Tudge at Merck who recognised that the same swapping process might be used to deliberately introduce the heavier hydrogen isotope, tritium, into a drug molecule as a radiolabel. "This is a classic example where you really need both partners," Chirik explains. "We were the catalyst experts, but they were the applications experts."

Stable obstacle

Though compounds labelled with tritium are used mostly in studies of metabolic processes, they can also be used early in the mapping of a drug-discovery route to help identify a biological target against which a potential drug can be tested. The biological target could be an enzyme or protein associated with a particular disease, for instance. The well-known class of cholesterol-lowering drugs, statins, for example, are known to target the enzyme HMG-CoA reductase.

To explore the scope of the reaction, Yu first optimized the reaction to incorporate deuterium atoms, which are used in test runs instead of the more hazardous and costly tritium. He found that the iron catalyst was surprisingly robust and successfully labelled many different types of compounds, including some from Merck’s library of past drug candidates.

"It was a very exciting project for me because I got to work with real drugs that are fully functionalized and useful," Yu says. One of their test substrates was the antihistamine Claritin, which Yu simply bought from a local store and extracted its active ingredient back in the laboratory. Yu eventually travelled to the Merck campus in Rahway for radioactivity training and performed the same reactions again this time with tritium gas, rather than deuterium. The team has also now demonstrated that the iron catalyst can replace hydrogen atoms with other groups besides deuterium and tritium atoms and is extending this chemistry into many other projects in the lab. There remains one obvious obstacle to the wider use of the iron catalyst in that it is extremely air and moisture sensitive and can only be handled in a glove box.

"The next steps are having the catalyst available commercially," Chirik told SpectroscopyNOW. "We are working with Green Centre Canada to prepare and distribute the catalyst to end users. From a technical standpoint, we need to improve catalyst handling. Right now it is an air-sensitive molecule meaning it is delicate and must be handled in an inert atmosphere glove box. While within the capabilities of many chemists, it is preferential to be able to handle it on the bench top in air."

Related Links

Nature 2016, 529, 195-199: "Iron-Catalyzed Tritiation of Pharmaceuticals"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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