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‘Radiolabeling’ lets scientists track the breakdown of drugs

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

Chemists consider thousands of compounds in the search for a new drug, and a candidate’s metabolism is a key factor that must be evaluated carefully and quickly. Researchers at Princeton University and pharmaceutical company Merck & Co., Inc. report in the journal Nature that scientists can selectively replace hydrogen atoms in molecules with tritium atoms — a radioactive form of hydrogen that possesses two extra neutrons — to “radiolabel” compounds. This technique can be done in a single step while preserving the biological properties of the parent compound.

While current state-of-the-art techniques are quite reliable, they only work when dissolved in specific solvents, ones that aren’t always capable of dissolving the drug compound of interest. The researchers’ method, however, used an iron-based catalyst that is tolerant to a wider variety of solvents, and it labels the molecules at the opposite positions as compared to existing methods.

“The fact that you can access other positions is what makes this reaction really special,” said corresponding author Paul Chirik, the Edwards S. Sanford Professor of Chemistry at Princeton. Previous methods only 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.

“Radiolabeled compounds help medicinal chemists get a better picture of what actually happens to the drug by showing how the drug is metabolized and cleared,” said David Hesk, a collaborator at Merck and co-author on the work. By rapidly assessing the compounds’ metabolism early on, scientists can shorten the time it takes to develop and bring a drug to market. “Having another labeling reaction is very powerful because it gives radiochemists another tool in the toolbox,” he said.

This unique reactivity was actually discovered unexpectedly. Renyuan Pony Yu, a graduate student in the Chirik lab, had originally set out to use their iron catalyst for a different reaction that they were collaborating on with Merck. To study the iron catalyst’s capabilities, Yu subjected it to a technique called proton nuclear magnetic resonance spectroscopy (NMR), which allows chemists to deduce the positions of hydrogen atoms in molecules.

“We started seeing this beautiful, very systematic pattern of signals in the NMR, but we didn’t really know what they were,” said Yu, who is first author on the new study. Particularly puzzling was the fact that the pattern of signals would disappear over time.