Dr. Benjamin Rothstein and collaborators have unveiled a simple operational method for preparing carbon-isotope-labeled versions of drugs and diagnostics.
New drug development depends on scientists’ ability to elegantly design specific drugs for targeted clinical trials. Isotope labeling of drug candidates in research laboratories is critical to this overall effort.
In a new study, the lab of Dr. Benjamin Rothstein at the Ottawa College of Medicine collaborated with colleagues to uncover a simple, operational method for preparing copies of drugs and diagnostics labeled with carbon isotopes. They developed a way to exchange a single atom in amino acids — the building blocks of proteins that are also used to make molecules — for its counterpart.
This is really important in drug development because we want to know where the drug goes in the body, how it’s metabolized and eliminated so we can plan appropriate dosing and toxicity studies. “
Dr. Benjamin Rotstein, MD, Associate Professor in the School of Medicine, Department of Biochemistry, Microbiology, and Immunology
The work is described in the paper in Nature’s chemistry High Impact Journal also published a separate article on the study in which two Danish scientists at Aarhus University described the team’s methods as “important to the field”.
Dr. Rothstein’s lab initially designed their experiments to work as a cofactor our bodies use: pyridoxal phosphate, which decarboxylates an amino acid and is the active form of vitamin B6. But he says they wanted to make it work in reverse, and it turns out the mechanism was a little different than they first expected. .
“We’re actually adding carbon dioxide, and then removing the acid. So it’s a different mechanism that allows us to look at better catalysts and extend the range beyond amino acids,” he says.
The research was carried out in collaboration with colleagues from the University of Alberta and chemists at the French pharmaceutical company Sanofi. Dr. Rothstein’s lab conducted carbon-11 studies and worked with these collaborators to uncover the reaction mechanism. His lab uses carbon-11 because it’s radioactive in a way that works well for medical imaging.
What are the next steps for his uOttawa lab? Dr. Rothstein and his team are now studying how to get the reaction to produce just one “mirror copy” of an amino acid so that researchers don’t need to separate it after the fact.
He says they’re particularly excited about using the 11-carbon amino acid to measure the rate at which our bodies produce proteins because this can be an indicator of disease.
“We’re also using these in imaging studies now to learn about metabolic rates and protein synthesis in different tissues,” says Dr. Rothstein, who is also director of the Molecular Imaging Probes and Radiochemistry Laboratory at the University of Ottawa’s Heart Institute.
Basharat, and. et al. (2022) Aldehyde-catalyzed carboxylate exchange of α-amino acids with isotope-labeled carbon dioxide. Nature’s chemistry. doi.org/10.1038/s41557-022-01074-0.