Manganese-Based Contrast Agent Offers Safer, Non-Toxic Option for MRI Scans

Contrast-enhanced MRI scans could be a good deal safer very soon, especially for patients with chronic kidney disease, thanks to research efforts from Massachusetts General Hospital (MGH) and Harvard Medical School.

Based on their efforts a new manganese-based contrast agent could replace gadolinium, the heavy metal that is currently used but that also is retained in the brain, bones, and other organs and is associated with nephrogenic systemic fibrosis.

MGH and Harvard researchers published their work on this contrast agent – Mn-PyC3A – in Investigative Radiology. Their work builds on previous studies that show how this agent is diagnostically equivalent to gadolinium-based contrast agents (GBCAs) for visualizing blood vessels and tumors.

“This manganese-based contrast agent Mn-PyC3A does everything a GBCAs would do,” said Eric M. Gale, Ph.D., co-inventor of the agent and a biomedical engineering at MGH and assistant professor of radiology at Harvard.

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The human body requires a certain amount of manganese, an element that is typically found in certain foods, such as nuts, legumes, seeds, leafy green vegetables, and whole grains. Consequently, the body can easily process and excrete it. But, it is the element’s magnetic properties that make it an appropriate, non-toxic replacement for gadolinium, he said.

“This is obviously important for patients with chronic kidney disease and other forms of renal insufficiency that might require careful risk/benefit analysis before undergoing a GBCA-enhanced MRI, but we can also envision giving Mn-PyC3A to any patient requiring a contrast-enhanced MRI,” he said. “There are patients who require many GBCA-enhanced MRI examinations over the course of years for disease surveillance or screening.”

In order for Mn-PyC3A to work, the investigators optimized it so it would hold manganese very tightly and create an MRI contrast that was as effective as commercially available GBCAs.

To test the agent's efficacy, the team used PET and MRI imaging to compare Mn-PyC3A with Mn-DPDP, an older manganese-based contrast agent that was previously used for liver imaging. By labeling both manganese-based agents with a positron-emitting manganese isotope, investigators used PET/MRI to see how Mn-PyC3A and Mn-DPDP move around the body and are eliminated in real time. They could also detect and measure any trace levels of residual manganese left in the body after several hours or days.

The key difference between the two agents, said Peter Caravan, Ph.D., co-inventor of Mn-PyC3A and co-director of the MGH Institute for Innovation in Imaging and radiology professor, is that Mn-DPDP still leaves substantial amounts of residual manganese in bone, salivary glands, the liver, and the gastrointestinal tract. Mn-PyC3A does not – it is rapidly processed by the body and does not accumulate in any tissue.

“PET/MRI spotlights major differences in manganese bio-distribution between Mn-PyC3A and Mn-DPDP,” Caravan said, “and demonstrates how robust Mn-PyC3A is against releasing the manganese ion.”

Based on their analysis, Mn-PyC3A is largely eliminated by the liver and excreted through feces, but a small amount is still processed by the kidneys, meaning that any limits to kidney function could make it harder for the body to process the contrast agent. But, PET/MRI conducted in renally impaired rats showed that Mn-PyC3A still cleared the body quickly and efficiently, indicating it could be a good option for patients with poor kidney function.

“Clinical GBCAs are eliminated only through the kidney, and, thus, remain in renally impaired patients for longer periods resulting in increased gadolinium exposure,” said Iris Yuwen Zhou, Ph.D., and MGH researcher and Harvard radiology instructor. “Our imaging data shows how for Mn-PyC3A, the liver compensates for diminished renal function and ensure rapid and complete elimination of Mn-PyC3A.”

In addition, in head-to-head comparison with equal doses of Mn-PyC3A and gadoterate, a state-of-the-art GBCA, the team highlighted Mn-PyC3A’s efficiency further. With renally impaired rats, they showed that, seven days post-administration, there was a significantly more efficient whole-body elimination of manganese in the rats than of gadolinium.

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