A natural substance present in the human body has been transformed into a new contrast agent for magnetic resonance imaging (MRI). With a single dose, researchers can monitor both rapid blood flow and slower distribution in organs. The result: gentler and more detailed scans, demonstrated in live images by researchers from the Technical University of Denmark and their colleagues at the Technical University of Cartegena in Spain.
An anaesthetised laboratory rat lies in the bed of an MRI scanner, which can produce clear images of the animal’s internal organs. A thin needle in its tail injects the new contrast agent, trimethyl-2H9-15N-glycine (15N,d9-betaine), into the bloodstream. On the screen in front of the researchers, the organs appear in clear contours. First, the rapid flow through the blood vessels appears, followed by the slower spread into the tissue. Even after 15 minutes, the signal is strong. Previously, this would have required repeated scans with different contrast agents.
This method was developed by Ingeborg Sæten Skre and Mathilde Hauge Lerche at the Center for Hyperpolarization in Magnetic Resonance at the Department of Health Technology of the Technical University of Denmark in collaboration with colleagues in Denmark and abroad. The results were published earlier this year in Science Advances and mark the first time that betaine has been used as a contrast agent for live images.
“We have developed a new contrast agent that can track physiological processes both shortly after and long after injection. This provides a new opportunity to examine organ function and disease processes more gently and in greater detail than before,” explains Ingeborg Sæten Skre.
How the new method works
MRI scanners use powerful magnets and radio waves to create images of the inside of the body without ionising radiation. A contrast agent is added to obtain clear images of blood flow or how a substance is distributed. In this study, the contrast agent is betaine, a natural substance produced by the human body and also present in food. It helps cells maintain the balance between fluids and salts and plays a central role in the liver’s metabolism, making it ideal for tracking in the body.
To make betaine visible enough for scanning, researchers give it an energy boost before injecting it. This is done in a special device in which betaine is cooled to very low temperatures and exposed to a powerful magnetic field and microwave irradiation. This process aligns many more of the atomic nuclei in the same direction, producing a signal many times stronger than normal.
This process, known as hyperpolarisation, lasts long enough for the researchers to capture both what happens right after injection and what unfolds in the following minutes.
From laboratory idea to clear images
The research team worked with a special form of betaine, 15N,d9-betaine, which has been chemically adjusted to retain the magnetic resonance signal longer than ordinary contrast agents. The first step was to produce 15N,d9-betaine in a stable quality that could withstand hyperpolarisation. Next, they fine-tuned the scanning sequences themselves. The timing had to be precise to record both the rapid blood flow and the slow distribution in the organs.
“Getting a signal strong enough to capture both the fast and the slow images was technically challenging,” says Ingeborg Sæten Skre. She and her colleagues found that the signal remained visible in the body for more than 14 minutes – much longer than the 13C-based contrast agents, which typically lose their strength after 1–2 minutes. This enabled the researchers to track the whole process – from the first passage through the bloodstream to its gradual build-up in the tissue.
To take advantage of the long signal lifetime, the researchers split the dose in two. First, they took lightning-fast images – one every second – so that the blood inflow could be seen in real time. This was followed by a series of images taken at longer intervals, which showed how the substance was slowly distributed in the organs. Finally, they supplemented this with high-resolution images. They did this all in one single process, which previously required several substances or multiple scans.
“Seeing that we could capture the entire process in a single scan was very satisfying,” notes Ingeborg Sæten Skre. “This opens completely new possibilities for using the technique in the future.”
From rats to people
Developing a method is one thing; determining what it can actually be used for is another. Myriad possibilities are now emerging, ranging from detailed studies of organ function in the laboratory to early detection of disease among people.
In the laboratory, 15N,d9-betaine can be used to investigate how the kidneys, liver, heart and brain manage fluid balance and metabolism over time. Clinically, the technique may eventually become a tool for detecting early signs of diseases in which betaine plays a role, such as kidney disease, steatotic liver disease and certain metabolic disorders. This makes the method relevant for some major public health problems.
The method can show both early changes in the bloodstream and the slow distribution in the organs – all from the same dose. This means that doctors can get both the acute picture and data for follow-up in a single scan without multiple procedures. This could reduce stress for patients and provide quicker answers and better opportunities to adjust treatment along the way.
A long way from trials to hospitals
Despite the promising results in rats, the technique is still a long way from clinical use. Using a new scanning technique on humans requires many steps. First, researchers must show that the image patterns they see in animals are also present in more advanced disease models. The method must then be tested in small, closely monitored trials with patients.
This requires researchers to clearly know what the technique can do and its limits. Even though the new method shows how 15N,d9-betaine is distributed in the body over time, it does not reveal anything about the biochemical mechanisms behind the changes. The method also requires a hyperpolarisation unit close to the scanner, and this equipment is not yet available in all hospitals. There are also important differences between rats and humans, and this requires further experiments before moving forward.
“We need to be sure that the images we see in animal experiments can also be translated for human patients,” says Ingeborg Sæten Skre.
What the researchers will test next
The researchers are already working on testing the technique in models of kidney and liver disease, precisely where betaine plays a central role in the human body’s regulation. The aim is to show that the method can be used to detect changes in organ function early in the disease trajectory and to monitor treatment response. In the longer term, the ambition is to participate in clinical studies in which the technique can become part of a more targeted and biologically relevant diagnostic imaging arsenal.
“If the method proves equally strong for humans, it could pave the way for a new generation of MRI scans: gentle yet precise,” explains Ingeborg Sæten Skre.
Unlike 13C-based contrast agents, which only provide a short window of a few minutes, 15N,d9-betaine can maintain the signal for more than 14 minutes.
“This gives doctors much more detailed insight into the condition of organs – without repeated scans and without additional stress for the patient. This is precisely what the researchers want to test in the next studies,” concludes Ingeborg Sæten Skre.
For the researchers, the vision is clear: 15N,d9-betaine could become a specialised tool to expand how to understand and monitor disease – in ways not previously possible.
