All-Organic MRI Contrast Agent Tested In Mice

To produce sharper images of organs through magnetic resonance imaging, doctors and researchers often inject patients with so-called contrast agents. The most commonly used agents contain the metal gadolinium. Researchers are looking for all-organic alternatives, in part, because the gadolinium compounds can cause serious adverse reactions in patients with kidney disease. Now scientists have designed a new practical organic contrast agent based on nitroxide radicals and demonstrated its use in living mice (J. Am. Chem. Soc., DOI: 10.1021/ja3079829).

Like gadolinium, nitroxide radicals are paramagnetic. Because of this similarity, researchers have long thought the radicals could serve as organic contrast agents. But research in this area has run into problems, says Murali C. Krishna, of the National Cancer Institute. Conditions inside the body quickly reduce nitroxides to hydroxyl amines, which are not paramagnetic. Also, compared to gadolinium, the radicals have low relaxivities. Relaxivity is a measure of the effect that a contrast agent has on nuclei in nearby molecules, typically water. These magnetic effects enhance the MRI signal.

To overcome the low relaxivity problem, a few groups had conjugated multiple copies of commercially available nitroxide radicals to dendrimers. Unfortunately, these scientists have only tested these dendrimers in limited applications, such as imaging tissue samples of cartilage, instead of whole, living organisms.

Andrzej Rajca of the University of Nebraska, Lincoln, and his colleagues saw an opportunity to develop improved organic radical contrast agents. Before building the contrast agents, the team synthesized nitroxide molecules with bulky spirocyclohexyl groups to make the radicals less reactive and give them longer lifetimes inside the body. In preliminary tests in water solutions, Rajca’s team found that an ascorbate reducing agent reacts with these more hindered molecules half as fast as with less hindered nitroxides.

They attached the hindered nitroxides to dendrimers, but soon discovered that the resulting polymers were nearly insoluble in water. To make the dendrimers more soluble, they decorated the dendrimers with hydrophilic polyethylene glycol polymers.

The resulting organic contrast agents have relaxivities that are comparable to gadolinium. When the team injected the dendrimers into the bloodstreams of mice, the agents lasted for at least 90 minutes, which is a useful lifetime for imaging, Rajca says.

Krishna, who was not involved in the research, says the researchers next need to study the toxicology of their contrast agents. But if those studies show no cause for concern, these agents could eventually represent an alternative to gadolinium in the clinic, he says.

Krishna also points out that gadolinium is a rare metal used in other applications, such as optics and magnetic memory. An all-organic agent, he says, would make more gadolinium available for these competing applications.