New Spin on Biomolecular Tags Lets MRI Catch Metabolic Wobbles

 In principle, magnetic resonance imaging (MRI) could be used to track disease-related biomolecular processes. In practice, magnetic resonance signals die out too quickly. Also, these signals are detectable only with incredibly expensive equipment. The necessary devices, called hyperpolarizers, are commercially available, but they cost as much as $3 million each.

    Yet magnetic resonance can be more practical, report scientists from Duke University. These scientists say that they have discovered a new class of molecular tags that enhance magnetic resonance signals by 10,000-fold and generate detectable signals that last over an hour, and not just a few seconds, as is the case with currently available tags. Moreover, the tags are biocompatible and inexpensive to produce, paving the way for widespread use of MRI to monitor metabolic process of conditions such as cancer and heart disease in real time.

    According to the Duke team, which was led by physicist Warren S. Warren, Ph.D., and chemist Thomas Theis, Ph.D., the hyperpolarization window to in vitro and in vivo biochemistry can be opened by combining two advances: (1) the use of ¹⁵N₂-diazirines as storage vessels for hyperpolarization, and (2) a relatively simple and inexpensive approach to hyperpolarization called SABRE-SHEATH.

    The details appeared March 25 in the journal Science Advances, in an article entitled, “Direct and Cost-Efficient Hyperpolarization of Long-Lived Nuclear Spin States on Universal ¹⁵N₂-Diazirine Molecular Tags.” The article explains that the promise of magnetic resonance in tracking chemical transformations has not been realized because of the limitations of existing techniques, such as dissolution dynamic nuclear polarization (d-DNP). Such techniques have lacked adequate sensitivity and are unable to detect small number of molecules without using unattainably massive magnetic fields.

    MRI takes advantage of a property called spin, which makes the nuclei in hydrogen atoms act like tiny magnets. Applying a strong magnetic field, followed by a series of radio waves, induces these hydrogen magnets to broadcast their locations. Most of the hydrogen atoms in the body are bound up in water; therefore, the technique is used in clinical settings to create detailed images of soft tissues like organs, blood vessels, and tumors inside the body.

    With greater sensitivity, however, magnetic resonance techniques could be used to track chemical transformations in real time. This degree of sensitivity, say the Duke scientists, could be within reach.

    “We use a recently developed method, SABRE-SHEATH, to directly hyperpolarize ¹⁵N₂ magnetization and long-lived ¹⁵N₂ singlet spin order, with signal decay time constants of 5.8 and 23 minutes, respectively,” wrote the authors of the Science Advances article. “We find >10,000-fold enhancements generating detectable nuclear MR signals that last for over an hour.” The authors added that ¹⁵N₂-diazirines represent a class of particularly promising and versatile molecular tags and can be incorporated into a wide range of biomolecules without significantly altering molecular function.

    “This represents a completely new class of molecules that doesn’t look anything at all like what people thought could be made into MRI tags,” said Dr. Warren “We envision it could provide a whole new way to use MRI to learn about the biochemistry of disease.”

    Qiu Wang, Ph.D., an assistant professor of chemistry at Duke and co-author on the paper, said the structure of ¹⁵N₂-diazirine is a particularly exciting target for hyperpolarization because it has already been demonstrated as a tag for other types of biomedical imaging.

    “It can be tagged on small molecules, macromolecules, amino acids, without changing the intrinsic properties of the original compound,” said Dr. Wang. “We are really interested to see if it would be possible to use it as a general imaging tag.” Magnetic resonance, added Dr. Theis, is uniquely sensitive to chemical transformations: “With magnetic resonance, you can see and track chemical transformations in real time.”

    The scientists believe their SABRE-SHEATH catalyst could be used to hyperpolarize a wide variety of chemical structures at a fraction of the cost of other methods. “You could envision, in five or ten years, you’ve got the container with the catalyst, you’ve got the bulb with the hydrogen gas,” explained Dr. Warren. “In a minute, you’ve made the hyperpolarized agent, and on the fly you could actually take an image. That is something that is simply inconceivable by any other method.”