Free radical hyperpolarizing agents for ultra-low field Overhauser MRI

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Overhauser-enhanced magnetic resonance imaging (OMRI) is a visualization method that uses in situ radiofrequency-initiated polarization transfer from unpaired electrons of free radicals to nuclei (i.e., neighboring protons)—Overhauser dynamic nuclear polarization (ODNP). Due to ODNP, the signal-to-noise ratio (SNR) from an OMRI can be improved by two orders of magnitude. This enhancement depends on the concentration of the free radical agent; therefore, OMR images reflect the distribution of exogenous free radical agents in the sample (tissues of an animal) and changes in spectral parameters of the radical. Therefore, OMRI provides essential functional information on physiology, oxygen concentration, reactive oxygen species (ROS) production, and enzymatic activity. Ischemic tissues and tumors often demonstrate significant redox status and ROS production changes. In light of this, OMRI currently attracts considerable interest as a potential technology for performing functional imaging in oncology. However, in vivo OMRI is limited because, at a high magnetic field, the required radiofrequency field for the excitation of electron spin levels is strongly absorbed by tissues and cannot permeate tissues deep enough. However, this issue is solved by low-field MR devices, which are now undergoing rapid development and may soon be deployed for routine medical diagnosis. Therefore, the development of biocompatible free radical hyperpolarizing contrast agents (HCAs) has become essential for efficient ODNP hyperpolarization of the nearby protons. An advantage of the HCAs is that hyperpolarization occurs inside the subject, enabling long-running MRI experiments. However, these agents must be optimized to provide high Overhauser enhancement (>100) at low radiofrequency power, high stability, and no toxicity in vivo. The WSIC-Tubingen and the US team are highly experienced in developing ODNP radicals, including isotope-enriched, bioreduction-resistant, biodegradable, and macromolecular-based targeted nitroxide-based radicals (WP1). These HCAs will be characterized for ODNP efficacy and responsiveness to physiologic biomarkers (redox and acidity) in a prototype ULF MRI system (WP2) and tested for biocompatibility and toxicity (WP3). Finally, the HCAs will be used for in vivo OMRI experiments (WP4). The successful completion of this proposal will allow addressing more specific questions in oncology to showcase the value of ULF MRI for active and functional diagnosis of tumors.