Free radical hyperpolarizing agents for ultra-low field Overhauser MRI

Overhauser增强磁共振成像（OMRI）是一种可视化方法，其使用从自由基的未配对电子到原子核的原位射频引发的极化转移（即，相邻质子）-奥弗豪泽动态核极化（ODNP）。由于ODNP，来自OMRI的信噪比（SNR）可以提高两个数量级。这种增强取决于自由基试剂的浓度;因此，OMR图像反映了样品（动物组织）中外源性自由基试剂的分布和自由基光谱参数的变化。因此，OMRI提供了生理学、氧浓度、活性氧（ROS）产生和酶活性的基本功能信息。缺血组织和肿瘤通常表现出显著的氧化还原状态和ROS产生变化。鉴于此，OMRI目前吸引了相当大的兴趣，作为一种潜在的技术，在肿瘤学中进行功能成像。然而，体内OMRI是有限的，因为在高磁场下，用于激发电子自旋能级所需的射频场被组织强烈吸收，并且不能渗透组织足够深。然而，低场磁共振设备解决了这个问题，现在正处于快速发展阶段，可能很快就会被部署用于常规医疗诊断。因此，生物相容性自由基超极化造影剂（HCAs）的发展已成为有效的ODNP超极化附近的质子至关重要。HCA的一个优点是在受试者体内发生超极化，从而能够进行长时间的MRI实验。然而，这些试剂必须被优化以在低射频功率下提供高Overhauser增强（>100）、高稳定性并且在体内没有毒性。WSIC-Tubingen和美国团队在开发ODNP自由基方面经验丰富，包括同位素富集，生物还原抗性，生物可降解和基于大分子的靶向氮氧自由基（WP 1）。这些HCA将在原型ULF MRI系统（WP 2）中表征ODNP功效和对生理生物标志物（氧化还原和酸度）的响应性，并测试生物相容性和毒性（WP 3）。最后，HCA将用于体内OMRI实验（WP 4）。该提案的成功完成将允许解决肿瘤学中更具体的问题，以展示ULF MRI在肿瘤主动和功能诊断中的价值。

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.