Free radical hyperpolarizing agents for ultra-low field Overhauser MRI

Overhauser增强磁共振成像(OMRI)是一种利用射频引发的原位极化从自由基未配对电子转移到原子核(即相邻质子)的可视化方法-Overhauser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。这种增强依赖于自由基剂的浓度；因此，OMR图像反映了外源自由基剂在样品(动物组织)中的分布和自由基光谱参数的变化。因此，OMRI提供了有关生理、氧浓度、活性氧物种(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明显的氧化还原状态和ROS产生的变化。有鉴于此，OMRI目前作为一种在肿瘤学中进行功能成像的潜在技术引起了人们的极大兴趣。然而，在体内，Omri是有限的，因为在高磁场下，激发电子自旋能级所需的射频磁场被组织强烈吸收，无法渗透到组织足够深的地方。然而，这个问题可以通过低场磁共振设备来解决，这种设备现在正在快速发展，可能很快就会被部署到常规医疗诊断中。因此，开发生物相容的自由基超极化造影剂(HCAs)已成为实现邻近质子高效ODNP超极化的关键。HCA的一个优点是，超极化发生在受试者体内，使长期运行的MRI实验成为可能。然而，这些药物必须经过优化才能在低射频功率、高稳定性和体内无毒性的情况下提供高Overhauser增强(&gt；100)。WSIC-Tubingen和美国团队在开发ODNP自由基方面经验丰富，包括同位素富集型、生物还原抗性、可生物降解性和基于大分子的靶向氮氧化物自由基(WP1)。这些HCA将在原型Ulf MRI系统(WP2)中表征ODNP有效性和对生理生物标记物(氧化还原和酸度)的响应，并进行生物兼容性和毒性测试(WP3)。最后，这些HCA将用于体内OMRI实验(WP4)。这项提案的成功完成将使我们能够解决肿瘤学中更具体的问题，以展示URF MRI在肿瘤主动和功能性诊断中的价值。

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.