Next Generation Molecular Probes for Magnetic Resonance Imaging and Sensing: Design, Synthesis, Evaluation and Application

核磁共振既可以用于波谱研究，也可以用于成像研究，因此在化学、生物和医学中得到了广泛的应用。这两种基于磁共振的技术的显著局限性是灵敏度较低。水是体内含量最丰富的分子，临床核磁共振成像需要依赖水的核磁共振氢谱信号。许多具有生物学或医学意义的分子事件，如蛋白质表达和pH波动，是核磁共振或核磁共振无法获得的。这项研究计划旨在开发新的化学探针，以提高磁共振成像和光谱传感的灵敏度和分子特异性。它们的应用将在分子水平上非侵入性地揭示生物系统的结构和功能信息，是高级生物医学研究和临床诊断的理想选择。 根据工作机制，该方案由两个互补的部分组成。第1部分重点介绍下一代磁共振造影剂(CA)。具有未成对电子的顺磁性金属络合物可以催化周围H2O分子的1H-核磁共振弛豫。它们被广泛应用于临床，作为增强信号强度和组织对比度的CA。传统的磁共振成像方法主要是基于具有7个不成对的f电子(S=7/2)的Gd(III)络合物，因此具有较高的磁偶极矩。Gd试剂的内在局限性包括松弛增强效率低(松弛系数)和体内从螯合物中释放有毒的游离Gd的风险。在过去的NSERC循环中，我们建立了一个基于锰(III)卟啉(MNP)的非Gd体系，具有更好的灵敏度和生物相容性。当前计划的第一部分旨在实现以下突破： 了解和进一步提高MNPs在强磁场下的高弛豫度； 开发用于特定应用的新型MNPs，包括血管成像、细胞成像和疾病靶向分子成像； 开发新的方法来操纵松弛，并将其用于MRI传感器的开发。 第二部分旨在开发基于新的化学机理的抗磁性核磁共振光谱传感器。它包括两个项目： 具有慢质子交换(SPE)机制的比率核磁共振pH传感器； 基于化学交换速率调制的超灵敏核磁共振传感器。 通过开发新的策略和选择合适的目标，高灵敏和准确的核磁共振传感器可能被应用于成像应用。此方法是对第1部分中基于MRI CA的方法的补充。 我们的计划整合了多学科的研究方法，包括基于理论的分子设计、化学合成、光谱研究、生物系统评估和疾病诊断应用。因此，它是培养化学、生物学和转化医学技术之间的高素质人才的理想平台。

Nuclear magnetic resonance can be used for both spectroscopy (NMR) and imaging (MRI) studies, and thus is widely applied in chemistry, biology and medicine. The hallmark limitation of both MR-based techniques is their low sensitivity. Clinical MRI has to rely on the 1H NMR signal of water, the most abundant molecule in vivo. Many molecular events with biological or medical significance, such as protein expression and pH fluctuation, are inaccessible by NMR or MRI. This research program aims to develop new chemical probes to improve the sensitivity and molecular specificity of MR imaging and spectroscopic sensing. Their application will non-invasively reveal structural and functional information about living biological systems at the molecular level, ideal for advanced biomedical research as well as for clinical diagnosis. The program consists of two complementary parts, based on the working mechanism. Part 1 focuses on next-generation MRI contrast agents (CAs). Paramagnetic metal chelates with unpaired electrons can catalytically accelerate the 1H-NMR relaxation of surrounding H2O molecules. They are widely used in clinics as CAs to enhance signal intensity and tissue contrast. Conventional MRI CAs are mainly based on chelated Gd(III) which has seven unpaired f-electrons (S = 7/2) and thus a high magnetic dipole moment. The intrinsic limitations of Gd agents include low relaxation-enhancement efficiency (relaxivity) and the risk of releasing toxic free Gd from the chelates in vivo. During the past NSERC cycle, we established a non-Gd system based on Mn(III)porphyrin (MnP), offering better sensitivity and biocompatibility. Part 1 of the current program aims to achieve the following breakthroughs: To understand and to further improve the high relaxivity of MnPs at high magnetic fields; To develop novel MnPs for specific applications, including vascular imaging, cellular imaging and disease-targeted molecular imaging; To develop new approaches to manipulate relaxivity, and utilize them for MRI sensor development. Part 2 aims to develop diamagnetic NMR spectroscopic sensors based on novel chemical mechanisms. It includes two projects: Ratiometric NMR pH sensors with a slow proton exchange (SPE) mechanism; Ultrasensitive NMR sensors based on the modulation of chemical exchange rate. By developing novel strategies and choosing appropriate targets, highly sensitive and accurate NMR sensors may be applied for imaging applications. This approach complements the MRI CA-based methods of Part 1. Our program integrates multidisciplinary research approaches, including theory-based molecular design, chemical synthesis, spectroscopic investigations, evaluations in biological systems, and applications for disease diagnosis. It is thus an ideal platform for training highly qualified personnel at the interfaces between chemistry, biology and translational medical technology.