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

用于磁共振成像和传感的下一代分子探针：设计、合成、评估和应用

• 批准号: RGPIN-2016-06589
• 负责人: Zhang, XiaoAn
• 金额: $ 2.19万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=683562
• 关键词: Next; Generation; Molecular; Probes; Magnetic

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.**

核磁共振可用于光谱（NMR）和成像（MRI）研究，因此广泛应用于化学，生物学和医学。这两种基于MR的技术的标志性限制是它们的低灵敏度。临床MRI必须依赖于水的1H NMR信号，水是体内最丰富的分子。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NMR或MRI无法获得的。该研究计划旨在开发新的化学探针，以提高MR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，非常适合先进的生物医学研究和临床诊断。该计划包括两个互补的部分，根据工作机制。第1部分重点介绍下一代MRI造影剂（CA）。具有未成对电子的顺磁性金属螯合物可以催化加速周围H2O分子的1H-NMR弛豫。它们在临床中广泛用作CA，以增强信号强度和组织对比度。传统的MRI CA主要基于螯合的Gd（III），其具有七个未配对的f电子（S = 7/2），因此具有高磁偶极矩。Gd试剂的内在限制包括低弛豫增强效率（弛豫率）和从体内螯合物释放有毒游离Gd的风险。在过去的NSERC循环中，我们建立了基于Mn（III）卟啉（MNP）的非Gd系统，提供了更好的灵敏度和生物相容性。当前计划的第1部分旨在实现以下突破：* 了解并进一步提高MNP在高磁场下的高弛豫率;* 开发用于特定应用的新型MNP，包括血管成像，细胞成像和疾病靶向分子成像;* 开发操纵弛豫率的新方法，并将其用于MRI传感器开发。第二部分旨在开发基于新化学机理的抗磁NMR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NMR pH传感器;* 基于化学交换速率调制的超灵敏NMR传感器。通过开发新的策略和选择合适的目标，高灵敏度和准确的NMR传感器可以应用于成像应用。这种方法补充了第1部分中基于MRI CA的方法。*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，生物系统的评估和疾病诊断的应用。因此，它是培养化学，生物学和转化医学技术之间接口的高素质人才的理想平台。