Development of Novel Molecular Imaging Agents and Methods for Magnetic Resonance Imaging

这项研究的中心目标是开发用于磁共振成像(MRI)的分子成像方法和试剂。分子成像是一门研究学科，旨在非侵入性地可视化、表征和量化发生在分子或细胞水平上的活体生物体的过程。由于MRI已经成为许多疾病的标准治疗手段，开发新的MRI试剂和方法来成像体内的分子过程引起了人们的极大兴趣。核磁共振成像能产生高对比度和分辨率的组织图像。它还能够提供“功能”信息，这可以为理解分子成像数据提供重要的背景。不幸的是，由于分子靶标在体内的浓度低，而且MRI的灵敏度有限，使用MRI往往很难检测到分子靶标。在这项发现拨款中提出的研究重点是开发新的分子成像剂和方法，具有高靶点灵敏度和特异性，用于磁共振成像。有三个一般的研究目标来支持这一研究目标。*我们的第一个研究目标是用弛豫测量法表征新的造影剂。许多MRI造影剂都是以顺磁性化合物为基础的，这种化合物可以增加附近组织的松弛。这些药剂的有效性以其松弛程度为特征。这是在一系列被称为核磁弛豫色散(NMRD)测量的实验中测量的。我们将与造影剂化学小组合作开发新的MRI试剂，向他们提供可用于设计下一代试剂的NMRD数据。此外，我们正在开发一种名为dreMR的MRI快速磁场循环方法，该方法可用于提高分子成像目标对比剂的“特异性”。*除质子外，其他核可用于MRI以确定有关细胞环境的重要信息。我们感兴趣的是用核磁共振对钠和碳13核进行活体成像，这可以揭示细胞内生化过程的重要信息。这需要为MRI开发特殊的软件(称为脉冲序列)和射频硬件。高效的脉冲序列和射频硬件将提高MRI的灵敏度，从而缩短图像采集时间，提高图像的空间分辨率。*我们的最终目标是开发一种用于磁共振和生物发光成像模式的报告基因和探针系统。核磁共振报告/探测系统可用于跟踪植入细胞的位置和命运。磁共振成像记者具有良好的图像分辨率和组织穿透性，但与生物发光记者相比缺乏敏感性。我们将使用基因组编辑方法将敏感的BLI和MRI报告基因添加到细胞系中，这将使改进动物细胞跟踪实验成为可能。

The central goal of this research is the development of molecular imaging methods and agents for use with magnetic resonance imaging (MRI). Molecular imaging is a research discipline, which seeks to non-invasively visualize, characterize and quantify processes taking place at the molecular or cellular level in living organisms. Since MRI is already the standard of care in many diseases, there is great interest in developing new agents and methods for MRI to image molecular processes in vivo. MRI produces excellent images of tissue with high contrast and resolution. It is also capable of providing “functional” information, which can provide important context for understanding molecular imaging data. Unfortunately it is often difficult to detect molecular “targets” using MRI due to their low in vivo concentration and the limited sensitivity of MRI. The research proposed in this Discovery Grant is focused on developing new molecular imaging agents and methods with high target sensitivity and specificity for use with MRI. There are three general research objectives to support this research goal.*** Our first research objective is the characterization of new contrast agents using relaxometry. Many contrast agents for MRI are based on paramagnetic compounds, which increase the relaxation of nearby tissue. The effectiveness of these agents is characterized by their relaxivity. This is measured in a series of experiments known as Nuclear Magnetic Relaxation Dispersion (NMRD) measurements. We will collaborate with contrast agent chemistry groups developing new MRI agents, providing them NMRD data, which can be used to engineer next-generation agents. In addition, we are developing a fast magnetic field-cycling method for MRI known as dreMR, which can be used to improve the “specificity” of targeted contrast agents for molecular imaging.***In addition to protons, other nuclei can be used with MRI to determine important information about the cellular environment. We are interested in in vivo imaging of sodium and carbon-13 nuclei with MRI, which can reveal important information about biochemical processes in cells. This requires development of special software (known as pulse sequences) and RF hardware for MRI. Efficient pulse sequences and RF hardware will increase the sensitivity of MRI so that we can reduce our image acquisition time and improve the spatial resolution of our images. *** Our final objective is the development of a reporter-gene and probe system for magnetic resonance and bioluminescence imaging modalities. MRI reporter/probe systems can be used for tracking the location and fate of implanted cells. MRI reporters have excellent image resolution and tissue penetration but lack sensitivity compared to bioluminescence reporters. We will use genome-editing methods to add sensitive BLI and MRI reporter genes to cell lines, which will enable improved cell tracking experiments in animals.