PARACEST Agents: Optimization for Human MR Imaging

描述(申请人提供)：顺磁化学交换饱和转移(PARACEST)试剂在磁共振成像中提供了一种潜在的新范式。这类试剂的一个优点是能够通过以其结合水共振或交换NH基团的频率施加的选择性射频照射来打开或关闭每个试剂。在“关”状态下，即在没有特别照射的情况下，PARACEST试剂不会干扰常规的磁共振成像序列，无论是否使用Gd。原则上，PARACEST试剂可以针对每种应用进行量身定做，因为它们的效果取决于它们的水交换率，而这些交换率可以使用合理的化学原理进行修改。这一功能也使它们成为开发响应性代理的一个有吸引力的平台。BRP的目标是通过系统地解决一些基本的、理论的和实际的问题，充分发挥这些化合物在体内作为造影剂的潜力。这些包括建立在成像实验中测量的效应的大小与水交换寿命、结合水和主体水之间的化学位移差的大小、饱和射频场的强度、SAR、浓度和活体局部环境之间的关系。这一合作伙伴关系由两个学术机构和一个产业合作者组成。三个主要重叠和互动的重点领域是：将在达拉斯大学(UTD)进行的稀土化学；将主要在通用电气全球研究中心(GEGRC)进行的脉冲序列实施、理论、模拟和体外验证，以及主要在北京国际数据中心进行的体内验证。Dean Sherry(UTD项目负责人)是国际公认的稀土络合物合成和表征专家，并在基本核磁共振交换理论方面拥有专业知识。Thomas Dixon和Ileana Hancu(项目负责人，GEGRC)都是核磁共振和磁共振成像方面的专家。罗伯特·伦金斯基(PI，BIDMC)是一名核磁共振光谱仪，在稀土试剂和磁共振成像方面都有专长。David Alsop(首席调查员，BIDMC)在优化动脉自旋标记灌注研究方面有着长期的记录，在这些研究中，检测射频辐射存在下的小信号强度变化是必要的。在过去的几年里，这个团队一直在PARACEST效应的理论和实践方面进行合作。该项目的成功完成将导致三种试剂(血管内、pH和氧化还原反应)和MR获取策略用于人体研究。

DESCRIPTION (provided by applicant): Paramagnetic chemical exchange saturation transfer (PARACEST) agents offer a potential new paradigm in MR imaging. An advantage to this class of agents is the ability to switch each agent on or off through selective RF irradiation applied at the frequency of either its bound water resonance or an exchanging NH group. In their "off" state, i.e. when not specifically irradiated, PARACEST agents will not interfere with conventional MR imaging sequences, with or without gadolinium. In principle, PARACEST agents can be tailored to each application because their effects depend on their water exchange rates, and these rates can be modified using rational chemical principles. This feature also makes them an attractive platform for the development of responsive agents. The goal of this BRP is to realize the full potential of these compounds as contrast agents in vivo, by systematically addressing a number of basic, theoretical and practical questions. These include establishing the relationships among the magnitude of the effect measured in an imaging experiment and the water exchange lifetime, the magnitude of the chemical shift difference between the bound and bulk water, the strength of the saturating RF field, SAR, concentration, and local environment in vivo. This partnership is made up of two academic institutions and an industrial collaborator. The three main overlapping and interactive areas of focus are: lanthanide chemistry, which will be carried out at UT Dallas (UTD); Pulse sequence implementation, theory, simulations and in vitro validation which will be carried out primarily at the General Electric Global Research Center (GEGRC) and in vivo validation carried out primarily at the BIDMC. Dean Sherry (Project Leader, UTD) is an internationally recognized expert in the synthesis and characterization of lanthanide chelates and has expertise in basic NMR exchange theory. Thomas Dixon and Ileana Hancu (Project Leaders, GEGRC) are both experts in NMR and MR imaging. Robert Lenkinski (PI, BIDMC) is an NMR spectroscopist with expertise both in lanthanide agents and MR imaging. David Alsop (Lead Investigator, BIDMC) has a long track record in optimizing Arterial Spin Labeling perfusion studies, where the detection of small signal intensity changes in the presence of RF irradiation is necessary. Over the past several years, this team has been collaborating on the theoretical and practical aspects of the PARACEST effect. The successful completion of this project will result in three agents (intravascular, pH, and Redox responsive) and MR acquisition strategies for use in human studies.