PARACEST Agents: Optimization for Human MR Imaging

描述（由申请人提供）：顺磁性化学交换饱和转移（PARACEST）试剂提供了MR成像的潜在新范例。这类试剂的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RF辐射来打开或关闭每种试剂。在其“关闭”状态下，即当未进行特定照射时，PARACEST试剂不会干扰常规MR成像序列，无论是否使用钆。原则上，PARACEST试剂可以针对每个应用进行定制，因为它们的效果取决于它们的水交换速率，并且可以使用合理的化学原理来修改这些速率。这一特性也使它们成为开发响应式代理的有吸引力的平台。该BRP的目标是通过系统地解决一些基本的、理论的和实践的问题，实现这些化合物作为体内造影剂的全部潜力。这些包括建立在成像实验中测量的效果的大小和水交换寿命之间的关系，结合和散装水之间的化学位移差的大小，饱和RF场的强度，SAR，浓度和局部环境在体内。该合作伙伴关系由两个学术机构和一个工业合作者组成。三个主要的重叠和互动领域是：镧系元素化学，这将在UT达拉斯（UTD）进行;脉冲序列实施，理论，模拟和体外验证，这将主要在通用电气全球研究中心（GEGRC）进行，体内验证主要在BIDMC进行。Dean Sherry（项目负责人，UTD）是国际公认的镧系元素螯合物合成和表征专家，并在基础NMR交换理论方面拥有专业知识。托马斯狄克逊和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。Robert Lenkinski（PI，BIDMC）是一位在镧系元素试剂和MR成像方面具有专业知识的NMR光谱学家。大卫Alsop（首席研究员，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，有必要检测射频辐照下的小信号强度变化。在过去的几年里，该团队一直在PARACEST效应的理论和实践方面进行合作。该项目的成功完成将产生三种药物（血管内、pH和氧化还原反应）和MR采集策略，用于人体研究。 公共卫生相关性：顺磁性化学交换饱和转移（PARACEST）试剂为MR成像提供了潜在的新范例。该BRP的目标是通过系统地解决一些基本的、理论的和实践的问题，实现这些化合物作为体内造影剂的全部潜力。该项目的成功完成将产生三种药物（血管内、pH和氧化还原反应）和MR采集策略，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. PUBLIC HEALTH RELEVANCE: Paramagnetic chemical exchange saturation transfer (PARACEST) agents offer a potential new paradigm in MR imaging. 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. 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.