Novel Approaches for CEST Labeling, Detection, Quantification and Translation

CEST 标记、检测、定量和翻译的新方法

• 批准号: 8304210
• 负责人: Peter CM Van Zijl
• 金额: $ 47.57万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8304210
• 关键词: Animal Model; Animals; Chemicals; Clinic; Coupling; Detection; Development; Drug Delivery Systems; Excision; Fourier Transform; Frequencies; Gene Expression; Goals; Human; Image; In Situ; In Vitro; Label; Magnetic Resonance Imaging; Magnetism; Measures; Methods; Molecular; Physiologic pulse; Process; Protons; Radio; Scheme; Series; Signal Transduction; Slice; System; Technology; Technology Transfer; Translations; Water; Work; base; design; in vivo; magnetic field; novel strategies; practical application; programs; radiofrequency

The overall Program Project focuses on the design and detection of bioorganic biodegradable Chemical Exchange Saturation Transfer (CEST) agents, with the ultimate goal of their practical application to cellular and molecular labeling and the imaging of drug delivery and gene expression in animals and humans. Much work is needed to make the use of such agents possible on a daily basis in the clinic. The overall goal of Project 1 is to develop quantitative IMRI approaches for detecting both exogenous and endogenous CEST agents in situ. As such, this project focuses on the design of new MRI pulse sequences to label and detect exchangeable protons, on the quantification of contrast generated by CEST agents, and on translation from phantoms to animal models and to humans. During these developments, we will be interacting closely with projects 2 and 3 to assure that we always have the best agents and that the technology is optimized for the actual agents being used under in vivo conditions. To accomplish our goal, we have set several specific aims: In AIM 1. we will develop new magnetic labeling schemes for detecting exchangeable protons. Until now, magnetization transfer (MT) processes in vivo have only been detected using transfer of induced saturation, both radio-frequency (RF) induced and dephasing induced. We will develop and optimize novel approaches for magnetic labeling that do not employ RF saturation, but instead a series of so-called Label-Transfer Modules (LTMs), each including a labeling section and exchange transfer section. We will use these to design frequency-selective inversion and dephasing label-transfer approaches, as well as methods based on frequency modulation, such as can be induced using chemical shifts and scalar coupling and detected using approaches similar to multi-dimensional Fourier-Transform (FT) NMR. In AIM 2. we focus on quantification of the water contrast caused by CEST agents. Proper quantification requires uncontaminated signal and thus selective detection of the effect of the agents through removal of the interfering effects of competing magnetization transfer processes and the detrimental effects of inhomogeneities in both static magnetic field (Bo) and applied radiofrequency field (Bi). Approaches to measure absolute concentrations will be designed and optimized and subsequently validated using known concentrations in phantoms. Finally, in AIM 3, we focus on translation of the developed exchange technologies to animal and human systems. This relates to the selective detection of both endogenous and exogenous CEST agents in vivo. The technologies developed in vitro in aims 1 and 2 will be implemented on both animal scanners (11.7T, 17.6T) and human scanners (3T, 7T). Both single-slice and multi-slice/3D MRI exchange-transfer technologies will be developed for this purpose. In the animal studies, we will evaluate endogenous effects as well as the exogenous systems developed in Projects 2 and 3. On the human scanners we will focus on endogenous compounds. These aims are expected to result in the availability of quantifiable exchange transfer contrast MRI approaches in vivo, optimized with respect to the specific drug-delivery and gene expression systems in animals and ready for application in humans.

总体方案项目重点关注生物有机可降解化学品的设计与检测 交换饱和转移（CEST）剂，其最终目标是在细胞和 分子标记以及动物和人类药物输送和基因表达的成像。很多工作是 需要使此类药物在诊所的日常使用成为可能。项目1的总体目标是 开发定量 IMRI 方法来检测外源性和内源性 CEST 因子 原地。因此，该项目专注于设计新的 MRI 脉冲序列来标记和检测 可交换质子、CEST 试剂产生的对比度的量化以及从 动物模型和人类的幻象。在这些发展过程中，我们将与 项目 2 和 3 确保我们始终拥有最好的代理商，并且技术针对 在体内条件下使用的实际试剂。为了实现我们的目标，我们设定了几个具体目标： 在 AIM 1 中，我们将开发新的磁性标记方案来检测可交换质子。到目前为止， 体内磁化转移（MT）过程仅通过诱导饱和转移来检测， 射频 (RF) 感应和移相感应。我们将开发和优化新方法 磁性标签不采用射频饱和，而是采用一系列所谓的标签转移模块 (LTM)，每个包括标签部分和交换传输部分。我们将使用这些来设计 频率选择性反转和移相标签转移方法，以及基于 频率调制，例如可以使用化学位移和标量耦合来诱导并使用来检测 方法类似于多维傅立叶变换 (FT) NMR。在 AIM 2 中，我们专注于量化 CEST 剂引起的水对比度。正确的定量需要未受污染的信号，因此 通过消除竞争性干扰物的影响来选择性检测药物的效果 磁化传递过程以及静磁场中不均匀性的有害影响 (Bo) 和应用射频场 (Bi)。将设计测量绝对浓度的方法 并使用模型中已知的浓度进行优化和随后验证。最后，在 AIM 3 中，我们 专注于将已开发的交换技术转化为动物和人类系统。这涉及到 体内内源性和外源性 CEST 试剂的选择性检测。开发的技术于 目标1和2中的体外将在动物扫描仪（11.7T、17.6T）和人体扫描仪（3T、 7T）。为此将开发单层和多层/3D MRI 交换传输技术 目的。在动物研究中，我们将评估内源性影响以及外源性系统 在项目 2 和 3 中开发。在人体扫描仪上，我们将重点关注内源性化合物。 这些目标预计将导致可量化交换转移对比 MRI 的可用性 体内方法，针对特定药物递送和基因表达系统进行了优化 动物并准备应用于人类。