Novel Approaches for CEST Labeling, Detection, Quantification and Translation

总体规划项目的重点是生物有机可生物降解化学品的设计和检测 交换饱和转移(CEST)试剂，其最终目标是将其实际应用于细胞和 在动物和人类中的药物传递和基因表达的分子标记和成像。很多工作都是 需要使这种药物在临床上的日常使用成为可能。项目1的总体目标是 建立检测外源性和内源性CEST病原体的定量IMRI方法 在原地。因此，本项目致力于设计新的磁共振脉冲序列来标记和检测 可交换质子，关于CEST试剂产生的对比度的量化，以及关于 幻影出现在动物模型和人类身上。在这些发展期间，我们将密切与 项目2和3，以确保我们始终拥有最好的工程师，并确保技术针对 在活体条件下使用的实际制剂。为了实现我们的目标，我们制定了几个具体目标： 在目标1中，我们将开发用于检测可交换质子的新的磁性标记方案。到目前为止， 体内的磁化转移(MT)过程仅使用诱导饱和的转移来检测， 射频(RF)诱导和去相诱导。我们将开发和优化新的方法来 磁性标签，不使用射频饱和，而是一系列所谓的标签传输模块 (LTMS)，每个包括标签部和交换转移部。我们将使用这些来设计 频率选择性反转和去相标签转移方法，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 方法类似于多维傅立叶变换(FT)核磁共振。在目标2中，我们将重点放在量化 CEST试剂引起的水色对比。正确的量化需要无污染的信号，因此 通过消除竞争的干扰效应来选择性地检测试剂的效果 两个静磁场中的磁化传递过程和不均匀的不利影响 (BO)和外加射频场(BI)。将设计测量绝对浓度的方法 并使用模体中的已知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。这与 体内选择性检测内源性和外源性CEST试剂。中开发的技术 AIMS 1和2中的体外实验将在动物扫描仪(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。在动物实验中，我们将评估内源性效应和外源性系统。 在项目2和3中开发。在人体扫描仪上，我们将重点放在内源性化合物上。 这些目标有望导致可量化的交换转移对比磁共振成像的出现 体内方法，针对特定的药物输送和基因表达系统进行优化 并准备好在人类身上应用。

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.