Novel Approaches for CEST Labeling, Detection, Quantification and Translation

整个项目的重点是生物有机可降解化学品的设计和检测 交换饱和转移（CEST）代理，其最终目标是将其实际应用于蜂窝和 分子标记以及动物和人类的药物输送和基因表达的成像。许多工作 需要在临床上每天使用这些试剂。项目1的总体目标是 开发定量IMRI方法，用于检测外源性和内源性CEST因子 在原地。因此，本项目的重点是设计新的MRI脉冲序列来标记和检测 可交换质子，对CEST试剂产生的对比度的定量，以及从 对动物模型和人类都是如此。在这些发展过程中，我们将与 项目2和3，以确保我们始终拥有最好的代理，并确保技术针对 在体内条件下使用的实际药剂。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，用于检测可交换质子。到目前为止， 体内的磁化转移（MT）过程仅使用感应饱和的转移来检测， 射频（RF）诱导的和失相诱导的。我们将开发和优化新的方法， 不使用RF饱和的磁性标记，而是使用一系列所谓的标签传输模块 （LTM），每个都包括标签部分和交换转移部分。我们将用这些来设计 频率选择性反转和移相标记转移方法，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 类似于多维傅里叶变换（FT）NMR的方法。在AIM 2中。我们专注于量化 CEST制剂引起的水对比度。正确的定量需要未受污染的信号， 通过去除竞争性干扰效应来选择性检测试剂的作用 磁化传递过程和不均匀性的不利影响，在静态磁场 (Bo)和施加的射频场（Bi）。将设计测量绝对浓度的方法 并使用已知的Phantom浓度进行优化和随后验证。在AIM 3中，我们 重点是将已开发的交换技术转化为动物和人类系统。这涉及 选择性检测体内内源性和外源性CEST试剂。技术开发在 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（3 T， 7T）。将为此开发单层和多层/3D MRI交换-传输技术 目的.在动物研究中，我们将评估内源性效应以及外源性系统 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的交换转移对比MRI的可用性 方法在体内，相对于特定的药物递送和基因表达系统优化， 动物和准备应用于人类。

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.