A novel design platform for diaCEST agents

diaCEST 代理的新颖设计平台

基本信息

批准号：
10194212
负责人：
Zoltan Kovacs
金额：
$ 20.48万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10194212
关键词：
Amides Buffers Chemicals Complex Contrast Media Data Analyses Detection Development Diagnostic Imaging Disadvantaged Exhibits Fatty acid glycerol esters Frequencies Funding Gadolinium Goals Hydrogen Bonding Image Image Enhancement In Vitro Individual Ionizing radiation Ions Lanthanoid Series Elements Lead Magnetic Resonance Imaging Measures Metals Modification Mus Naphthalene Nature Pattern Peptides Performance Plasma Positioning Attribute Property Proteins Protons Relaxation Renal clearance function Reporting Resolution Safety Series Signal Transduction Structure Technology Testing Time Tissues Toxic effect Vertebral column Water base clinical imaging contrast imaging design expectation experimental study high resolution imaging imaging agent imaging modality improved in vivo in vivo evaluation innovation kidney imaging metal complex novel protonation soft tissue trend water solubility

项目摘要

Abstract Magnetic resonance imaging (MRI) is one of the most important clinical imaging modalities because it can provide high resolution images of soft tissues in a non-invasive manner. Gadolinium contrast media enhance image contrast by shortening the T1 and T2 relaxation times of tissue water protons. Alternatively, image contrast can be generated using chemical exchange saturation transfer (CEST) mechanism. CEST requires the existence of at least two slowly exchanging pools of protons with different NMR chemical shifts, and generates contrast by transferring saturated 1H spins from the small pool (agent) to the bulk (tissue) water pool. The key parameters in CEST are the exchange rate constant (kex) and the chemical shift (frequency) separation of the exchanging pools (Δω). CEST requires slow exchange condition, (kex ≤ Δω). CEST agents can be exogenous or endogenous diamagnetic molecules (diaCEST) or paramagnetic metal complexes (paraCEST) with labile protons. ParaCEST agents exhibit large frequency difference that easily satisfies the requirement for CEST but they have potential toxicity due to in vivo metal release. DiaCEST agents are metal free by their chemical nature but the chemical shift separation of diaCEST agents is usually less than 5 ppm from the bulk water. This small frequency separation poses severe limitations on current diaCEST agents such as poor selectivity due to the spectral overlap with other exchanging proton resonances, strong interference from tissue background magnetization transfer and direct water saturation. Here we propose to develop a new diaCEST platform technology that would overcome the shortcomings of current diaCEST agents by relying on slowly exchanging, highly downfield shifted (15 ppm from water) protons present in structurally constrained monoprotonated peri-naphthalene derivatives. Synthesis and in vitro characterization of the proposed agents will be accomplished in Specific Aim 1. The goal of Specific Aim 2 is to demonstrate the in vivo applicability of these probes in imaging experiments in mice. The proposed agents would offer several advantages over existing CEST agents including improved CEST efficiency, high selectivity without interference from proteins and fats, easier data analysis due to weaker tissue magnetization transfer effect and asymmetry, significantly reduced or eliminated direct water saturation, pH- independent CEST effect and improved safety profile due to metal free composition. This platform would allow the design and synthesis of non-specific agents without the confounding effect of pH as well as the construction of targeted and responsive MR agents through the modification of the naphthalene backbone.

抽象的磁共振成像（MRI）是最重要的临床成像方式之一，因为它可以以非侵入性方式提供软组织的高分辨率图像。通过缩短组织水质子的 T1 和 T2 弛豫时间来提高图像对比度。可以利用化学交换饱和转移(CEST)机制来生成CEST需要存在。至少两个具有不同 NMR 化学位移的缓慢交换质子池，并通过以下方式生成对比度将饱和 1H 自旋从小水池（代理）转移到大水池（组织）关键参数。 CEST 中是交换率常数 (kex) 和交换的化学位移（频率）分离 CEST 需要缓慢的交换条件，(kex ≤ Δω) 可以是外源性或内源性的。抗磁性分子 (diaCEST) 或具有不稳定质子的顺磁性金属络合物 (paraCEST)。代理表现出较大的频率差异，很容易满足 CEST 的要求，但它们有潜力 DiaCEST 制剂由于其化学性质而不含金属，但化学物质由于体内金属释放而产生毒性。 diaCEST 试剂与散装水的分离频率通常小于 5 ppm。对当前 diaCEST 试剂的分离造成严重限制，例如由于光谱导致的选择性差与其他交换质子共振重叠，来自组织背景磁化的强烈干扰在这里，我们建议开发一种新的 diaCEST 平台技术，该技术将通过缓慢交换、高度低场转移克服了当前 diaCEST 试剂的缺点（水中 15 ppm）质子存在于结构受限的单质子化邻萘衍生物中。所提议药物的合成和体外表征将在具体目标 1 中完成。目标具体目标 2 的目的是证明这些探针在小鼠成像实验中的体内适用性。与现有 CEST 代理相比，拟议的代理将提供多种优势，包括提高 CEST 效率、高选择性，不受蛋白质和脂肪的干扰，由于组织较弱，数据分析更容易磁化传递效应和不对称性，显着降低或消除直接水饱和度、pH- 由于不含金属成分，该平台将允许独立的 CEST 效应和改进的安全性。不受pH混杂影响的非特异性试剂的设计和合成以及构建通过对萘主链的修饰来制备靶向和响应性 MR 试剂。