A novel design platform for diaCEST agents

diaCEST 代理的新颖设计平台

• 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
• 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

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。 Gadolinium对比介质增强 图像对比缩短了组织水质子的T1和T2松弛时间。或者，图像对比度 可以使用化学交换满意度转移（CEST）机制生成。 cest需要存在 至少两个缓慢地交换具有不同NMR化学位移的质子的池，并形成对比度 将饱和的1H旋转从小池（试剂）转移到散装（组织）水池。关键参数 CEST是汇率常数（KEX）和交换的化学位移（频率）分离 池（δΩ）。 CEST需要缓慢的交换条件（KEX≤ΔΩ）。 CEST代理可以是外源或内源性的 二磁分子（二氧）或不稳定质子的顺磁金属络合物（Paracest）。最有用的 代理暴露了很大的频率差异，很容易满足CEST的要求，但它们具有潜力 由于体内金属释放而引起的毒性。二氧剂的化学性质是无金属的，但化学 与大量水相比，透明药物的移位分离通常小于5 ppm。这个很小的频率 分离位置严重限制了当前透明剂，例如由于光谱而导致的选择性差 与其他交换质子共振重叠，组织背景磁化强烈干扰 转移和直接水满意度。在这里，我们建议开发一种新的Diacest平台技术 克服当前透明药物的缺点，依靠缓慢交换，高度下场变化 （水从水结构约束的单尾旁苯乙烯衍生物中存在）（来自水的15 ppm）。 在特定目标1中将完成所提出的代理的合成和体外表征。目标 特定目的2是在小鼠的成像实验中证明这些问题的体内适用性。 拟议的代理人将提供比现有CEST代理的几个优势，包括提高CEST效率， 高选择性而不会干扰蛋白质和脂肪，由于组织较弱而引起的数据分析更容易 磁化转移效果和不对称性，显着降低或消除了直接水饱和，pH- 由于无金属成分而引起的独立CEST效果和改善的安全性。这个平台将允许 非特异性药物的设计和合成，而没有pH的混杂作用以及构造 通过修饰萘主链的靶向和响应性MR代理。