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CEST MRI Agents for Receptor Imaging

CEST MRI Agents for Receptor Imaging
用于受体成像的 CEST MRI 试剂
批准号:
10226212
负责人:
MICHAEL T MCMAHON
金额:
$25.66万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-09-15 至 2024-06-30

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中文摘要
翻译
研发总结4 研发4的首要目标是将精确医学的概念引入化学交换饱和。 传输(CEST)磁共振成像(MRI)。CEST磁共振放大来自大分子物种的信号 其中含有质子与水进行交换。目前,CEST利用适当的化学位移频率 以及酰胺或羟基质子的交换率。可以使用CEST来检测天然的蛋白质 含有许多这样的功能,或用于外源性给药的人造制剂,如富含赖氨酸的 因此CEST本身并不是一个固有的靶点(针对表型表达的蛋白质)或 精确法。BTRC的研发4将产生和传播精密CEST试剂。我们将发展 用于受体成像的非金属、靶向磁共振试剂,重点关注聚合物物种,以确保足够的 信号。目前,大约三分之一的MRI扫描依赖于非特异性松弛基础上的给药 然而,在临床上,使用Gd造影剂有助于区分健康组织和病变组织 由于最近对脑组织和骨骼中Gd蓄积的担忧,对非 金属试剂。CEST MRI使低浓度化合物的成像具有MRI的摩尔灵敏度 并且还具有CEST试剂可以被设计为可生物降解的优点。我们将综合 基于受体成像的可翻译CEST MRI试剂及其获取和分析方法 它们针对每个单独代理的属性进行了优化。为了实现这一点,在目标1中,我们将结合一个 PSMA靶向高敏CEST聚合物的配基,包括作为生物相容性试剂的葡聚糖聚合物 和水杨酸聚合物作为更高灵敏度的聚合物。然后我们将优化脉冲序列以进行检测 在汇率和化学位移方面的聚合试剂(目标2)。中开发的脉冲序列 目标2也将应用于研发2。在目标3中,我们将进一步研究另外两个临床相关的 受体,碳酸酐酶IX(CA-IX),其表达与肿瘤有关 微环境和Axl酪氨酸激酶。CA-IX是一种表达于肾透明细胞癌的抗原 (CcRCC),可为根治性肾切除术和肾癌监测提供有价值的信息。在AIM 4、我们将生成翻译分子中心最有希望的项目的cGMP级材料 在人类使用的道路上进行成像。在这一步中,产生的试剂将在初步毒性测试中 研究将在GLP毒性测试之前进行。
英文摘要
SUMMARY for TR&D 4 The overarching goal of TR&D 4 is to introduce concepts of precision medicine to chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI). CEST MRI amplifies signal from macromolecular species that contain protons in exchange with water. Currently CEST leverages the suitable chemical shift frequencies and exchange rates of amide or hydroxyl protons. One may use CEST for detection of proteins that naturally contain many such functionalities or for exogenously administered, artificial agents, such as the lysine-rich reporter from TR&D 2. As such CEST is not an inherently targeted (to phenotypically expressed proteins) or precision method. TR&D 4 of the BTRC will generate and disseminate precision CEST agents. We will develop non-metallic, targeted MR agents for receptor imaging with a focus on polymeric species to ensure adequate signal. Currently, about one third of all MRI scans rely on administration of non-specific relaxation-based gadolinium contrast agents to aid in the clinical differentiation of healthy and diseased tissues, however in view of recent concerns about accumulation of gadolinium in brain and bone, there is an increasing demand for non- metallic agents. CEST MRI allows the imaging of low-concentration compounds with the molar sensitivity of MRI and also has the advantages that CEST agents can be designed to be biodegradable. We will synthesize translatable CEST MRI agents for receptor-based imaging together with acquisition and analysis approaches that are optimized for the properties of each individual agent. To accomplish this, in Aim 1, we will conjugate a PSMA targeting ligand to highly sensitive CEST polymers, including dextran polymers as biocompatible agents and salicylic acid polymers as higher sensitivity polymers. We will then optimize pulse sequences for detecting the polymeric agents in terms of exchange rate and chemical shift (Aim 2). The pulse sequences developed in Aim 2 will also be applied to TR&D 2. In Aim 3 we will further proceed to investigate two other clinically relevant receptors, carbonic anhydrase IX (CA-IX), the expression of which has implications for the tumor microenvironment, and Axl tyrosine kinase. CA-IX is an antigen expressed on clear cell renal cell carcinoma (ccRCC), and could provide valuable information for radical nephrectomy and renal cancer surveillance. In Aim 4, we will generate cGMP-grade material of the most promising item in the Center for Translational Molecular Imaging on the pathway to human use. For this step, the agents generated will be tested in preliminary toxicity studies will be performed prior to GLP toxicity testing.
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