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: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226212
• 关键词: Amides; Antigen Targeting; Antigens; Binding; Brain; Cells; Chemicals; Clear cell renal cell carcinoma; Clinical; Clinical Research; Contrast Media; Cyclic GMP; Detection; Development; Dextrans; Disease; Ensure; FOLH1 gene; Foundations; Frequencies; Gadolinium; Goals; Human; Hydroxyl Radical; Image; In Vitro; Individual; Investigation; Iron; Lesion; Libraries; Ligands; Link; Lysine; MRI Scans; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of prostate; Methods; Modeling; Monitor; Nephrectomy; Nonionizing Radiation; PC3 cell line; Pathway interactions; Peptoids; Phenotype; Physiologic pulse; Polymers; Preparation; Property; Protein Tyrosine Kinase; Proteins; Protons; Relaxation; Renal carcinoma; Reporter; Resolution; Resources; Salicylic Acids; Scheme; Signal Transduction; Techniques; Testing; Therapeutic; Tissues; Toxic effect; Toxicity Tests; Translations; Tumor Antigens; Validation; Water; base; biomaterial compatibility; bone; carbonate dehydratase; clinical diagnostics; clinically relevant; contrast enhanced; cost efficient; design; flu; histological image; imaging agent; imaging detection; improved; in vivo; innovation; molecular imaging; overexpression; pre-clinical; precision medicine; preclinical study; radio frequency; radiotracer; receptor; receptor binding; soft tissue; targeted agent; targeted imaging; therapeutic target; tool; tumor microenvironment; uptake

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.

TR&D 4摘要 TR&D 4的首要目标是将精确医学的概念引入化学交换饱和 转移（CEST）磁共振成像（MRI）。CEST MRI放大来自大分子物质的信号 质子与水的交换。目前CEST利用合适的化学位移频率 以及酰胺或羟基质子的交换率。可以使用CEST来检测蛋白质， 含有许多这样的功能性或用于外源施用的人工试剂，例如富含赖氨酸的 来自TR&D 2的记者。因此，CEST不是固有靶向的（针对表型表达的蛋白质）或 精密方法BTRC的TR&D 4将生成和分发精确的CEST代理。我们将开发 用于受体成像的非金属靶向MR试剂，重点关注聚合物物质，以确保足够的 信号了目前，大约三分之一的MRI扫描依赖于基于非特异性弛豫的给药。 钆造影剂有助于健康和患病组织的临床区分，然而， 由于最近对钆在脑和骨中积累的关注，对非钆的需求日益增加， 金属剂CEST MRI允许以MRI的摩尔灵敏度对低浓度化合物进行成像 并且还具有可以将CEST试剂设计成可生物降解的优点。我们将合成 用于基于受体的成像的可翻译CEST MRI试剂以及采集和分析方法 针对每一种药物的特性进行优化。为了实现这一点，在目标1中，我们将共轭一个 PSMA靶向高度敏感的CEST聚合物的配体，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， 在交换率和化学位移方面的聚合剂（目标2）。这些脉冲序列是在 目标2也将适用于TR&D 2。在目标3中，我们将进一步研究其他两个临床相关的 受体，碳酸酐酶IX（CA-IX），其表达对肿瘤有影响 微环境和Axl酪氨酸激酶。CA-IX是肾透明细胞癌上表达的抗原 （ccRCC），可为肾癌根治术和肾癌监测提供有价值的信息。在Aim中 4、我们将生成转化分子中心最有前途的cGMP级材料 人类使用的途径上的成像。对于该步骤，将在初步毒性中测试生成的药剂 将在GLP毒性试验前进行研究。