High-throughput radiochemistry platform for accelerated discovery and development of novel PET imaging agents for cancer

高通量放射化学平台，用于加速发现和开发新型癌症 PET 成像剂

• 批准号: 9231796
• 负责人: Robert Michael van Dam
• 金额: $ 30.8万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9231796
• 关键词: Address; Affinity; Animals; Architecture; Basic Science; Biochemical Process; Biological; Biological Process; Cancer Biology; Cell surface; Cells; Chemistry; Chromatography; Clinical Trials; Collection; Computer software; Development; Devices; Ensure; Evaluation; Fluorine; Formulation; Generations; Goals; Heating; Image; Imaging Techniques; In Vitro; Individual; Injection of therapeutic agent; Integrins; Isotopes; Label; Libraries; Liquid Chromatography; Liquid substance; Malignant Neoplasms; Measurement; Methods; Microfluidics; Peptide Library; Peptides; Performance; Phase; Play; Positioning Attribute; Positron-Emission Tomography; Process; Production; Property; Proteins; Protocols documentation; Public Health; Radioactive Tracers; Radiochemistry; Radioisotopes; Radiolabeled; Reaction; Reagent; Reporting; Reproducibility; Robotics; Role; Saline; Selection Criteria; Site; Solid; Speed; System; Technology; Time; Tracer; Variant; base; cancer biomarkers; clinical decision-making; clinical imaging; clinical practice; cost; density; design; drug development; drug discovery; enzyme activity; high throughput technology; imaging agent; in vitro Assay; in vivo; in vivo imaging; novel; novel therapeutics; pre-clinical; pre-clinical research; prototype; receptor; response; screening; small molecule; targeted imaging; therapeutic target; tool; whole body imaging

PROJECT SUMMARY/ABSTRACT Positron emission tomography (PET) is an advanced imaging technique, relying on the injection of radioactive “tracers” to image specific biochemical processes in living subjects. By developing appropriate tracers, PET can provide measurements of the abundance of cell surface markers/receptors, degree of enzyme activity, or the rate of a biological processes. These measurements help understand the biology of cancer, discover and develop new drugs, and provide critical information for clinical trials or clinical decision making. Though basic research has led to the discovery of many new cancer markers and potential therapeutic targets, the development of suitable PET tracers to image these targets typically lags years behind. Beginning with approaches such as library screening to identify candidate tracers, the candidates are ranked based on in vitro criteria (e.g. affinity, selectivity). Due to high costs, only a very tiny number of these candidates are usually labeled for further evaluation. This leads to a slow, incremental tracer development process, exacerbated by the issue that in vitro selection criteria don't correlate well with in vivo performance. This proposal seeks to address this issue by making it practical and affordable to perform in vivo screening of much larger candidate libraries. High-throughput methods already exist for generation of (unlabeled) libraries of candidate tracers, and the potential for high-throughput in vivo imaging has also been reported. However, there does not currently exist a practical approach for performing the middle step in a high-throughput fashion, i.e. rapidly radiolabeling a compound library. This is due not only to the lack of technology for high-throughput radiosynthesis, but also the large volume used in conventional radiosynthesis methods, which leads to high precursor cost and low specific activity. Recent advances in microfluidic radiochemistry, in which reactions are performed in microliter-scale droplets, can overcome all of these limitations. This proposal leverages these advances to create a high-throughput radiolabeling platform. Aim 1 develops a microfluidic reaction array to perform at least 48 simultaneous reactions. In Aim 2, a liquid delivery system is developed to efficiently and rapidly distribute precursor, radiolabeling agent etc. to the reaction sites as needed. An integrated, automated system is developed in Aim 3 and validated using various commonly-used labeling chemistries. Finally, in Aim 4, UPLC chromatography and SPE plates are evaluated as potential means for performing high-throughput purification and formulation so the synthesized tracers are ready for injection. Ultimately, this proposal seeks to make screening a practical, routinely-available tool to accelerate and reduce the cost of novel PET tracer development.

项目总结/摘要 正电子发射断层扫描（PET）是一种先进的成像技术，依靠注射放射性核素， “示踪剂”，以图像特定的生物化学过程中生活的主题。通过开发适当的示踪剂，PET可以 提供细胞表面标志物/受体的丰度、酶活性的程度、或 一个生物过程的速率。这些测量有助于了解癌症的生物学，发现和 开发新药，并为临床试验或临床决策提供关键信息。虽然基本 研究已经发现了许多新的癌症标志物和潜在的治疗靶点， 用于对这些目标成像的合适PET示踪剂的开发通常落后数年。 首先采用文库筛选等方法来识别候选示踪剂， 基于体外标准（例如亲和力、选择性）。由于费用高昂，这些候选人中只有极少数 通常会被标记以供进一步评估。这导致缓慢的、增量的跟踪程序开发过程， 由于体外选择标准与体内性能不相关的问题而加剧。这项建议 试图通过使其实用和负担得起的进行体内筛选大得多的 候选库。 已经存在用于产生候选示踪剂的（未标记的）文库的高通量方法，并且 还报道了高通量体内成像的潜力。然而，目前还没有一个 以高通量方式进行中间步骤的实用方法，即快速放射性标记 复合图书馆这不仅是由于缺乏高通量放射合成技术， 在常规放射合成方法中使用大体积，这导致高的前体成本和低的特异性。 活动 微流控放射化学的最新进展，其中反应在微升规模的液滴中进行， 可以克服所有这些限制。该提案利用这些进步来创建高吞吐量 放射性标记平台。目的1开发了一种微流控反应阵列，可以同时进行至少48个反应。 在目标2中，开发了一种液体输送系统，以有效和快速地分配前体、放射性标记剂 等根据需要将其转移到反应位点。在Aim 3中开发了一个集成的自动化系统，并使用 各种常用的标记化学物质。最后，在目标4中，UPLC色谱和SPE板是 评价为进行高通量纯化和配制的潜在手段，因此合成的 示踪剂已准备好注入。最终，该提案旨在使筛查成为一种实用的， 工具，以加快和降低成本的新型PET示踪剂的发展。