Development of Radio-Fluorination Methods and Novel Molecular Imaging Agents

放射性氟化方法和新型分子成像剂的发展

• 批准号: RGPIN-2019-05098
• 负责人: Hou, Jinqiang
• 金额: $ 1.75万
• 依托单位: Lakehead University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=747911
• 关键词: Development; Radio; Fluorination; Methods; Novel

Traditionally drug discovery is a lengthy, high-risk, and costly process, entrenched with a high degree of uncertainty that a drug will eventually succeed. Molecular imaging techniques allow noninvasive assessment of biochemical and biological processes in vivo. Molecular imaging has become indispensable in clinical use and is believed to hold promise for personalized medicine. Advances in molecular imaging technologies and imaging probes for humans and for small animals are extending the applications of imaging further into drug discovery and development, and have the potential to accelerate the process. However, the challenges of imaging agent discovery, e.g. limited radiochemical transformation methods available and a limited number of imaging agents being developed, have significantly restricted the potential of molecular imaging modalities in clinical use and drug discovery. Our research group has a long term goal to develop novel and useful radiochemical transformations and application of those transformations to the challenge of preparing target molecules with biological significance. It further seeks to develop novel molecular imaging probes as tools to investigate biochemical and biological processes in vivo. In this proposal, we will describe our plans to address the above long term objectives by addressing the following more focused short term objectives in detail: (1) The use of the Mitsunobu reaction and Pd(0) catalyzed reactions for the development of late-stage stereospecific radio-fluorination methods, (2) the development of novel imaging agents targeting lysophosphatidic acid receptor 1 (LPA1), for the study of LPA1 related biological processes, (3) the development of in silico screening approaches and the discovery of novel imaging agents targeting prostate-specific membrane antigen. A total of 12 HQP (2 PhD, 5 MSc and 5 undergraduate students) will be trained over the next 5 years. The above chemistry is anticipated to enrich the `radiochemical tool box' and allow radiochemists greater access to target molecules that has previously not or been difficult to access synthetically. The novel imaging agents discovered and the new approaches developed in this fundamental research program will be powerful tools to allow the study and understanding of important biochemical and biological processes in vivo, which will be pursued in future CIHR grant application.

传统上，药物发现是一个漫长、高风险和昂贵的过程，具有高度的不确定性，药物最终是否会成功。分子成像技术可以对体内的生化和生物过程进行非侵入性评估。分子成像已经成为临床应用中不可或缺的一部分，并被认为是个性化医学的希望所在。分子成像技术和用于人类和小动物的成像探针的进步正在将成像的应用进一步扩展到药物发现和开发中，并有可能加速这一过程。然而，显像剂发现的挑战，如现有的有限的放射化学转化方法和正在开发的有限数量的显像剂，大大限制了分子成像方式在临床应用和药物发现方面的潜力。我们的研究小组有一个长期的目标，那就是开发新的和有用的放射化学转化，并将这些转化应用于制备具有生物学意义的靶分子的挑战。它进一步寻求开发新的分子成像探针，作为研究体内生化和生物过程的工具。在这项建议中，我们将详细介绍我们为实现上述长期目标而制定的计划，具体包括以下短期目标：(1)利用Mitsunobu反应和Pd(0)催化的反应开发晚期立体特异性放射氟化方法；(2)开发针对溶血磷脂酸受体1(LPA1)的新型显像剂，用于研究LPA1相关的生物过程；(3)电子筛选方法的发展以及针对前列腺特异性膜抗原的新型显像剂的发现。未来5年将培训12名HQP(2名博士、5名硕士和5名本科生)。上述化学预计将丰富“放射化学工具箱”，并使放射化学家能够更多地接触到以前无法或难以通过合成手段获得的靶分子。在这项基础研究计划中发现的新的显像剂和开发的新方法将成为研究和了解体内重要的生化和生物过程的强大工具，这将在未来的CIHR拨款申请中进行追求。