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: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=714934
• 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、高风险且成本高昂的过程，药物最终能否成功具有高度的不确定性。分子成像技术可以对体内生化和生物过程进行无创评估。分子成像在临床应用中已变得不可或缺，并被认为有望实现个性化医疗。用于人类和小动物的分子成像技术和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，并有可能加速这一过程。然而，显像剂发现的挑战，例如可用的放射化学转化方法和正在开发的显像剂数量有限，严重限制了分子成像方式在临床使用和药物发现中的潜力。 我们的研究小组的长期目标是开发新颖且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目标分子的挑战。它进一步寻求开发新型分子成像探针作为研究体内生化和生物过程的工具。在本提案中，我们将通过详细解决以下更有针对性的短期目标来描述我们实现上述长期目标的计划：（1）利用 Mitsunobu 反应和 Pd(0) 催化反应来开发后期-阶段立体特异性放射性氟化方法，(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) 计算机筛选方法的开发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名高级人才（2名博士生、5名硕士生和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好地获得以前无法或难以合成获得的目标分子。在这一基础研究项目中发现的新型显像剂和开发的新方法将成为研究和理解体内重要生化和生物过程的强大工具，这将在未来的 CIHR 拨款申请中得到实现。