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的，高风险且昂贵的过程，并以高度不确定性最终成功。分子成像技术允许对体内生化和生物学过程进行非侵入性评估。分子成像在临床用途中已成为必不可少的，并且据信具有个性化医学的希望。人类和小动物的分子成像技术和成像探针的进步正在扩展进一步成像在药物发现和发育中的应用，并有可能加速过程。但是，成像剂发现的挑战，例如有限的放射化学转化方法可用，开发的成像剂数量有限，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。我们的研究小组有一个长期目标，可以开发新颖而有用的放射化学转化，并将这些转换的应用在制备具有生物学意义的靶标分子的挑战中。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学过程的工具。 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相关的生物学过程，（3）在硅氧筛选方法中的发展以及针对前列腺特异性膜抗原的新型成像剂的发现。在接下来的5年中，将对总共12个HQP（2个博士学位，5名MSC和5名本科生）进行培训。预计上述化学物质将丰富“放射化学工具盒”，并使放射化学家更大的访问以前尚未或难以合成的目标分子。该基本研究计划中发现的新型成像剂和在体内重要的生物化学和生物学过程的研究和理解将是在未来的CIHR赠款应用中进行的。