Development of Radio-Fluorination Methods and Novel Molecular Imaging Agents

传统上，药物发现是一个漫长、高风险和昂贵的过程，并且药物最终能否成功存在高度的不确定性。分子成像技术允许非侵入性评估的生化和生物过程中的体内。分子影像学在临床应用中已成为不可或缺的，并被认为是个性化医疗的希望。分子成像技术和用于人类和小动物的成像探针的进展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，成像剂发现的挑战，例如有限的放射化学转化方法和有限数量的成像剂正在开发中，已显着限制了分子成像模式在临床应用和药物发现中的潜力。我们的研究小组有一个长期的目标，开发新的和有用的放射化学转化和应用这些转化的挑战，制备具有生物意义的目标分子。它进一步寻求开发新的分子成像探针作为研究体内生物化学和生物学过程的工具。在本建议书中，我们将详细描述我们通过实现以下更集中的短期目标来实现上述长期目标的计划：（1）Mitsunobu反应和Pd（0）催化的反应用于开发后期立体特异性放射性同位素方法，（2）开发靶向溶血磷脂酸受体1（LPA 1）的新型显像剂，LPA 1相关生物学过程的研究;（3）电子筛选方法的发展和靶向前列腺特异性膜抗原的新型显像剂的发现。在未来5年内，将培养12名HQP（2名博士，5名硕士和5名本科生）。预计上述化学方法将丰富“放射化学工具箱”，并使放射化学家能够更容易地获得以前无法或难以合成的靶分子。在这个基础研究计划中发现的新型显像剂和开发的新方法将是强大的工具，可以研究和理解体内重要的生化和生物过程，这将在未来的CIHR资助申请中进行。

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.