Development of Radio-Fluorination Methods and Novel Molecular Imaging Agents

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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.