Design, synthesis, and evaluation of novel lysophosphatidic acid receptor-targeting small molecules as therapeutic and diagnostic agents

Abstract

Breast cancer has the highest incidence rate of all cancers among Canadian women and accounts for nearly 14% of all cancer-related deaths in Canada. This type of cancer is often detected using medical imaging modalities such as mammography, breast ultrasound, and breast MRI, but each of these modalities can face harsh limitations for the detection of certain types of breast cancer. Positron emission tomography (PET) is another common imaging modality that is reported to have the highest sensitivity among all medical imaging modalities, but it is underused for breast cancer imaging due to the lack of a specific breast cancer-targeting PET radiopharmaceutical. Current breast cancer therapy methods also face limitations and are associated with negative effects. This leaves room for the development of a new PET radiopharmaceutical that is more specific for breast tumours, and for a new breast cancer chemotherapy agent. Lysophosphatidic acid receptor 1 (LPA1) has been identified as having elevated expression in breast cancer, and activation of LPA1 has been shown to increase cell migration and invasion. As such, the development of antagonists that target LPA1 would have extensive clinical benefits. This thesis focused on the design, synthesis, and biological evaluation of a library of highly potent and selective novel molecules targeting LPA1 that are derived from the previously reported compound, RO6842262. A novel 3H-1,2,3-triazolo[4,5-d]pyrimidine scaffold was identified through scaffold hopping and molecular docking studies. Based on the chemical structure of this novel scaffold, a six-step synthetic scheme and a fluorine-18 radiolabeling scheme were proposed, and one final compound was able to be synthesized. [...]