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. [...]