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Verena, Arsyangela

University of British Columbia

Oncology practice is rapidly shifting toward personalize cancer diagnosis and treatment by utilizing targeted therapies or probes against the specific molecular drivers of tumors in individual patients. Molecular imaging has been playing a major role in personalized cancer management, including detection, staging, and treatment response assessment. However, tumor heterogeneity limits the utility of monospecific radiotracers in prostate cancer diagnosis and therapy. Utilizing heterodimeric radiotracers to target different proteins overexpressed in tumor has been shown to be a promising strategy to overcome these limitations and improve lesion detection. Previous studies evinced that prostate-specific membrane antigen (PSMA) and fibroblast activation protein (FAP) are overexpressed in prostate cancer, and their expressions are associated with poor prognosis. Therefore, both PSMA and FAP are promising biomarkers of prostate cancer and many PSMA- and FAP-targeting radioligands have been developed for imaging and therapy. Despite many effective PSMA-targeting radiotherapeutic agents being developed, patients with low to no PSMA expression are not eligible for these PSMA-targeted radioligand therapies and have very limited treatment options. Since FAP and PSMA are concomitantly expressed in prostate cancer, the use of bispecific PSMA/FAP-targeting radioligands is expected to increase lesion detection sensitivity in this patient cohort. We hypothesize that the bispecific PSMA/FAP-targeting radiotracers will have comparable or even higher tumor uptake than the monospecific radiotracers. In this thesis, we synthesized several bispecific PSMA/FAP-targeting radiotracers, evaluated their binding affinity in vitro using cell-based competitive binding assays, imaging potential and biodistribution in tumor-bearing mice, and compared their data with the monospecific PSMA- and FAP- targeting radiotracers. Here, we also describe the work of developing pyridine-based FAP-targeted pharmacophore which we hypothesized to be more hydrophilic than the quinoline-based pharmacophore, resulting in higher tumor-to-background contrast ratio of the derived radiotracers. Lastly, we synthesized two bispecific PSMA/FAP-targeting tracers containing the pyridine-based FAP-targeted pharmacophore. Overall, this research demonstrates the feasibility of designing PSMA/FAP-targeting radiotracers and how linker selection, length, pharmacophore selection and modification, and hydrophilicity of the compounds affect the binding affinity, tumor uptake, tumor-to-background contrast ratio of the bispecific PSMA/FAP-targeting radiotracers. This can give insights on parameters to consider in designing PSMA/FAP bispecific radiotracers.

Text

2023-12-14

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/86953

Interdisciplinary Oncology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/