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UBC Theses and Dissertations

PET/CT imaging of the human bradykinin 1 receptor using radiolabeled peptides for cancer detection Amouroux, Guillaume Paul Victor


Many compounds mimicking endogenous molecules have been used as a starting point to develop targeted diagnostic and therapeutic radiotracers. In particular, radiolabeled peptidomimetics, in association with positron emission tomography combined with computed tomography (PET/CT), are powerful tools to detect cancer with high sensitivity. Peptide-based radiotracers have the advantage of combining favorable pharmacokinetics that allow the use of short-lived isotopes, with a flexible modular design that offers a high versatility for functionalization, making them optimal for developing targeted imaging probes. The bradykinin receptors, which are powerful mediators of inflammation, have been shown to be highly expressed in many common cancers, notably breast and prostate cancers. The purpose of this project was to evaluate the human Bradykinin Receptor 1 (hB1R) as a potential target for cancer imaging and radionuclide therapy. Analogs of [des-Arg¹⁰] Kallidin (KD) were synthesized and labeled with ⁶⁸Ga or ¹⁸F. Following determination of their affinity for hB1R, selected tracers were evaluated in vitro and in vivo using hB1R expressing cells to select optimal radiotracers to imaging by positron emission tomography. The replacement of key amino acids at peptidase cleavage points by unnatural aminoacids improved the stability of the radiolabeled [des-Arg¹⁰]KD analogs in vitro and in vivo. Such peptides were used successfully for h1BR imaging by PET/CT in preclinical models. The use of hydrophilic and in particular cationic linker significantly improved tumour accumulation of various bradykinin analogues. Tracers combining the most favorable features gave high tumour to normal tissue contrast, by combining specific and high tumour uptake with low background and rapid clearance. The accumulation of agonist and antagonist radiotracers in tumours was also compared. In summary, we developed several promising bradykinin receptor ligands, as radiolabeled probes for cancer imaging.

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