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UBC Theses and Dissertations

Metal chelating agents for medicinal radionuclides Li, Lily


Medical radionuclides can be classified into non-metallic and metallic. Due to the much broader decay spectrum, radiometal ions are generally of greater interest in radiopharmaceutical designs. Since free radionuclides are rapidly taken up by the non-targeting organs/tissues such as bone, liver and kidney, causing unnecessary radiation burden to the body, they need to be stably coordinated by a suitable bifunctional chelator conjugated to a biological targeting vector, which directs the radiation doses specifically to the tumor site. This thesis describes several picolinate-based ligand scaffolds (H4octapa, H4pypa and H4py4pa) with denticity from eight to eleven to accommodate radionuclides as small as scandium-44 and as large as actinium-225. Apart from rapid and stable chelation, versatile bifunctionalization is a crucial but often under-valued property of a ligand. The chemical properties of the linker can significantly alter the biodistribution of the chelate-bioconjugate, while the position of the linker in the ligand can dictate the coordination geometry. The second effect was observed in two newly developed 177Lu-labeled H4octapa peptide conjugates discussed in this thesis. This observation prompted the development of two functionally versatile chelators, H4pypa and H4py4pa, with increased rigidity imposed by the central pyridyl moiety that connects the pendent chelating arms. The central pyridyl moiety also serve as a convenient and robust bioconjugation spot. Studies of H4pypa with scandium-44, lutetium-177, indium-111, yttrium-86, zirconium-89, and H4py4pa with actinium-225 were conducted, while their biological properties were evaluated with either the peptide- or the antibody-conjugates, showing favorable radiolabeling results and stability which even surpassed the current “gold-standard” chelator, DOTA, rendering them highly promising for the applications in nuclear medicine.

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