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UBC Theses and Dissertations

Acyclic chelating ligands for radiometals Ramogida, Caterina Fortunata


This thesis presents studies on a class of acyclic (open chain) chelating ligands based on the picolinic acid moiety. Our recent reports of the promising hexadentate chelator H₂dedpa and octadentate analogue H₄octapa for Ga(III) and In(III)/Lu(III) complexation, respectively, have spurred our interest in further developing this class of chelators, which have subsequently been dubbed the “pa” family of ligands. These ligands possess the potential to bind a variety of clinically relevant radiometal ions, such as ⁶⁸Ga, ⁶⁴Cu, ¹¹¹In, ¹⁷⁷Lu, or ⁸⁶/⁹⁰Y. When harnessed properly, the radiative emissions of these radiometals can be utilised in radiopharmaceuticals for imaging (via γ-rays for single photon emission computed tomography (SPECT) or β+ particles for positron emission tomography (PET)) or therapy (via highly ionizing radiation from α, β-, or Auger electron emission). A key component of these radiometal-based radiopharmaceuticals is the chelating ligand, used to securely bind the radiometal which ensures proper delivery the radioactive dose to the area of interest in vivo. This work focuses on further exploiting the H₂dedpa (N₄O₂) and H₄octapa (N₄O₄) scaffolds that possess ideal properties for ⁶⁷/⁶⁸Ga and ¹¹¹In radiopharmaceuticals, respectively – such as mild room temperature radiolabeling in 10 min, and the ability to form kinetically inert complexes – rare manifestations for acyclic ligands. Herein, efforts were made to incorporate dedpa²- into a small molecule imaging agent for ⁶⁸Ga PET. A variety of dedpa²- (and one octapa⁴-) analogues were synthesized, characterized, and evaluated through thermodynamic stability, in vitro kinetic inertness, and radiolabeling studies to assess their “usefulness” as ligands in radiopharmaceutical design. The chiral ligands H₂CHXdedpa and H₄CHXoctapa are highlights of this work; [Ga(CHXdedpa)]+ and [In(CHXoctapa)]- were found to be more, or equally, stable versus their achiral counterparts H₂dedpa and H₄octapa. Nitroimidazole-containing H₂dedpa and H₂CHXdedpa derivatives were also studied as potential ⁶⁸Ga PET imaging agents of tumour hypoxia. The radio-tracers showed exceptional in vitro stability (86 to >99% intact), and promising preferential uptake in hypoxic cell lines suggesting these ligands would be ideal candidates for further testing in vivo.

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