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Fiaccabrino, Desiree

University of British Columbia

Advances in nuclear medicine, particularly in radiotheranostic medicine, where a single agent is used for both diagnosis and therapy, have provided new avenues for diagnosing, treating, and studying diseases. Central to these innovations are radiopharmaceuticals, drugs that carry radioactive elements (metal-based or organic) and harness emitted radiation for their function. In metal-based radiopharmaceuticals, four key components work together: the radionuclide (serving a diagnostic, therapeutic, or theranostic role), a bifunctional chelator that securely binds the metal, a targeting biomolecule that directs the drug to specific cells, and a molecular tether that links the chelator to the targeting vector. This thesis focuses on the development of chelators based on the triaza-18-crown-6 macrocyclic scaffold for theranostic applications in nuclear medicine. By functionalizing the three nitrogen atoms with groups of varied denticity and hardness/softness, the modified macrocycle can coordinate isotopes that differ in size and coordination preferences. The first chelator, H₃trica, features three acetate arms to complex larger metal ions such as [²²⁵Ac]Ac³⁺ (therapy) and [¹⁵⁵Tb]Tb³⁺ (imaging). The coordination behaviour of H₃trica was characterized using NMR spectroscopy, potentiometric titration, and DFT calculations, and further supported by radiolabeling studies with ²²⁵Ac and ¹⁵⁵⧸¹⁶¹Tb. Building on this platform, a bifunctional analogue, H2trica-TATE, was developed in collaboration with Dr. David Perrin to assess how the removal of one coordinating arm to attach the targeting moiety affects performance and stability, as evaluated in vitro and in vivo with ²²⁵Ac. A third chelator, H₃tripa, incorporates three picolinic acid moieties to target softer metal ions like the theranostic ²¹²/²⁰³Pb pair and ²¹³Bi; the coordination properties were studied using UV-potentiometric analysis, NMR spectroscopy, and DFT calculations, complemented by radiolabeling experiments with ²⁰³Pb and ²³Bi. Lastly, integrating three 1,2-hydroxypyridinone (HOPO) arms produced H₃trihopo, designed to bind the theranostic pair ²²⁷Th (therapy) and ⁸⁹Zr (imaging). Characterization with Zr⁴⁺ and natural [²³²Th]Th⁴⁺, along with radiolabeling studies with ²²⁷Th, explored its potential in radiotheranostic applications.

Text

2025-06-19

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/91372

Chemistry

University of British Columbia

UBCV

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