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Synthesis and characterization of H5decapa and related ligands Arane, Karen


Radiopharmaceuticals have provided a great breakthrough in tumor imaging and treatment, and the continued exploration in the field is required to make their use widespread. This vast potential lies in the variety of the radioisotopes, due to the different emission profiles and half-lives, and it is the chemist’s job to harness these isotopes into functional pharmaceuticals. Bifunctional chelators (BFC), that incorporate a radiometal into a ligand scaffold that is functionalized to target a specific biological site, provide a mode to access many of these isotopes: α, β-, or auger electron emitters for therapy, β+ emitters for positron emission tomography (PET) imaging, and γ emitting isotopes for single photon emission computed tomography (SPECT) imaging. The first requirement of a BFC is the thermodynamic stability and kinetically inert complex it forms with the isotope, especially in vivo. The Orvig group has discovered the promise of the ligands H₂dedpa for ⁶⁷/⁶⁸Ga and H₄octapa for ¹¹¹In, and has thus led to the idea of expanding this scaffold for larger radioisotopes. An improved synthetic scheme for H₅decapa, a decadentate ligand, allowed for thermodynamic testing and radiolabeling experiments to be performed with ⁸⁹/⁹⁰Y, ¹⁷⁷Lu and ⁸⁹Zr. H₅decapa showed promising serum stability over 5 days with ¹⁷⁷Lu, and was able to quantitatively bind ⁸⁹Zr after 30 minutes at room temperature. A bifunctional version of H₅decapa was synthesised, coupling para-nitroethylbenzene to the central nitrogen, for future conjugation to biomolecules. As well, preliminary investigation into creating a version of H₅decapa with hydroxamate groups catered to binding Zr⁴⁺ was undertaken.

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