Synthesis, evaluation, and application of new ligands for radiometal based radiopharmaceuticals

Radiometals comprise many useful radioactive isotopes of various metallic elements. When properly harnessed, these have valuable emission properties that can be used for diagnostic imaging techniques, such as single photon emission computed tomography (SPECT, e.g. ⁶⁷Ga, ⁹⁹mTc, ¹¹¹In, ¹⁷⁷Lu) and positron emission tomography (PET, e.g. ⁶⁸Ga, ⁶⁴Cu, ⁴⁴Sc, ⁸⁶Y, ⁸⁹Zr), as well as therapeutic applications (e.g. ⁴⁷Sc, ¹¹⁴mIn, ¹⁷⁷Lu, ⁹⁰Y, ²¹²/²¹³Bi, ²¹²Pb, ²²⁵Ac, ¹⁸⁶/¹⁸⁸Re). A fundamental critical component of a radiometal-based radiopharmaceutical is the ligand that binds the radiometal ion in a tight stable coordination complex so that it can be properly directed to a desirable molecular target in vivo. This thesis describes the design, synthesis, and evaluation of novel acyclic ligands based on the versatile picolinic acid moiety. Acyclic ligands have been selected because facile ambient temperature radiolabeling is an important property when working with heat sensitive molecules such as antibodies, as many currently used ligands require high temperatures for optimal radiolabling performance. Previous work in the Orvig group has determined the acyclic ligand H₂dedpa to possess ideal properties for ⁶⁷/⁶⁸Ga radiochemistry. In light of this success, this thesis has been dedicated to expansion of the H₂dedpa molecular scaffold to accommodate larger radiometals with ligand denticities ranging from 8-10. Once synthesized, new ligands are studied by standard chemical characterization, as well as potentiometric titrations to determine thermodynamic stability parameters, and radiolabeling and in vitro/in vivo stability studies of both “bare” ligands and antibody bioconjugates. The ligand H₄octapa is a highlight of this body of work, and has been found to possess excellent properties with the radiometals ¹¹¹In and ¹⁷⁷Lu, matching or in some cases surpassing the current industry “gold standard” ligand DOTA. A second highlight is the ligand H₆phospa, which is demonstrated to possess enhanced ⁸⁹Zr radiolabeling properties to H₄octapa, showing the best ⁸⁹Zr radiolabeling performance of any new ligand in several decades, with only DFO retaining superior properties.Science, Faculty ofChemistry, Department ofGraduat