Development of Chelators for Enhancing Radiometal-based Radiopharmaceuticals
Zirconium-89 is one of the few radionuclides among positron emitters which have a relatively long physical half-life compatible with the biological half-life of most antibodies. Zirconium-89’s low positron energy, well studied and established production and purification protocols, cost effective and wide availability illustrates it as the best currently available radionuclide for immuno-positron emission tomography (immuno-PET). To employ zirconium-89 in monoclonal antibody-based radiotracers a bifunctional chelator is required to attach the radiometal securely to the antibody and assure site specific delivery of the radiometal. Desferrioxamine (DFO) has been used as the “gold standard” chelator for zirconium-89 labeled monoclonal antibodies preclinically and clinically. However, the hexadentate nature of DFO is insufficient to saturate the coordination sphere of [89Zr]Zr4+, thus in vivo sub-optimal stability of it has been reported in various studies. The released oxophilic and osteophilic zirconium (IV) ion accumulates in healthy tissue particularly in bone. Furthermore, DFO, apart from binding to diagnostic radiometal like zirconium-89, it is not known to stably bind to any therapeutic radiometals which means it has little theranostic potential. Thus, the development of optimized chelators for zirconium-89 is ongoing and demands for new bifunctional chelators which can stably bind the radiometal and conjugate to targeting vectors such as antibodies has grown considerably in the last decade. This thesis describes the design, synthesis and evaluation of novel high denticity (8-12) desferrioxamine based ligands/chelators for zirconium-89 and potentially other high valent therapeutic radiometals. Following the synthesis and characterization of the new chelators with standard chemical characterization methods, the radiolabeling properties and in vitro/in vivo stability of unconjugated “bare” chelators and antibody conjugates were evaluated by using various radiochemical assays and animal studies. Two families of chelators are the highlights of this thesis: the DFO2 family with 12 possible coordination sites, and an amino acid-based chelator family with 8-coordination sites. Each of the families consist of two chelators, for which their stabilities with zirconium-89 have been found to surpass the “gold standard” chelator DFO, and their higher denticities compared to DFO might offer the potential for utilizing other high valent and oxophilic radiometal ions such as thorium-227 or actinium-225 for theranostic applications.
Zirconium-89, Bifunctional chelator, Positron Emission Tomography
Doctor of Philosophy (Ph.D.)