Development of a Thorium Complex for Radiotherapeutic Applications

Chapter 1. A brief history of the use of ionizing radiation for cancer therapy is presented, as the motivation for modern clinical investigations on alpha therapy and the use and development of bifunctional chelators in targeted medicine. Recent studies on targeted therapy with alpha-emitters, such as 223Ra and 227Th, are described. The chemistry of Th(IV) is presented with a survey of important coordination compounds, with special emphasis on those developed by the Raymond group./nChapter 2. The rational design of a ligand as a suitable bifunctional chelator for 227Th therapy is described in the context of ligands developed by the Raymond group for actinide sequestration. A novel Φ ligand topology incorporating macrocyclic and pendant terephthalamide binding groups aims to address the kinetic and thermodynamic requirements of targeted alpha therapy. The syntheses of the model ligands Φ(2,2)moeTAM and Φ(3,3)moeTAM are detailed, from which a derivative of Φ(2,2)moeTAM is developed. Functionalization of a pendant terephthalamide of the model ligand gives the asymmetric bifunctional chelate Φ(2,2)NBuTAM via the strategic use of protecting groups./nChapter 3. The evaluation of the solution thermodynamic behavior of Φ(2,2)moeTAM is extensively detailed. The protonation constants of the ligand and its affinity for Th(IV) is measured by spectrophotometric titration. The thorium complex was found to have a remarkably high thermodynamic stability, with a formation constant of 1054, surpassing the stabilities of previously measured complexes. Efforts to elucidate the effects of the Φ topology on the coordination of Th(IV) using thermodynamic studies of the linear analog 3,4,3-LiMeTAM as well as the shape analyses of the crystal structure of Th[Φ(2,2)moeTAM] are described. The surprising geometry adopted by Φ(2,2)moeTAM in the thorium complex relative to its structure as the free ligand is further investigated with DFT studies./nChapter 4. While the measurement of the thermodynamic parameters of the thorium complex provides an assessment of its inertness, its formation kinetics are also of paramount importance due to the inherent time sensitivity of radiotherapeutic agents. Difficulties encountered in preliminary kinetic experiments with existing octadentate ligands and Φ(2,2)moeTAM lead to the use of indirect kinetics. Dye-displacement kinetic studies with the Φ ligands, 3,4,3-LiMeTAM, and the aminocarboxylic acid ligands provide a useful qualitative comparison of the rates of complexation of these ligands with Th(IV). Φ(2,2)moeTAM is observed to be a much more rapid chelator than the prevailing DTPA and DOTA, and its association (a second-order reaction with a rate constant of k2 = 1.8(1) x 104 M-1s-1) can be directly measured using stopped-flow kinetics./nChapter 5. The application of Φ(2,2)moeTAM toward the coordination of the lanthanide analogs cerium and praseodymium is presented. The crystal structure of the Ce(IV) complex with Φ(2,2)moeTAM is isomorphous to that of the Th(IV) complex, prompting solution thermodynamic and electrochemical studies to investigate the stability of the Ce(IV) complex. Spectrophotometric titration indicates an unprecedented formation constant on the order of 1061, and a Nernstian shift of the Ce(III)-(IV) couple of 2.0 V upon complexation is observed by cyclic voltammetry. The strong preference of Φ(2,2)moeTAM for the +4 oxidation state relative to the +3 is further highlighted by the solution thermodynamics of Pr(III).

Advisor: Raymond, Kenneth N.