Towards synthesis of a novel chelator for zirconium-89

The radioisotope zirconium-89 has attracted attention in recent years as a candidate for clinical use in positron emission tomography (PET), due to its favourable properties. Zirconium-89 has a long half-life of 78.4 hours, rendering it suitable for use in conjugation to monoclonal antibodies (mAB), therefore giving potential applications in personalised medicines. it also has favourable emission characteristics, such as low energy positron emissions. Furthermore, it can be produced at low cost. These factors combine to support zirconium-89 as a cheap and high-resolution radioisotope for PET imaging. The most widely used chelator of zirconium-89, desferrioxamineB (DFO), forms an insufficiently stable complex with zirconium-89 and undergoes some demetallation in vivo, leading to ablation of zirconium-89 to bone tissues. While recent efforts have focussed on developing novel chelators with more stable properties, B9Zr-DFO is the only complex which has been examined in a clinical setting, and novel zirconium chelators have required either difficult synthetic procedures or are insufficiently soluble. it is hypothesised that the ideal chelator for zirconium-89 will: bind via hydroxamate groups in an octadentate manner; be bifunctional; and be simple to synthesise. The novel chelators 8 and 10 were designed based on these criteria and to examine the feasibility of a zirconium-89 chelator incorporating a-amino acids. Synthesis of both compounds was attempted via a modular solution-phase peptide synthesis. The molecular subunits 4a and 4b were synthesised with overall yields of 21% and 48% respectively. However, during the latter stages of the synthesis intramolecular degradation of compounds 7 and 8 resulted in the formation of an alternative product: compound 8.1. Analytical evidence obtained through 1HNMR and HRMS suggested this occurred by a mechanism akin to aspartimide formation, as seen in solid-phase peptide synthesis. To examine this hypothesis, an alternative chelator 14 was designed, incorporating ~-alanine in place of glycine. This compound was successfully synthesised via solid-phase peptide synthesis and identified with HRMS and 1HNMR. As the monohydroxamate compound 8.1 was isolated as a pure product, it was of interest to assess its binding affinity for the radiometals zirconium-89 and gallium-68: The chelator was compared to DFO and subject to challenge assays to assess resistance to competitive metal ions, transchelation by EDTA, and non-specific protein binding. While it was evident that compound 8.1 was inferior to DFO as a chelator of zirconium-89 under all conditions, it did display significantly increased stability than previously reported for monohydroxamate chelators. However, both compound 8.1 and DFO displayed low stability when complexed with gallium-68.Thesis (MPhil) -- University of Adelaide, School of Physical Sciences, 202