Copper-mediated radiosynthesis of 18F- and 123I-radiolabelled PARP inhibitors

Thesis

This thesis aims to develop copper-mediated radiosynthesis to incorporate fluorine-18 and iodine-123 into FDA-approved poly(ADP-ribose) polymerase (PARP) inhibitors for cancer diagnosis and treatment, consisting the development of 18F-radiolabelled rucaparib for positron emission tomography (PET) application in cancer diagnosis and development of 123I-radiolabelled rucaparib and olaparib analogues as potential theragnostic agents for Auger therapy.

Chapter I presents a general introduction of DNA damage, PARP and PARP inhibitors.

Chapter II starts with a brief overview of PET, and 18F-fluorination of (hetero)arenes, and discusses two copper-mediated radiosynthesis approaches of 18F-radiolabelled rucaparib from pinacol boronic ester precursors. Full radiosynthesis of the most successful approach is demonstrated. In vitro data, in vivo dynamic PET imaging and ex vivo biodistribution of [18F]rucaparib are presented subsequently.

Chapter III provides a summary of Auger therapy and current methodologies to access 123I-radiolabelled (hetero)arenes. Development of 123I-rucaparib analogue and 123I-olaparib analogue via copper-mediated 123I-iodination from pinacol boronic ester precursors are discussed separately.

Chapter IV provides experimental data for compounds and procedures of radiosynthesis discussed in this thesis.

Authors: Chen, Z

• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English