Development of Small Molecule Positron Emission Tomography Tracers Targeting Mutated Epidermal Growth Factor Receptor Kinase

This thesis aims to drive the research on identifying NSCLC mutations in vivo using small molecule tyrosine kinase inhibitor (TKI) PET tracers to facilitate targeted drug therapy development, focusing mainly on EGFR mutations. An EGFR PET tracer could be used, e.g., for disease progression monitoring and stratification for personalized therapy or as a tool to develop new inhibitors. Chapter 2 reflects on the history of EGFR inhibitor development and how the field has evolved as it has. It discusses the key findings that drove the targeted (small molecule) drug therapy research forward, what has been learned from EGFR-targeting PET, and why certain evaluation methods became standard practice. While the first-generation TKI PET tracer [11C]erlotinib has been demonstrated to target primary EGFR mutations, it has been indicated to be unable to differentiate between treatment-sensitive primary Del19 mutations and treatment-resistant secondary T790M mutations in vivo [14]. Osimertinib, a third-generation TKI, has been shown to be effective in the clinical treatment of the T790M resistance mutation [15]. Chapter 3 describes the synthesis of two osimertinib 11C-labeled isotopologs. The study aimed to evaluate the potential of 11C-labeled osimertinib to be used as a tracer for PET imaging tumors bearing the EGFR T790M resistance mutation. As many receptor kinases in NSCLC are closely related, a drug that blocks the function of a specific section of one kinase might show affinity for another structurally related kinase. These drugs can be considered multi-kinase inhibitors. Chapter 4 describes the 11C-labeling of an ALK inhibitor, brigatinib, which was also proposed to inhibit EGFR [16]. This study evaluated the suitability of [methylpiperazine-11C]brigatinib as a PET tracer for EML4-ALK and EGFR mutational status assessment in NSCLC xenografted mice. As the disease progresses, a tertiary resistance mutation in the form of C797S has been observed following treatment with osimertinib [17]. Due to the constant resistance mutation development, alternative ways of inhibiting the function of mutated receptors are constantly being researched. One such alternative inhibitor is EAI045. In Chapter 5, EAI045 was radiolabeled with carbon-11 and tritium to gain further knowledge and understanding of the tumor-targeting potential of this alternative inhibition pathway.