Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Chemistry

Collaborative Specialization

Molecular Imaging

Supervisor

Luyt, Leonard G.

Abstract

Molecular imaging is making possible the understanding of intricate biological processes in real-time in both healthy and diseased tissues. The ability to non-invasively locate biomarkers of disease with good sensitivity and specificity affords the ability to provide accurate and early diagnoses, and patient stratification for therapy. The chemokine receptor CXCR4 is one biomarker of interest, as it is overexpressed in many cancers, yet has low expression elsewhere in normal physiology. This thesis will document a method of combinatorial chemistry to construct libraries of new potential peptide-based imaging agents for positron emission tomography (PET) imaging. It will also incorporate the study of strain-promoted alkyne-azide cycloaddition (SPAAC) as a type of copper-free click chemistry used as a method for radiofluorination of biological structures.

Chapter 2 discusses the synthesis of a library of N-terminal modified peptides created using a one-bead one-compound (OBOC) approach. Each peptide in the library contains a single fluorine atom incorporated through established SPAAC chemistry. The library of complete imaging agents was put through multiple stages of screening against CXCR4, resulting in the discovery of a peptide-based imaging agent with an IC50 of 138 µM.

Chapter 3 discusses the development of a new 18F-labelled cyclooctyne-based prosthetic group for incorporation into azide-functionalized biological structures. This 18F-azadibenzocyclooctyne (ADIBO-F) was radiolabelled from its toluenesulfonate precursor in 21–35 % radiochemical yields, and subsequently incorporated into two cancer-targeting peptides through SPAAC chemistry. The result is two novel peptide‐based PET imaging agents that possess high affinities for their targets, the growth hormone secretagogue receptor 1a (GHSR‐1a) and gastrin‐releasing peptide receptor (GRPR), with IC50 values of 9.7 and 0.50 nM, respectively.

Chapter 4 discusses the synthesis of an OBOC library with an imaging moiety integrated within the peptide structures. A two-pool OBOC strategy was developed to distribute the fluorine-containing amino acid throughout the peptide sequence during library synthesis. The ADIBO-F prosthetic group from Chapter 2 was employed for simple translation of peptide hits into their radiofluorinated counterparts. An on-bead two-colour screen was performed in one step and resulted in the discovery of three CXCR4-specific peptide-based imaging agents with micromolar affinities of 28, 86 and 109 µM.

Summary for Lay Audience

Not applicable.

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