Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Chemistry

Supervisor

Dr. Leonard Luyt

Abstract

Molecular imaging probes allow for the non-invasive diagnosis of many diseases through the use of a targeting entity for site specific delivery, as well as a signal for external visualization of probe accumulation in the body. This thesis will focus on the development of new approaches to synthesize targeting peptides and chelators for radionuclide incorporation towards the design of novel molecular imaging probes.

Histidine is a tridentate chelator that can be attached in a pendant fashion to a biomolecule in order to coordinate technetium-99m. Once coordinated, it forms a neutral complex that is capable of forming diastereomers with inverted stereochemistry at the alpha amine of the histidine. This is demonstrated through the synthesis and characterization, with LC-MS and 2D NMR spectroscopy, of four different histidine chelators that upon rhenium coordination form two products.

Copper-catalyzed azide-alkyne cycloaddition, or “click”, reactions form a 1,2,3-triazole that can be used to cyclize peptides, as well as coordinate [99mTc/Re(CO)3]+. Clickable peptides can be developed combining these two concepts, such that a chelation site is created as a result of peptide cyclization in order to facilitate incorporation of [99mTc/Re(CO)3]+ within the peptide. In order to do this, azide and alkyne modified amino acids can be incorporated into peptide sequences and reacted to form a triazole containing chelation sphere while simultaneously cyclizing the peptide.

Simultaneous peptide cyclization and [99mTc/Re(CO)3]+ coordination was also performed with pentapeptides of the form Ac-HAAAH-OH. This was done in a [2+1] fashion using the imidazole of the N-terminal histidine and the imidazole and carboxylic acid of the C-terminal histidine. Peptide coordination was verified through LC-MS, while computational studies as well as 2D and VT NMR spectroscopy allowed for the determination of the mode of coordination.

Finally, water soluble gold nanoparticles were conjugated with bombesin, a peptide known to target gastrin-releasing peptide receptors that are overexpressed in prostate cancer. This was done through the use of click chemistry to attach an azide modified bombesin to alkyne modified gold nanoparticles. Through transmission electron microscopy studies, these targeted nanoparticles showed specific uptake in prostate cancer cells, demonstrating their utility for targeting prostate cancer for both diagnostic and therapeutic purposes.

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