Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Chemistry

Supervisor

Luyt, Leonard G

Abstract

Molecular imaging is a non-invasive way to diagnose disease. Molecular imaging probes consist of a targeting entity that has a high affinity for a biological target and a signaling source for external detection. Multimodality imaging combines the advantages of different imaging modalities, at the same time eliminating their shortcomings, thereby providing more accurate results. This thesis focuses on the development of novel dual PET/fluorescence imaging agents based on peptides as targeting entities.

Porphyrins are suitable for multimodality imaging applications due to their innate characteristics such as an ability to fluoresce and to coordinate metals. A gallium-protoporphyrin IX(PPIX)-ghrelin based analogue was designed as a potential dual PET/fluorescence imaging probe for detection of growth hormone secretagogue receptor 1a (GHS-R1a) and it was found that fluorescence was not quenched upon coordination to Ga. The PPIX-ghrelin analogue was also successfully radiolabeled with 68Ga. The specific uptake of this analogue by the receptor target, GHS-R1a, was demonstrated through confocal fluorescence microscopy using OVCAR-8 cells transfected with GHS-R1a. Thus, these dual modality probes can aid in bridging the gap and extend research from in vitro fluorescence imaging to in vivo PET imaging. 69/71Ga-hematoporphyrin-bombesin analogues were synthesized as potential PET/fluorescence imaging probes for the gastrin releasing peptide receptor (GRP-R), but the reaction yields were low and all the components of the hematoporphyrin-bombesin mixture could not be coordinated with gallium and this mixture of coordinated and the uncoordinated analogues could not be analyzed by optical methods. Nonetheless, the ability of hematoporphyrin to act as a chelator for Ga and to couple to peptides was demonstrated.

BODIPY dyes are widely used for fluorescence imaging but suffer from drawbacks such as complicated synthesis and small Stokes shifts. However, novel BF2-formazanate dyes have favourable properties such as convenient synthesis and optical properties that can be tuned by modifying the structure. BF2-formazanate- peptide based analogues were developed as fluorescence imaging agents for GHS-R1a and GRP-R. Use of a modified ghrelin sequence led to an improvement in the IC50 value. Specific uptake of the probes could be visualized through fluorescence microscopy.

Keywords

Optical imaging, positron emission tomography, protoporphyrin, hematoporphyrin, GHS-R1a, GRP-R, BF2-formazanate

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