Manganese porphyrin for Synthesis of Targeted Contrast Agents for Improving Specificity in Cardiac Magnetic Resonance Imaging

Specificity in imaging narrows our view from the physical anatomy of damaged tissues, to imaging the processes behind it. These are the benefits provided by nuclear medicine in oncology, whose contrast specificity is provided by chelated radionucleotides whose pharmacokinetics are controlled by a chemically conjugated targeting ligand. Drawbacks of nuclear medicine like ionizing radiation, poor resolution and lack of anatomical information limit its effective use in cardiac imaging. Magnetic resonance imaging by comparison provides full anatomical and functional details at high resolution without ionizing radiation and is currently considered the gold standard in most cardiac imaging applications. Unfortunately, current clinical contrast agents are limited by the toxicity associated with the release of free Gd3+. While this risk can be decreased by improving the kinetic stability of Gd3+ chelation, high kinetic barrier for metal coordination is also a barrier to the synthesis of targeted contrast agents, with high temperatures required for the metalation of complexes lead to the breakdown of their targeting ligands.The principal aim of this thesis was to test a manganese porphyrin for use in the synthesis of targeted T1 contrast agents. This thesis demonstrates a Mn3+ porphyrin as a functionalized bifunctional chelating agent, with very high kinetic stability which surpasses current clinical Gd3+ agents. The high kinetic and chemical stability of Mn3+ proved to allow its use pre-metalated in the conjugation chemistry of thiourea, amide, guanidine and thiocarbamates, as well as the photocatalytic synthesis of urea and carbamates. This chemistry was used to couple Mn3+ porphyrin to several targeting ligands, producing contrast agents for use as specific agents in cardiac imaging. This included intravascular agents for specific MRI angiography, by conjugating Mn3+ porphyrin to either human serum albumin or albumin binding ligands. Conjugation of Mn3+ porphyrin to a collagen I binding ligand provided specific imaging of myocardial fibrosis. Functionalization of Mn3+ porphyrin with a nitric oxide reactive moiety provided specific contrast to myocardial inflammation. Finally, Mn3+ porphyrin was conjugated with several biomaterials, including; collagen, polyurethane and alginate for tracking of materials which have been researched as clinical therapeutic interventions for myocardial injury.

Department dc:contributor.department

Biomedical Engineering

Year dc:date.issued

2025

Author dc:creator

• Vollett, Kyle

Advisor dc:contributor.advisor

• Cheng, Hai-Ling Margaret

• Bifunctional Chelating Agent
• Conjugation
• Isothiocyanates
• Molecular Imaging
• MRI
• Targeted Imaging

Statement dc:rights

• Attribution 4.0 International

Licence dc:rights.uri

• http://creativecommons.org/licenses/by/4.0/

Handle dc:identifier.uri

https://hdl.handle.net/1807/150702

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/150702