Development Of Peptide-Based 19F Mri Tracers And Mr-Based Thermometry Sensors

Abstract

Molecular imaging is defined as the visualization, characterization, quantification of biological processes at the cellular and subcellular level in living subjects. To conduct molecular imaging on specific target, a molecular imaging agent is needed, which is composed of a specific recognition group for a molecular target and an imaging domain. Of various molecular imaging modalities, ¹⁹F MRI is gaining increasing attention with its favorable imaging properties. However, the low sensitivity of ¹⁹F MRI remains a major challenge. The design of imaging agents with high fluorine content is essential for overcoming the challenge associated with signal detection limits. In addition to perfluorocarbon and fluorinated polymers, fluorinated peptides offer an additional strategy for creating sequence-defined ¹⁹F MRI imaging agents with high fluorine signal. The first part of this dissertation gives a general introduction of ¹⁹F MRI as one molecular imaging modality. Major categories of ¹⁹F MRI imaging agents are covered with individual strength and weaknesses highlighted. A complementary category of fluorinated peptide is also discussed in detail. The constructs of those peptides were where the designs of my ¹⁹F MRI molecular tracers originated. A brief introduction of the biomarker of choice for molecular imaging and the multivalent CSAN construct for signal amplification follows, both of which were important in the design of my molecular tracers. As other important applications of ¹⁹F MRI, thermometry and oximetry with ¹⁹F MRI is also covered with the challenges in the design of the sensors. The second part of this dissertation focused on the development of peptide-based imaging agents. The designs were based on the unstructured peptides previously reported by our group. Chapter 2 focuses on addressing the challenges of those reported peptides through developing new fluorinated amino acids to improve the peptides’ detection limits and modifying the peptide structures to remove the undesired non- specific cellular interactions. Chapter 3 focused on addressing the challenge of limited signal in cell-based ¹⁹F NMR with the molecular imaging agent prepared in previous chapter. Efforts were made by engineering the molecular imaging agent into multivalent nanoring to further increase the fluorine content while maintain the favorable cellular interactions. Apart from molecular imaging, ¹⁹F MRI is also utilized in thermometry applications. Accurate temperature measurement via magnetic resonance is valuable for both in vitro and in vivo analysis of local tissue for evaluating disease pathology and medical interventions. The third part of this dissertation focused on the development of ¹⁹F MRI temperature sensors. Those temperature sensors were developed in Chapter 4 with the goals to improve the temperature sensitivity, being ready for encapsulation, and addressing the environmental persistence concerns. The last part of this dissertation covered the projects on stapled peptides. One is about the cellular interaction on stapled peptides to albumin under the collaboration with Ratmir Derda group; the other one is about the macrocyclization of MLL fragments on their interaction with KIX domain.