Kirberger, Steven2021-09-242021-09-242019-07https://hdl.handle.net/11299/224594University of Minnesota Ph.D. dissertation. July 2019. Major: Chemistry. Advisor: William Pomerantz. 1 computer file (PDF); x, 340 pages.Molecular imaging is the process of using targeted probes to detect abnormalities at the molecular level by observing interactions to specific biomarkers. Magnetic resonance imaging (MRI) presents an interesting avenue with respect to development of probes for the early detection of disease. In particular, 19F MRI shows promise for this development as the fluorine nucleus possesses many similar characteristics as the conventionally used proton but has the distinction of a lack of background signal found natively in biological systems. State of the art 19F MRI agents involve the use of perfluorinated compounds that often suffer from stability issues, bioaccumulation, as well as persistence within the environment. The first part of this dissertation describes the design and optimization of a peptide-based 19F MRI agent. These peptide scaffolds show promise for future use as 19F MRI probes due to their high signal, water solubility, and facile degradation in vivo to prevent bioaccumulation. The resultant byproducts have also been shown to be environmentally benign. This work is the focus of Chapters 2 and 3 of this document. In a second project, the development of a small molecule inhibitor of an epigenetic protein target is described. AU1, the first reported small molecule inhibitor of the bromodomain of a protein called BPTF, was discovered in the Pomerantz lab in 2015. As BPTF is a relatively understudied protein, there exists a need to improve the potency of AU1 as a probe for the various functions of its bromodomain, as it has been implicated in numerous diseases including: pancreatic cancer, melanoma, colorectal cancer, hepatocellular carcinoma, breast cancer, bladder cancer, and lung cancer. Structural analogs have been developed and analyzed in an attempt to improve upon AU1 in terms of its potency, solubility, and reduction of potential off-target binding. The work described in Chapter 4 of this document shows progress toward these goals, and the development of our 19F NMR assays for the analysis of protein ligands. A collaborative effort involving the (S)-enantiomer of AU1 is briefly described in Chapter 1. In a third section, the collaborative work between our lab and that of Ratmir Derda to develop peptide auxiliaries to improve therapeutic life-time in vivo is described. Chapter 5 details the use of 19F NMR to analyze the binding strength and location of numerous fluorinated peptides designed in the Derda lab.en19F MRIBPTFBromodomainsMolecule ImagingNMRPeptidesThesis or Dissertation