Development of Nitrogen-15- and Carbon-13-Labeled Biochemical Probes for Hyperpolarized Metabolic Imaging




Suh, Eul Hyun

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13C and 15N dynamic nuclear polarization coupled with nuclear magnetic resonance study provides an opportunity to non-invasively monitor metabolic fluxes in vivo using appropriately designed 13C or 15N enriched metabolic probes. However, hyperpolarized spin states have a short lifetime because the hyperpolarized magnetization decays by T1 relaxation. This restricts the biological applications of hyperpolarized probes. Therefore, the goal of this dissertation work is to develop 13C and 15N enriched probes with long T1 values that quickly enter cells and actively metabolize or act as reporters of important biological metal ions involved in metabolism. The first project focuses on cell permeable 15N labeled hyperpolarized probes designed to report zinc levels, which play a crucial role in the onset and progression of prostate cancer. Deuterated 15N-tris(pyridylmethyl)amine designed and synthesized for this purpose was found to have extremely long T1 values and an altered 15N chemical shift upon Zn2+ binding. Its applicability for zinc mapping was demonstrated in hyperpolarized 15N MRI experiments in phantoms. The second project was to demonstrate the feasibility of using hyperpolarized [1-13C]ketoisocaproic acid as an imaging agent to detect altered branched-chain amino acid metabolism in glioma. This probe was successfully used to monitor both branched-chain aminotransferase and alpha-keto acid dehydrogenase activity in glioma by hyperpolarized 13C imaging in vivo. Both 13C- ketoisocaproic acid in vivo imaging and 13C-leucine infusion study provided strong evidence for increased catabolism of ketoisocaproic acid in tumor compared to the contralateral normal appearing brain tissue. The third project involved the design and synthesis of 13C labeled glyoxylate in an attempt to image the glyoxylate shunt pathways. [1-13C]Glyoxylate hydrate was successfully synthesized and was evaluated as a metabolic probe for the glyoxylate cycle in cells. However, the incorporation of [1-13C]glyoxylate via the glyoxylate cycle was not observed in the mouse embryonic fibroblasts and yeast cells. This is likely due to the high chemical reactivity of glyoxylate toward free amino groups of proteins. In summary, in these projects, 15N and 13C labeled hyperpolarized probes have been investigated for noninvasive monitoring of physiochemical sensing and metabolic processes, which could provide a key to detect abnormality of cancer metabolism.

General Notes

Pages 44-75 are misnumbered as pages 43-74, pages 76-103 are misnumbered as pages 73-100, pages 104-129 are misnumbered as pages 100-125, and pages 130-134 are misnumbered as pages 125-129.

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