Thesis (Ph.D.) -- University of Adelaide, Dept. of Chemistry, 1999. / Errata pasted onto front end-paper. Bibliography: leaves 173-188.

Thesis (M.Sc.). / Written for the Dept. of Chemistry. Title from title page of PDF (viewed 2008/05/28). Includes bibliographical references.

Thesis (Ph.D.). / Written for the Dept. of Biomedical Engineering. Title from title page of PDF (viewed 2009/06/18). Includes bibliographical references.

Thesis (M.S.)--University of Missouri-Columbia, 2005. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file viewed on (January 11, 2006) Includes bibliographical references.

Thesis (Ph. D.)--Chemistry and Biochemistry, Georgia Institute of Technology, 2006. / Fahrni, Christoph, Committee Chair ; Doyle, Donald, Committee Member ; Wilkinson, Angus, Committee Member ; Zhang, Z. John, Committee Member ; Radhakrishna, Harish, Committee Member.

published_or_final_version / abstract / Chemistry / Doctoral / Doctor of Philosophy

This thesis describes efforts at the interface of chemistry and neuroscience to design and characterize fluorescent probes capable of tracing neurotransmitters from individual release sites in brain tissue. As part of the Fluorescent False Neurotransmitters (FFNs) program, small organic fluorophores have been developed that undergo uptake into specific presynaptic release sites and synaptic vesicles by utilizing the native protein machinery, which can then be released during neuronal firing. The most advanced generation of FFNs are pH-sensitive, and display an increase in fluorescence when released from the acidic vesicular lumen into the extracellular space, called a “FFN Flash.” In Chapter 2, the utility of the dopamine-selective and pH-sensitive functionality of FFN102 to study the mechanisms that regulate changes in pre-synaptic plasticity, a critical component of neurotransmission was explored. This included using the FFN flash to quantitatively trace dopamine release, changes in the release probability of individual release sites, and changes in vesicular loading that can affect quantal size. The second goal of this thesis research, as detailed in Chapters 3 and 4, sought to expand the substrate scope of the FFN program to neurotransmitter systems other than dopamine. Described in Chapter 3, is the identification of a fluorescent phenylpyridinium, APP+, with excellent labeling for dopamine, norepinephrine, and serotonin neurons, however, the properties of the probe were found to be ill-suited for measuring neurotransmitter release. As a result, it was concluded that this class of compounds was not suitable for generating viable FFN leads. In contrast, Chapter 4 highlights the design, synthesis, and screening towards generating the novel noradrenergic-specific FFN, FFN270. This probe was further tested for application in acute murine brain slices where it labeled noradrenergic neurons, and was demonstrated to release upon stimulation. This chapter also describes the application of this compound in a series of in vivo experiments, where the ability to measure norepinephrine release from individual release sites was demonstrated in a living animal for the first time. This work opens the possibility for many exciting future FFN experiments studying the presynaptic regulation of neurotransmission in vivo.

Thesis (Ph. D.)--University of Nevada, Reno, 2005. / "May, 2005." Includes bibliographical references. Online version available on the World Wide Web. Library also has microfilm. Ann Arbor, Mich. : ProQuest Information and Learning Company, [2005]. 1 microfilm reel ; 35 mm.

Zinc is an important micronutrient but the biological function of its labile form is poorly understood. Zinc selective fluorescence sensors, recognized as the major tool to gain information about the role of zinc in living systems, have been attracting more and more interest. The most promising solution currently being studied comes in the form of ratiometric sensors. Unlike sensors based on the switch-on mechanism, ratiometric sensors determine the free metal concentration directly from the ratio of the emission intensities at two wavelengths. The major restriction on the design of this type of sensor is from the necessity for a spectral-shift upon binding metal ions. To develop novel ratiometric sensors, we have developed designs based on excited-state intramolecular proton transfer (ESIPT). In the absence of ZnII at neutral pH, the 2-(2 -sulfonamidophenyl)benzimidazole family undergoes ESIPT to yield a highly Stokes-shifted emission from the proton-transfer tautomer. Coordination of ZnII inhibits the ESIPT process and yields a significant hypsochromic shift of the fluorescence emission maximum. By implementing structural modifications, we were able to gauge free ZnII concentrations in the millimolar to picomolar range. To tune the peak excitation towards lower energy, a property that is of particular importance in the light of biological applications, we modified the platform molecule with extended pi-conjugation and by substituent engineering. The position of the modification and the nature of the substituents strongly influenced the photophysical properties of the investigated derivatives. Several fluorophores revealed emission ratiometric properties with a large dynamic range combined with a peak absorption beyond 350 nm, rendering these probes promising candidates for applications. To further understand the origin of the substituent effect, we studied five derivatives for the solvatochromic shift analysis and quantum chemical studies. The results showed that the negative solvatochromic shift behavior was most pronounced in protic solvents presumably due to specific hydrogen-bonding interactions. The extrapolated gas-phase emission energies correlated qualitatively with the trends in Stokes shifts, suggesting that solute-solvent interactions do not play a significant role in explaining the divergent emission energy shifts. Detailed quantum chemical calculations not only confirmed the moderately polarized nature of the ESIPT tautomers but also provided a rationale for the observed emission shifts based on the differential change in the HOMO and LUMO energies. This study revealed the great potential of 2-(2 -arylsulfonamidophenyl)- benzimidazoles, such as tunable peak absorption and emission, a very wide dynamic range regarding to zinc binding, very little solvent polarity dependence, and especially, the emission ratiometric property. All these properties make this system a unique candidate to tackle the problems in the research of zinc biology.

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy