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dc.contributor.advisorKrol, Edward
dc.creatorNwabufo, Chukwunonso Kingsley 1991-
dc.date.accessioned2019-03-10T06:00:56Z
dc.date.available2019-03-10T06:00:56Z
dc.date.created2019-02
dc.date.issued2019-03-10
dc.date.submittedFebruary 2019
dc.identifier.urihttp://hdl.handle.net/10388/11896
dc.description.abstractThe development of disease-modifying drugs and differential diagnostic agents is a current focus of research in Parkinson’s disease (PD) and one putative target is alpha-synuclein (AS). Recently, we reported that two bifunctional compounds composed of a caffeine scaffold attached to nicotine (C(8)-6-N) and 1-aminoindan (C(8)-6-I) could prevent AS mediated toxicity in a yeast model of PD. Although caffeine linked to caffeine (C(8)-6-C(8)) did not show any therapeutic potentials, it demonstrated the strongest binding to AS. To better understand the biodistribution of C(8)-6-I, C(8)-6-N, and C(8)-6-C(8) in vivo we are developing methods to label the bifunctional compounds with Fluorine-18 (18F) to use in positron emission tomography (PET) imaging studies. Given the therapeutic and diagnostic potentials of these bifunctional compounds, it is necessary to conduct further preclinical studies to understand their safety and efficacy. The overall goal of this study is to establish the tandem mass spectrometric fingerprints of the target compounds which can help in metabolite identification and for the development of qualitative and quantitative methods. Also, the metabolic profile for C(8)-6-I, C(8)-6-N, and C(8)-6-C(8) in human, mouse, and rat liver microsomes (HLM, MLM, and RLM) were evaluated. Tandem mass spectrometric studies were performed using hybrid quadrupole-time of flight and triple quadrupole-linear ion trap mass spectrometers. Metabolite profiling was accomplished using accurate mass measurement and tandem mass spectrometry. A significant observation in the fragmentation of C(8)-6-C(8) suggests that a previously reported loss of acetaldehyde during caffeine fragmentation is instead a loss of carbon dioxide. While the caffeine scaffold in C(8)-6-N, C(8)-6-I, and C(8)-6-C(8) was metabolically stable, the nicotine and 1-aminoindan moieties were either cleaved off (dealkylation) or hydroxylated in HLM, MLM and RLM indicating that the caffeine moiety may be the preferable spot for the inclusion of 18F radioisotope in these bifunctional compounds. Given the similarity in the metabolic pathways, mouse and rat may be useful surrogates for future animal studies of C(8)-6-I, C(8)-6-N, and C(8)-6-C(8).
dc.format.mimetypeapplication/pdf
dc.subjectParkinson's disease
dc.subjectalpha-synuclein
dc.subjectdrug metabolism
dc.subjecttandem mass spectrometry
dc.subjectbifunctional compounds
dc.subjectpositron emission tomography imaging probes
dc.subjectdisease-modifying drugs
dc.subjectdifferential diagnostic probes
dc.subjectnew chemical entities
dc.subjectliver microsomes
dc.titlePreclinical Development of Novel Bifunctional Compounds for Parkinson's Disease
dc.typeThesis
dc.date.updated2019-03-10T06:00:56Z
thesis.degree.departmentPharmacy and Nutrition
thesis.degree.disciplinePharmacy
thesis.degree.grantorUniversity of Saskatchewan
thesis.degree.levelMasters
thesis.degree.nameMaster of Science (M.Sc.)
dc.type.materialtext
dc.contributor.committeeMemberEl-Aneed, Anas
dc.contributor.committeeMemberKatselis, George
dc.contributor.committeeMemberDadachova, Kate
dc.creator.orcid0000-0002-1889-0334


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