Preclinical Development of Novel Bifunctional Compounds for Parkinson's Disease
Date
2019-03-10
Journal Title
Journal ISSN
Volume Title
Publisher
ORCID
0000-0002-1889-0334
Type
Thesis
Degree Level
Masters
Abstract
The 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).
Description
Keywords
Parkinson's disease, alpha-synuclein, drug metabolism, tandem mass spectrometry, bifunctional compounds, positron emission tomography imaging probes, disease-modifying drugs, differential diagnostic probes, new chemical entities, liver microsomes
Citation
Degree
Master of Science (M.Sc.)
Department
Pharmacy and Nutrition
Program
Pharmacy