Chemistry Seminar - Omozojie Paul Aigbogun, PhD Candidate, University of Saskatchewan
Omozojie Paul Aigbogun, PhD Candidate in the Department of Chemistry, University of Saskatchewan, will present a seminar at 2:00 pm in Thorvaldson 110.
Topic
Synthesis and evaluation of novel α-synuclein binding compounds as PET probes for Parkinson’s disease
α-synuclein aggregates are associated with pathophysiology of Parkinson’s disease and they are present in Lewy Bodies found in the brains of Parkinson’s patients. Neuroprotective compounds prevent the formation of these aggregates and are potential therapeutics for Parkinson’s disease. Previously, our group have developed bifunctional compounds composed of caffeine linked to 1-aminoindan via a six carbon chain (C8-6-I) and caffeine linked to nicotine via a six carbon chain (C8-6-N), both of which bind to α-synuclein and protect yeast cells from α-synuclein mediated toxicity. In order to utilize these compounds as therapeutics or probes for Parkinson’s disease, it is important to perform pre-clinical studies such as in vitro phase 1 metabolism, hepatic enzyme kinetics, and Positron Emission Tomography (PET) imaging and biodistribution of the fluorinated analogues.
Our metabolic stability studies of C8-6-I, and C8-6-N indicate that both compounds undergo phase 1 P450 metabolism in mouse, rat, and human liver microsomes. We utilized this metabolic information to guide the design of fluorinated analogues for use as PET probes. Phase 1 metabolism studies of 19F-C8-6-I and 19F-C8-6-N indicate that the fluorine atom is stable to P450 biotransformation. We are currently investigating 18F-C8-6-I and 18F-C8-6-N in mice using PET and in order to fully interpret our PET data, we have performed in vitro kinetic studies of the bifunctional compounds to obtain their microsomal half-life, (t1/2), maximum rate of metabolism, (Vmax), Michaelis-Menten constant, (KM) and intrinsic clearance (Clint) in mouse liver microsomes.
Another important goal in Parkinson’s Disease research is the development of diagnostics that can selectively bind to a-synuclein aggregates in vivo. In an effort to probe molecular features that contribute to binding of a-synuclein aggregates we have performed pharmacophore modelling and used our bifunctional compounds as templates towards the design of novel trifunctional compounds which we are investigating for strong and selective binding to α-synuclein aggregates.
This will be a two part presentation. The first part will focus on our efforts at developing neuroprotective compounds and probes for α-synuclein aggregates while the second part will focus on our efforts at developing new markers or diagnostic tools for α-synuclein aggregates.
Date: Friday, June 10, 2022
Time: 2:30 pm
Location: Thorvaldson 110