Aggregates of the protein α-synuclein are associated with pathophysiology of Parkinson’s disease and are present in Lewy Bodies found in the brains of Parkinson’s patients. We previously demonstrated that bifunctional compounds composed of caffeine linked via a 6 carbon chain to either 1-aminoindan (C8-6-I) or nicotine (C8-6-N) bind α-synuclein and protect yeast cells from α-synuclein mediated toxicity.A critical step in development of Positron Emission Tomography (PET) probes for neurodegenerative diseases is evaluation of their metabolic stability. We determined that C8-6-I, and C8-6-N both undergo phase 1 P450 metabolism in mouse, rat, and human liver microsomes. We utilized this metabolic information to guide the design of fluorinated analogs for use as PET probes and determined that the fluorine in 19F-C8-6-I and 19F-C8-6-N is stable to P450 enzymes.We have developed and validated an analytical HPLC-UV method following FDA and EMA guidelines to measure in vitro Phase 1 kinetics of these compounds and determine their Vmax, KM and CLint,u in mouse liver microsomes. We found that C8-6-I and 19F-C8-6-I have a 2 - 4 fold lower CLint,u than C8-6-N, and 19F-C8-6-N. Our approach shows a simple, specific, and effective step by step system to design and develop compounds as PET probes.
No takes yet. Share an insight, caveat, or question.
Aigbogun et al. (2022) studied this question.
Synapse has enriched 5 related papers. Consider them for comparative context: