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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 six carbon chain to either 1-aminoindan (C 8 -6-I) or nicotine (C 8 -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 C 8 -6-I, and C 8 -6-N both undergo phase 1 P450 metabolism in mouse, rat, and human liver microsomes. We utilised this metabolic information to guide the design of fluorinated analogues for use as PET probes and determined that the fluorine in  19 F-C 8 -6-I and  19 F-C 8 -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 V max , K M  and CL int,u  in mouse liver microsomes. We found that C 8 -6-I and  19 F-C 8 -6-I have a two- to fourfold lower CL int,u  than C 8 -6-N, and  19 F-C 8 -6-N. Our approach shows a simple, specific, and effective system to design and develop compounds as PET probes. 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 six carbon chain to either 1-aminoindan (C 8 -6-I) or nicotine (C 8 -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 C 8 -6-I, and C 8 -6-N both undergo phase 1 P450 metabolism in mouse, rat, and human liver microsomes. We utilised this metabolic information to guide the design of fluorinated analogues for use as PET probes and determined that the fluorine in  19 F-C 8 -6-I and  19 F-C 8 -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 V max , K M  and CL int,u  in mouse liver microsomes. We found that C 8 -6-I and  19 F-C 8 -6-I have a two- to fourfold lower CL int,u  than C 8 -6-N, and  19 F-C 8 -6-N. Our approach shows a simple, specific, and effective system to design and develop compounds as PET probes.

An HPLC-UV validated bioanalytical method for measurement of in vitro phase 1 kinetics of α-synuclein binding bifunctional compounds