Thioesters for the in vitro evaluation of agents to image brain cholinesterases

Abstract

Cholinesterases are associated with pathology characteristic of conditions such as Alzheimer’s disease and are therefore, considered targets for neuroimaging. Ester derivatives of N-methylpiperidinol are promising potential imaging agents; however, methodology is lacking for evaluating these compounds in vitro. Here, we report the synthesis and evaluation of a series of N-methylpiperidinyl thioesters, possessing comparable properties to their corresponding esters, which can be directly evaluated for cholinesterase kinetics and histochemical distribution in human brain tissue. N-methylpiperidinyl esters and thioesters were synthesized and they demonstrated comparable cholinesterase kinetics. Furthermore, thioesters were capable, using histochemical method, to visualize cholinesterase activity in human brain tissue. N-methylpiperidinyl thioesters can be rapidly evaluated for cholinesterase kinetics and visualization of enzyme distribution in brain tissue which may facilitate development of cholinesterase imaging agents for application to conditions such as Alzheimer’s disease.

Keywords::

• Butyrylcholinesterase
• acetylcholinesterase
• brain histochemistry
• neuroimaging
• Alzheimer’s disease

Acknowledgements

The authors thank Eric Joy for technical assistance.

Declaration of interest

Portions of this work were supported by grants from Canadian Institutes of Health Research, Canada Foundation for Innovation, Natural Sciences and Engineering Research Council of Canada, Vascular Health and Dementia Initiative (through Canadian Institutes of Health Research, Heart & Stroke Foundation of Canada, the Alzheimer Society of Canada and Pfizer Canada Inc.), Capital District Health Authority Research Fund, Nova Scotia Health Research Foundation, Brain Tumour Foundation of Canada, Multiple Sclerosis Society of Canada, National Institutes of Health, Dalhousie Medical Research Foundation, Faculty of Medicine of Dalhousie University and the Committee on Research and Publications of Mount Saint Vincent University.