Dose-dependent sigma-1 receptor occupancy by donepezil in rat brain can be assessed with 11C-SA4503 and microPET

Sigma-1 receptor agonists are under investigation as potential disease-modifying agents for several CNS disorders. Donepezil, an acetylcholinesterase inhibitor used for the symptomatic treatment of Alzheimer's disease, is also a high-affinity sigma-1 agonist. The objectives of the present study were to investigate if the sigma-1 agonist tracer C-11-SA4503 and microPET can be used to determine sigma-1 receptor occupancy (RO) of donepezil in the rat brain; to establish RO of donepezil at doses commonly used in rodent behavioural studies; and to determine the effective plasma concentration of donepezil required for 50 % of max-min occupancy (EC50). Male Wistar rats were pre-treated with donepezil (0.1 to 10 mg/kg) for about 1 h before microPET scans using C-11-SA4503. The total distribution volume (V (T)) of the tracer was determined by Logan graphical analysis using time activity curves from arterial plasma and regions of interest drawn around the entire brain and individual brain regions. RO by donepezil was calculated from a modified Lassen plot, and ED50 was estimated from the sigmoidal dose-response curves obtained when the RO was plotted against log donepezil dose. A dose-dependent reduction was observed for V (T) in the whole brain as well as individual brain regions. RO increased dose-dependently and was 93 % at 10 mg/kg. ED50 was 1.29 mg/kg. Donepezil, in the common dose range, was found to dose-dependently occupy a significant fraction of the sigma-1 receptor population. The data indicate that it is possible to determine sigma-1 RO by an agonist drug in rat brain, using C-11-SA4503 and microPET.