In vivo visualization of donepezil binding in the brain of patients with Alzheimer's disease

Aims: The aims of this study were to visualize in vivo binding of donepezil to acetylcholinesterase (AChE) in the brain and to establish a method for measuring the amount of binding of orally administered donepezil. Methods: [5-¹¹C-methoxy]-donepezil ([¹¹C]-donepezil) was radiolabelled as a positron emission tomography (PET) tracer. The biodistribution of [¹¹C]-donepezil was measured by PET in 10 AD patients and six elderly normal subjects. Two AD patients underwent additional PET measurements after oral administration of donepezil for 6 months. Results: [¹¹C]-donepezil-PET images demonstrated high densities of tracer distribution in AChE-rich brain regions such as the striatum, thalamus, and cerebellum. Compared with elderly normal subjects, patients with mild AD exhibited about 18-20% reduction of donepezil binding in the neocortex and hippocampus, while patients with moderate AD exhibited about 24-30% reduction of donepezil binding throughout the brain. Orally administered donepezil (5 mg day^-1) induced 61.6-63.3% reduction of donepezil binding in AD brains. The distribution volume of [¹¹C]-donepezil in the hippocampus was significantly correlated with MMSE scores in AD patients. Conclusions: [¹¹C]-donepezil-PET enables quantitative measurement of donepezil binding in the brain. AD patients exhibited reduction of donepezil binding in the brain, even in the early stage of disease. Longitudinal evaluation by this technique enables determination of AChE binding occupancy of orally administered donepezil.