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

Br J Clin Pharmacol. 2008 Apr;65(4):472-9. doi: 10.1111/j.1365-2125.2007.03063.x. Epub 2007 Dec 7.


What is already known about this subject: * Deficit in central cholinergic neurotransmission is a consistent change associated with Alzheimer's disease (AD). * Donepezil hydrochloride exhibits selective inhibition of acetylcholinesterase (AChE) and is widely used for the treatment of AD. * The biodistribution of donepezil in the brain after administration is not precisely understood in vivo. * There is no method to measure the amount of binding of orally administered donepezil to AChE.

What this study adds: * This study clearly visualizes the distribution of donepezil in human brain using [(11)C]-donepezil and positron emission tomography. * This study demonstrates prominent reduction of the donepezil binding site in the AD brain. * This study provides methodology to measure the AChE binding occupancy of orally administered donepezil and provides a new surrogate marker for evaluation and prediction of response to donepezil treatment.

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-(11)C-methoxy]-donepezil ([(11)C]-donepezil) was radiolabelled as a positron emission tomography (PET) tracer. The biodistribution of [(11)C]-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: [(11)C]-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 [(11)C]-donepezil in the hippocampus was significantly correlated with MMSE scores in AD patients.

Conclusions: [(11)C]-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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism*
  • Administration, Oral
  • Aged
  • Alzheimer Disease / diagnostic imaging*
  • Brain / diagnostic imaging
  • Brain / metabolism*
  • Cholinesterase Inhibitors / administration & dosage
  • Cholinesterase Inhibitors / metabolism*
  • Donepezil
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Indans / administration & dosage
  • Indans / metabolism*
  • Male
  • Piperidines / administration & dosage
  • Piperidines / metabolism*
  • Positron-Emission Tomography / methods
  • Reproducibility of Results
  • Temporal Lobe / diagnostic imaging
  • Temporal Lobe / enzymology
  • Treatment Outcome


  • Cholinesterase Inhibitors
  • Indans
  • Piperidines
  • Donepezil
  • Acetylcholinesterase