High occupancy of σ1 receptors in the human brain after single oral administration of donepezil: a positron emission tomography study using [11C]SA4503

Abstract

The acetylcholinesterase (AChE) inhibitor donepezil is also a σ₁ receptor agonist. We examined whether donepezil binds to σ₁ receptors in the living human brain after a single oral administration. Dynamic positron emission tomography (PET) data acquisition using the selective σ₁ receptor ligand [¹¹C]SA4503 was performed to evaluate quantitatively the binding of [¹¹C]SA4503 to σ₁ receptors in eight healthy male volunteers. Each subject had a PET scan before and after receiving a single dose of donepezil (5 or 10 mg). The binding potential of [¹¹C]SA4503 was calculated. Doses of 5 mg and 10 mg donepezil bound to σ₁ receptors in the human brain with occupancies of ∼60% and ∼75%, respectively, in a dose-dependent manner. This study demonstrated that donepezil binds to σ₁ receptors in the living human brain at therapeutic doses. Therefore, σ₁ receptors may be implicated in the pharmacological mechanism of donepezil in the human brain.