Cardiac 11 C-Donepezil Binding Increases With Age in Healthy Humans: Potentially Signifying Sigma-1 Receptor Upregulation

Donepezil may have cardioprotective properties, but the mechanism is unclear. Using positron-emission tomography (PET), we explored C-donepezil uptake in the heart of humans in relation to age. The results are discussed in the context of the cardioprotective property of donepezil. We included data from 57 patients with cardiac C-donepezil PET scans. Linear regression analyses were performed to explore the correlation between cardiac C-donepezil standardized uptake value (SUV) and age. Subgroup analyses were performed for healthy controls, patients with prodromal or diagnosed Parkinson disease (PD), males, and females. In the total group of 57 patients, linear regression analysis revealed a significant positive correlation between cardiac C-donepezil uptake and age ( r = .63, P < .0001). The average increase was ≈1.25 SUV per decade and a 2-fold increase in SUV from age 30 to 65 years. Subgroup analyses also showed significant correlations: healthy control patients alone (n = 28, r = .73, P < .0001), prodromal or diagnosed PD (n = 29, r = .28, P = .03), male patients (n = 34, r = .49, P < .0001), and female patients (n = 23, r = .82, P < .0001). No other organs showed increased C-donepezil binding with age. C-donepezil SUV increases robustly with age in the normal human heart. We speculate that the increased donepezil binding is caused primarily by sigma-1 receptor upregulation. If our interpretation is correct, it shows that sigma-1 receptors are dynamically regulated and may represent an overlooked target for pharmacological intervention studies.