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

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.