In Vivo Imaging of Human Acetylcholinesterase Density in Peripheral Organs Using 11C-Donepezil: Dosimetry, Biodistribution, and Kinetic Analyses

Brain cholinergic function has been previously studied with PET but little effort has been devoted to imaging peripheral organs. Many disorders, including diabetes and Parkinson disease, are associated with autonomic dysfunction including parasympathetic denervation. Nonneuronal cholinergic signaling is also involved in immune responses to infections and in cancer pathogenesis. 5-C-11-methoxydonepezil, a noncompetitive acetylcholinesterase ligand, was previously validated for imaging cerebral levels of acetylcholinesterase. In the present study, we explored the utility of C-11-donepezil for imaging acetylcholinesterase densities in peripheral organs, including the salivary glands, heart, stomach, intestine, pancreas, liver, and spleen. Methods: With autoradiography, we determined binding affinities and levels of nonspecific C-11-donepezil binding to porcine tissues. Radiation dosimetry was estimated by whole-body PET of a single human volunteer. Biodistribution and kinetic analyses of C-11-donepezil time-activity curves were assessed with dynamic PET scans of 6 healthy human volunteers. A single pig with bacterial abscesses was PET-scanned to explore C-11-donepezil uptake in infections. Results: Autoradiography showed high C-11-donepezil binding (dissociation constant, 6-39 nM) in pig peripheral organs with low nonspecific signal. Radiation dosimetry was favorable (effective dose, 5.2 mu Sv/MBq). Peripheral metabolization of C-11-donepezil was low (>90% unchanged ligand at 60 min). Slow washout kinetics were seen in the salivary glands, heart, intestines, pancreas, and prostate. A linear correlation was seen between C-11-donepezil volumes of distribution and standardized uptake values, suggesting that arterial blood sampling may not be necessary for modeling uptake kinetics in future C-11-donepezil PET studies. High standardized uptake values and slow washout kinetics were seen in bacterial abscesses. Conclusion: C-11-donepezil PET is suitable for imaging acetylcholinesterase densities in peripheral organs. Its uptake may potentially be quantitated with static whole-body PET scans not requiring arterial blood sampling. We also demonstrated high C-11-donepezil binding in bacterial abscesses. We propose that C-11-donepezil PET imaging may be able to quantify the parasympathetic innervation of organs but also detect nonneuronal cholinergic activity in infections.