Abstract
PurposeAcetylcholinesterase (AChE) inhibitors have been used for patients with Alzheimer's disease. However, its pharmacokinetics in non-target organs other than the brain has not been clarified yet. The purpose of this study was to evaluate the relationship between the whole-body distribution of intravenously administered 11C-Donepezil (DNP) and the AChE activity in the normal rat, with special focus on the adrenal glands.MethodsThe distribution of 11C-DNP was investigated by PET/CT in 6 normal male Wistar rats (8 weeks old, body weight = 220±8.9 g). A 30-min dynamic scan was started simultaneously with an intravenous bolus injection of 11C-DNP (45.0±10.7 MBq). The whole-body distribution of the 11C-DNP PET was evaluated based on the Vt (total distribution volume) by Logan-plot analysis. A fluorometric assay was performed to quantify the AChE activity in homogenized tissue solutions of the major organs.ResultsThe PET analysis using Vt showed that the adrenal glands had the 2nd highest level of 11C-DNP in the body (following the liver) (13.33±1.08 and 19.43±1.29 ml/cm3, respectively), indicating that the distribution of 11C-DNP was the highest in the adrenal glands, except for that in the excretory organs. The AChE activity was the third highest in the adrenal glands (following the small intestine and the stomach) (24.9±1.6, 83.1±3.0, and 38.5±8.1 mU/mg, respectively), indicating high activity of AChE in the adrenal glands.ConclusionsWe demonstrated the whole-body distribution of 11C-DNP by PET and the AChE activity in the major organs by fluorometric assay in the normal rat. High accumulation of 11C-DNP was observed in the adrenal glands, which suggested the risk of enhanced cholinergic synaptic transmission by the use of AChE inhibitors.
Highlights
Acetylcholinesterase (AChE) is one of the most crucial enzymes in the nervous system
11C-Donepezil positron emission tomography (PET) and Acetylcholinesterase Activity in Normal Rats inhibitors have been used for the treatment of Alzheimer’s disease (AD), such as donepezil (DNP), galantamine, and rivastigmine [4]
Analysis of the PET images showed that the Vt was the highest in the liver, followed by that in the adrenal glands, stomach, salivary glands, and small intestine
Summary
Acetylcholinesterase (AChE) is one of the most crucial enzymes in the nervous system. AChE is a tetrameric serine hydrolase that rapidly degrades the neurotransmitter acetylcholine (ACh) into choline and acetate [1]. It is mainly found at the neuromuscular junctions and cholinergic synapses in the central nervous system, where its activity serves to terminate synaptic transmission. 11C-Donepezil PET and Acetylcholinesterase Activity in Normal Rats inhibitors have been used for the treatment of AD, such as donepezil (DNP), galantamine, and rivastigmine [4]. DNP is the most well-known, with a 15-year history of clinical use in AD patients
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