Distribution of Intravenously Administered Acetylcholinesterase Inhibitor and Acetylcholinesterase Activity in the Adrenal Gland: 11C-Donepezil PET Study in the Normal Rat

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.

Dihydroquinoline Carbamate Derivatives as “Bio-oxidizable” Prodrugs for Brain Delivery of Acetylcholinesterase Inhibitors: [11C] Radiosynthesis and Biological Evaluation

“…However, the highest uptake was seen in the adrenal glands (1.7 %ID/g) at 10 min after injection of [ 11 C] 1a and decreased to about 0.7% at 30 min. This finding is consistent with a recent in vivo study highlighting the relationship between the high level of radioactivity observed in the adrenal glands after administration of [ 11 C]­donepezil in the rat and the high activity of AChE measured by fluorometric assays in this organ . In our case, the radioactivity uptake observed in adrenal glands would emanate from peripheral redox activation of prodrug [ 11 C] 1a into [ 11 C] 2a .…”

“…This finding is consistent with a recent in vivo study highlighting the relationship between the high level of radioactivity observed in the adrenal glands after administration of [ 11 C]donepezil in the rat and the high activity of AChE measured by fluorometric assays in this organ. 22 In our case, the radioactivity uptake observed in adrenal glands would emanate from peripheral redox activation of prodrug [ 11 C]1a into [ 11 C] 2a. Accumulation of the radioactivity was significant in the excretory organs, the kidneys and the liver (0.84−0.88 %ID/g), at 10 min after [ 11 C]1a injection and lower in the spleen, heart, and lung (0.26−0.39 %ID/g).…”

Molecular Imaging of Hydrolytic Enzymes Using PET and SPECT

“… 38 - 40 Since publication of those reviews, several more articles on PET imaging of AChE have appeared. 41 - 47 …”

“…[38][39][40] Since publication of those reviews, several more articles on PET imaging of AChE have appeared. [41][42][43][44][45][46][47] More recently, butyrylcholinesterase (BChE) was identified as a potential imaging target since it also can play a role in acetylcholine metabolism, especially in patients with neurodegenerative diseases such as Alzheimer's. 48 Specific imaging of BChE is a new area of interest, and recently agents specifically targeting BChE have been reported.…”

“…155 Although sufficient levels can be produced to obtain a useful PET image of HDAC distribution, improvements in radiochemical yield are needed to reduce safety issues around handling large amounts of the starting material [ 11 C]CO 2 . In part to address this need, the Hooker group also prepared 3 18 F-labeled derivatives (45)(46)(47) 44. Further studies such as biodistribution and metabolism studies will require an improved radiosynthesis.…”