title: Distribution of intravenously administered acetylcholinesterase inhibitor and acetylcholinesterase activity in the adrenal gland: 11C-donepezil PET study in the normal rat.
abstract: OBJECTIVE
  Acetylcholinesterase (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 (11)C-Donepezil (DNP) and the AChE activity in the normal rat, with special focus on the adrenal glands.
  
  
  METHODS
  The distribution of (11)C-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 (11)C-DNP (45.0 ± 10.7 MBq). The whole-body distribution of the (11)C-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.
  
  
  RESULTS
  The PET analysis using Vt showed that the adrenal glands had the 2nd highest level of (11)C-DNP in the body (following the liver) (13.33 ± 1.08 and 19.43 ± 1.29 ml/cm(3), respectively), indicating that the distribution of (11)C-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.
  
  
  CONCLUSIONS
  We demonstrated the whole-body distribution of (11)C-DNP by PET and the AChE activity in the major organs by fluorometric assay in the normal rat. High accumulation of (11)C-DNP was observed in the adrenal glands, which suggested the risk of enhanced cholinergic synaptic transmission by the use of AChE inhibitors.
authors.affiliation: Department of Molecular Imaging in Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; PET molecular Imaging Center, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Watabe
authors.affiliation: Osaka University Hospital, Suita, Osaka, Japan.
authors.forename: Sadahiro
authors.initials: S
authors.lastname: Naka
authors.affiliation: Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Ikeda
authors.affiliation: Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Genki
authors.initials: G
authors.lastname: Horitsugi
authors.affiliation: Department of Molecular Imaging in Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; PET molecular Imaging Center, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Yasukazu
authors.initials: Y
authors.lastname: Kanai
authors.affiliation: PET molecular Imaging Center, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Kayako
authors.initials: K
authors.lastname: Isohashi
authors.affiliation: Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Mana
authors.initials: M
authors.lastname: Ishibashi
authors.affiliation: PET molecular Imaging Center, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kato
authors.affiliation: PET molecular Imaging Center, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Eku
authors.initials: E
authors.lastname: Shimosegawa
authors.affiliation: Department of Molecular Imaging in Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; PET molecular Imaging Center, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watabe
authors.affiliation: PET molecular Imaging Center, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Hatazawa
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D061605:Administration, Intravenous; D000311:Adrenal Glands / Q000000981:diagnostic imaging* / Q000378:metabolism*; D000818:Animals; D002250:Carbon Radioisotopes; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000077265:Donepezil; D007189:Indans / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D010880:Piperidines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D051381:Rats; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D002250:Carbon Radioisotopes; D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D000077265:Donepezil; D000110:Acetylcholinesterase