title: Synthesis and evaluation of radioiodine-labelled CP-118,954 for the in-vivo imaging of acetylcholinesterase.
abstract: OBJECTIVE
  Alzheimer's disease (AD) is characterized by reduced acetylcholinesterase (AChE) activity in the post-mortem tissues of AD patients. Therefore, AChE has been an attractive target for the diagnosis of AD. In the present study, 5,7-dihydro-3-[2-(1-(phenylmethyl)-4-piperidinyl)ethyl]-6H-pyrrolo[3,2-f]-1,2-benzisoxazol-6-one (CP-118,954), a potent AChE inhibitor, was labelled with radioiodine and evaluated as an AChE imaging agent for SPECT.
  
  
  METHODS
  Radioiodine-labelled CP-118,954 was prepared from CP-144,885 and [(125)I]iodobenzyl bromide, and anti-AChE activities of iodine-substituted CP-118,954 were measured. Metabolism studies were carried out in samples of blood and whole brain of mice injected with 2-[(123)I]iodo-CP-118,954 ((123)I-1). Tissue distribution studies were also performed in mice injected with I-1, and samples of blood, thyroid, stomach, and brain tissue (cerebellum, striatum and cortex) were removed, weighed and counted.
  
  
  RESULTS
  Of the ligands, 2-iodo-CP-118,954 exhibited higher binding affinity for AChE (IC50=24 nM) than the other positional isomers. 2-[(125)I]Iodo-CP-118,954 was found to have a lipophilicity (log P=2.1) favouring brain permeability and metabolic stability in mouse brain, but a marginal target (striatum) to non-target (cerebellum) uptake ratio (1.1) in mouse brain.
  
  
  CONCLUSIONS
  This result demonstrates that 2-[(125)I]iodo-CP-118,954 may be unsuitable for AChE imaging. These findings suggest that radioligands suitable for AChE imaging should have not only a specific structure but also a sub-nanomolar to low nanomolar IC50.
authors.affiliation: Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Kangnam-ku, Seoul 135-710, Korea.
authors.forename: Iljung
authors.initials: I
authors.lastname: Lee
authors.forename: Yearn Seong
authors.initials: YS
authors.lastname: Choe
authors.forename: Eun Kyoung
authors.initials: EK
authors.lastname: Ryu
authors.forename: Byoung Wook
authors.initials: BW
authors.lastname: Choi
authors.forename: Joon Young
authors.initials: JY
authors.lastname: Choi
authors.forename: Yong
authors.initials: Y
authors.lastname: Choi
authors.forename: Kyung-Han
authors.initials: KH
authors.lastname: Lee
authors.forename: Byung-Tae
authors.initials: BT
authors.lastname: Kim
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000201:enzymology*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics; D004353:Drug Evaluation, Preclinical; D007457:Iodine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics*; D007553:Isotope Labeling; D007555:Isoxazoles / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008813:Mice, Inbred ICR; D010880:Piperidines / Q000737:chemistry / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: C095054:5,7-dihydro-3-(2-(1-(phenylmethyl)-4-piperidinyl)ethyl)-6H-pyrrolo(3,2-f)-1,2-benzisoxazol-6-one; D002800:Cholinesterase Inhibitors; D007457:Iodine Radioisotopes; D007555:Isoxazoles; D010880:Piperidines; D019275:Radiopharmaceuticals; D000110:Acetylcholinesterase