title: Synthesis and evaluation of 5,7-dihydro-3-[2-[1-(4-[18F]-fluorobenzyl)-4-piperidinyl]ethyl]-6H-pyrrolo[3,2-f]-1,2-benzisoxazol-6-one for in vivo mapping of acetylcholinesterase.
abstract: OBJECTIVE
  Acetylcholinesterase (AChE) is an important cholinergic marker for the diagnosis of Alzheimer's disease (AD). A recent study has demonstrated that C-labelled 5,7-dihydro-7-methyl-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-6H-pyrrolo[3,2-f]-1,2-benzisoxazol-6-one (CP-126,998) shows promising results. The demethylated form of this ligand (CP-118,954) is a more potent and selective inhibitor than CP-126,998. In this study, therefore, CP-118,954 was labelled with F and evaluated for the in vivo mapping of AChE.
  
  
  METHODS
  The 4-fluoro (1). and 2-fluoro (2). derivatives of CP-118,954 were synthesized from 4-methyl-3-nitroanisole in 11 steps. Their in vitro binding affinities to AChE were measured using Ellman's method. The preparation of [F]-1 was carried out by reductive alkylation of the piperidine precursor with 4-[F]-fluorobenzaldehyde, followed by high-performance liquid chromatography (HPLC) purification. In vitro autoradiography was performed by incubating rat brain coronal slices with [F]-1. Tissue distribution studies were performed in mouse brain and the data were expressed as the percentage of the injected dose per gram of tissue (%ID x g).
  
  
  RESULTS
  Two fluorine-substituted AChE inhibitors were synthesized and their in vitro binding data showed that the 4-fluoro and 2-fluoro derivatives (1 and 2) had similar or superior binding affinity to that of the unsubstituted ligand, CP-118,954. The F-labelled ligand was synthesized in 20-35% radiochemical yield (EOS) and with high effective specific activity (36-42 GBq x micromol). Autoradiography showed high uptake of [F]-1 in the striatum and this striatal uptake was completely inhibited by the unlabelled ligand 1. Tissue distribution studies demonstrated that high radioactivity was accumulated in the striatum, an AChE-rich region.
  
  
  CONCLUSIONS
  This study demonstrates that [F]-1 may hold promise as a radioligand for the in vivo mapping of AChE.
authors.affiliation: Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Sang-Yoon
authors.initials: SY
authors.lastname: Lee
authors.forename: Yearn Seong
authors.initials: YS
authors.lastname: Choe
authors.forename: Yu Ri
authors.initials: YR
authors.lastname: Kim
authors.forename: Jin-Young
authors.initials: JY
authors.lastname: Paik
authors.forename: Byoung Wook
authors.initials: BW
authors.lastname: Choi
authors.forename: Sang Eun
authors.initials: SE
authors.lastname: Kim
authors.forename: Kyung-Han
authors.initials: KH
authors.lastname: Lee
authors.forename: Yong
authors.initials: Y
authors.lastname: Choi
authors.forename: Byung-Tae
authors.initials: BT
authors.lastname: Kim
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D007553:Isotope Labeling / Q000379:methods; D007555:Isoxazoles / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008813:Mice, Inbred ICR; D009928:Organ Specificity; D010880:Piperidines / Q000737:chemistry / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D051381:Rats; 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; D015415:Biomarkers; D005462:Fluorine Radioisotopes; D007555:Isoxazoles; D010880:Piperidines; D019275:Radiopharmaceuticals; D000110:Acetylcholinesterase