title: Synthesis and evaluation of 11C-labeled naphthalene derivative as a novel non-peptidergic probe for the β-secretase (BACE1) imaging in Alzheimer's disease brain.
abstract: BACKGROUND
  As a first trial for in vivo imaging of β-secretase (BACE1) in Alzheimer's disease brain, we applied a novel non-peptidergic small molecule which has high affinity to the enzyme, naphthalene-1-carboxylic acid (3'-chloro-4'-fluoro-4-piperazin-1-yl-biphenyl-3-yl)amide (NCFB) into positron emission tomography (PET) probe. In the current study, N-(11)C-methylated compound of NCFB, [(11)C]Me-NCFB was synthesized and evaluated for the visualization of BACE1 in brain.
  
  
  METHODS
  BACE1 inhibitory constant was measured by FRET assay. [(11)C]Me-NCFB was synthesized from NCFB with [(11)C]methyl triflate. To evaluate properties of [(11)C]Me-NCFB, log P value, stability in mouse plasma and brain uptake index were measured. The biodistribution in 6-week-old ddY mice was also studied.
  
  
  RESULTS
  BACE1 inhibitory constant showed an affinity of Me-NCFB to the enzyme (IC50=2.3 ± 0.80 μM). [(11)C]Me-NCFB was synthesized in a 3.0% ± 0.55% decay-corrected radiochemical yield. [(11)C]Me-NCFB showed high lipophilicity, high stability in mouse plasma and blood-brain barrier (BBB) permeability. Injected to 6-week-old ddY mice, [(11)C]Me-NCFB penetrated BBB and was retained in the brain (0.79% ± 0.22% ID/g at 2 min and 0.75% ± 0.08% ID/g at 60 min after injection, respectively), moreover, rapid blood clearance was observed.
  
  
  CONCLUSIONS
  [(11)C]Me-NCFB could have a potential as a PET probe for the imaging of BACE1 in the brain.
authors.affiliation: Department of Patho-functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshidashimoadachi-cho, Sakyo-ku, Kyoto, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Kawai
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Kawashima
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kuge
authors.forename: Hideo
authors.initials: H
authors.lastname: Saji
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000813:Anilides / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000201:enzymology*; D002250:Carbon Radioisotopes; D060326:Chemistry Techniques, Synthetic; D007700:Kinetics; D008297:Male; D051379:Mice; D057054:Molecular Imaging / Q000379:methods*; D009281:Naphthalenes / Q000737:chemistry* / Q000378:metabolism; D011854:Radiochemistry; D051381:Rats
chemical_list: D000813:Anilides; D002250:Carbon Radioisotopes; D009281:Naphthalenes; C585530:naphthalene-1-carboxylic acid (3'-chloro-4'-fluoro-4-piperazin-1-yl-biphenyl-3-yl)amide; C031721:naphthalene; D053829:Amyloid Precursor Protein Secretases