title: Synthesis and structure-affinity relationships of novel dibenzylideneacetone derivatives as probes for β-amyloid plaques.
abstract: A new and extensive set of dibenzylideneacetone derivatives was synthesized and screened for affinity toward Aβ(1-42) aggregates. Structure-activity relationships revealed the binding of dibenzylideneacetones to be affected by various substituents. The introduction of a substituent group in the ortho position reduced or abolished the binding. However, the para position was highly tolerant of sterically demanding substitutions. Three radioiodinated ligands (6, 70, and 71) and two (18)F fluoro-pegylated (FPEG) ligands (83 and 85) were prepared, all of which displayed high affinity for Aβ(1-42) aggregates (K(i) ranging from 0.9 to 7.0 nM). In biodistribution experiments, they exhibited good initial penetration (1.59, 4.68, 4.56, 4.13, and 5.15% ID/g, respectively, at 2 min) of and fast clearance from the brain. Autoradiography with sections of postmortem AD brain and transgenic mouse brain confirmed the high affinity of these tracers. These preliminary results strongly suggest the dibenzylideneacetone structure to be a potential new scaffold for β-amyloid imaging probes.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Mengchao
authors.initials: M
authors.lastname: Cui
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ono
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kimura
authors.forename: Boli
authors.initials: B
authors.lastname: Liu
authors.forename: Hideo
authors.initials: H
authors.lastname: Saji
mesh_terms: D000368:Aged; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D015195:Drug Design; D005260:Female; D005462:Fluorine Radioisotopes; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D015335:Molecular Probes / Q000737:chemistry* / Q000378:metabolism* / Q000493:pharmacokinetics; D010422:Pentanones / Q000737:chemistry* / Q000378:metabolism* / Q000493:pharmacokinetics; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D058225:Plaque, Amyloid / Q000000981:diagnostic imaging / Q000378:metabolism*; D049268:Positron-Emission Tomography; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D011854:Radiochemistry; D013329:Structure-Activity Relationship; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D016229:Amyloid beta-Peptides; D005462:Fluorine Radioisotopes; D008024:Ligands; D015335:Molecular Probes; D010422:Pentanones; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C533260:dibenzylidene acetone