Polyfluorinated bis-styrylbenzene beta-amyloid plaque binding ligands.
beta-Amyloid (Abeta) binding affinities and specificities for six bis-styrylbenzenes with multiple magnetically equivalent fluorine atoms in the form of a tetrafluorophenyl core or symmetrical trifluoromethyl and trifluoromethoxy groups were determined by means of fluorescence titrations with amyloid peptide Abeta1-40 and a novel in vitro fluorescence-based assay using APP/PS1 transgenic mouse brain sections. Bis-styrylbenzenes with a tetrafluorophenyl core had increased Abeta binding affinities compared to their monofluorophenyl or phenyl counterparts. Bis-styrylbenzenes with carboxylic acid functional groups had lower Abeta binding affinities than their neutral counterparts. Selected bis-styrylbenzenes were demonstrated to have good blood-brain barrier penetration capabilities. These data extend the SAR of bis-styrylbenzene Abeta binding and provide direction for the development of a noninvasive probe for early detection of Alzheimer's disease using 19F MRI.
Flaherty
Daniel P
DP
University of Nebraska Medical Center, College of Pharmacy, 986025 Nebraska Medical Center, Omaha, Nebraska 68198, USA.
Walsh
Shannon M
SM
Kiyota
Tomomi
T
Dong
Yuxiang
Y
Ikezu
Tsuneya
T
Vennerstrom
Jonathan L
JL
D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D005453:Fluorescence; D005464:Fluorobenzenes / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013343:Styrenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D005464:Fluorobenzenes; D008024:Ligands; D010446:Peptide Fragments; D013343:Styrenes; C078592:amyloid beta-protein (1-40)