title: Dicyanovinylnaphthalenes for neuroimaging of amyloids and relationships of electronic structures and geometries to binding affinities.
abstract: The positron-emission tomography (PET) probe 2-(1-[6-[(2-fluoroethyl)(methyl)amino]-2-naphthyl]ethylidene) (FDDNP) is used for the noninvasive brain imaging of amyloid-β (Aβ) and other amyloid aggregates present in Alzheimer's disease and other neurodegenerative diseases. A series of FDDNP analogs has been synthesized and characterized using spectroscopic and computational methods. The binding affinities of these molecules have been measured experimentally and explained through the use of a computational model. The analogs were created by systematically modifying the donor and the acceptor sides of FDDNP to learn the structural requirements for optimal binding to Aβ aggregates. FDDNP and its analogs are neutral, environmentally sensitive, fluorescent molecules with high dipole moments, as evidenced by their spectroscopic properties and dipole moment calculations. The preferred solution-state conformation of these compounds is directly related to the binding affinities. The extreme cases were a nonplanar analog t-butyl-FDDNP, which shows low binding affinity for Aβ aggregates (520 nM K(i)) in vitro and a nearly planar tricyclic analog cDDNP, which displayed the highest binding affinity (10 pM K(i)). Using a previously published X-ray crystallographic model of 1,1-dicyano-2-[6-(dimethylamino)naphthalen-2-yl]propene (DDNP) bound to an amyloidogenic Aβ peptide model, we show that the binding affinity is inversely related to the distortion energy necessary to avoid steric clashes along the internal surface of the binding channel.
authors.affiliation: Department of Chemistry and Chemical Technology,  University of Ljubljana, 1000 Ljubljana,  Slovenia.
authors.forename: Andrej
authors.initials: A
authors.lastname: Petric
authors.forename: Scott A
authors.initials: SA
authors.lastname: Johnson
authors.forename: Hung V
authors.initials: HV
authors.lastname: Pham
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Simon
authors.initials: S
authors.lastname: Ceh
authors.forename: Amalija
authors.initials: A
authors.lastname: Golobic
authors.forename: Eric D
authors.initials: ED
authors.lastname: Agdeppa
authors.forename: Gerald
authors.initials: G
authors.lastname: Timbol
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Gyochang
authors.initials: G
authors.lastname: Keum
authors.forename: Nagichettiar
authors.initials: N
authors.lastname: Satyamurthy
authors.forename: Vladimir
authors.initials: V
authors.lastname: Kepe
authors.forename: Kendall N
authors.initials: KN
authors.lastname: Houk
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Barrio
mesh_terms: D015081:2-Naphthylamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D000181:Acrylonitrile / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D000544:Alzheimer Disease / Q000175:diagnosis / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D059906:Neuroimaging / Q000379:methods*; D058225:Plaque, Amyloid / Q000175:diagnosis* / Q000378:metabolism; D011485:Protein Binding
chemical_list: C116723:2-(1,1-dicyanopropenyl-2-)-6-dimethylaminonaphthaleney; D016229:Amyloid beta-Peptides; D015081:2-Naphthylamine; D000181:Acrylonitrile