Dicyanovinylnaphthalenes for neuroimaging of amyloids and relationships of electronic structures and geometries to binding affinities

Title
Dicyanovinylnaphthalenes for neuroimaging of amyloids and relationships of electronic structures and geometries to binding affinities
Authors
Andrej PetricScott A. JohnsonHung V. PhamYing LiSimon CehAmalija GolobicEric D. AgdeppaGerald TimbolJie Liu금교창Nagichettiar SatyamurthyVladimir KepeKendall N. HoukJorge R. Barrio
Keywords
Neuroimaging; Alzheimer; Positron Emission tomography (PET); FDDNP; beta-amyloid
Issue Date
2012-10
Publisher
Proceedings of the National Academy of Sciences of the United States of America
Citation
VOL 109, NO 41, 16492-16497
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 Ki) in vitro and a nearly planar tricyclic analog cDDNP, which displayed the highest binding affinity (10 pM Ki). 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.
URI
http://pubs.kist.re.kr/handle/201004/43205
ISSN
00278424
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