Petric, Andrej Johnson, Scott A. Pham, Hung V. Li, Ying Ceh, Simon Golobic, Amalija Agdeppa, Eric D. Timbol, Gerald Liu, Jie Keum, Gyochang Satyamurthy, Nagichettiar Kepe, Vladimir Houk, Kendall N. Barrio, Jorge R. 2024-01-20T13:35:07Z 2024-01-20T13:35:07Z 2021-08-31 2012-10-09 0027-8424 https://pubs.kist.re.kr/handle/201004/128769 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-beta (A beta) 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 A beta 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 A beta 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 A beta 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. English NATL ACAD SCIENCES VISCOSITY-SENSITIVE FLUOROPHORE MOLECULAR-IMAGING PROBE ALZHEIMERS-DISEASE IN-VITRO PLAQUES MALONONITRILE DERIVATIVES INHIBITORS DESIGN DDNP Dicyanovinylnaphthalenes for neuroimaging of amyloids and relationships of electronic structures and geometries to binding affinities Article 10.1073/pnas.1214134109 1 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v.109, no.41, pp.16492 - 16497 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 109 41 16492 16497 scie scopus 000310280300030 Multidisciplinary Sciences Science & Technology - Other Topics Article VISCOSITY-SENSITIVE FLUOROPHORE MOLECULAR-IMAGING PROBE ALZHEIMERS-DISEASE IN-VITRO PLAQUES MALONONITRILE DERIVATIVES INHIBITORS DESIGN DDNP density functional theory M06-2X docking