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.

Amyloid-β Deposits Target Efficient Near-Infrared Fluorescent Probes: Synthesis, in Vitro Evaluation, and in Vivo Imaging

“…Moreover, the emission maxima of these solvatochromic probes displayed significant solvent dependency and occurred at higher wavelengths with increasing solvent polarities ( Figure S3, S4 and Table S1 in Supporting Information), indicative of the ongoing ICT transition with an increased dipole moment in the excited state when compared with that of the ground state. [20][21][22] Notably, when compared with the DANIR 3b and 3c, these four NIRFs maintained excellent fluorescent properties, including long Table 1), which are prerequisites of an optimal fluorochrome for in vivo NIR imaging. However, the excitation maxima of the NIRFs were less than 600 nm (Table 1), which limited the penetration depth of excitation light, and therefore, further modifications are necessary.…”

A comparative study between para‐aminophenyl and ortho‐aminophenyl benzothiazoles using NMR and DFT calculations

“…This aspect is important in terms of utility of these compounds as Alzheimer's imaging agents, because all the known imaging agents (thioflavin T derivatives) are planar which aids the binding of these molecules to amyloid fibrils . Recently, Petric et al . reported the binding affinities of two planar molecules of dicyanovinyl naphthalenes for neuroimaging of amyloid and came to the conclusion that the most planar analogues showed the highest binding affinities towards amyloid while the least planar analogue showed lowest binding affinity.…”

Topological Analysis and Frequency Dependent Hyperpolarizability Calculations of FDDNP: a DFT Study

“…The 2-(1-{6-[(2-fl uoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP) is a functional fl uorescent biomarker belonging to the family of dicyanovinyl naphthalene labels, which binds to its ligand through hydrophobic interactions [6]. FDDNP also binds to amyloid plaques with high affi nity [7].…”

“…So far, only a few electronic structure studies on FDDNP and other dicyanovinyl naphthalene biomarkers, based on ab initio calculations have been performed. Petrič et al [6] performed a combined experimental and theoretical study on FDDNP and its analogs to explain the chemical modifi cation effects on binding affi nity of biomarkers to amyloid plaques and their fl uorescence Quantum yields. Given the close relationship between the structure and nonlinear activities, and the functional importance of default molecule, it is necessary to develop a deeper vision on electron-topological properties, in order to predict its different optical capabilities.…”

“…For example, the non-centrosymmetric structure of fi brillar collagen is the major source of the SHG signals in different tissues [2,3], and for cellular and subcellular samples. For this purpose, several SHG labels have been used [4,5].The 2-(1-{6-[(2-fl uoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP) is a functional fl uorescent biomarker belonging to the family of dicyanovinyl naphthalene labels, which binds to its ligand through hydrophobic interactions [6]. FDDNP also binds to amyloid plaques with high affi nity [7].…”