Binding Characteristics of Radiofluorinated 6-Dialkylamino-2-Naphthylethylidene Derivatives as Positron Emission Tomography Imaging Probes for β-Amyloid Plaques in Alzheimer's Disease

Abstract

Senile plaques (SPs) and neurofibrillary tangles (NFTs) are hallmark pathologies accompanying the neurodegeneration involved in Alzheimer's disease (AD), for which beta-amyloid (Abeta) peptide is a major constituent of SPs. Our laboratories previously developed the hydrophobic, fluorescent molecular-imaging probe 2-(1-(6-[(2-[(18)F]fluoroethyl)(methyl)amino]-2-naphthyl)ethylidene)malononitrile ([(18)F]FDDNP), which crosses the blood-brain barrier and determines the localization and load of SPs and NFTs in vivo in AD patients. In this report, we used fluorimetric and radioactive binding assays to determine the binding affinities of FDDNP and its analog, 1-(6-[(2-[(18)F]fluoroethyl)(methyl)amino]naphthalen-2-yl)ethanone ([(18)F]FENE), to synthetic fibrils of Abeta(1-40). FDDNP and FENE both appeared to bind to two kinetically distinguishable binding sites on Abeta(1-40) fibrils. Fluorescence titrations yielded apparent K(d) values of 0.12 and 0.16 nm for high-affinity binding sites for FDDNP and FENE, respectively, and apparent K(d) values of 1.86 and 71.2 nm for the low-affinity binding sites. The traditional radioactive binding assays also produced apparent K(d) values in the low nanomolar range. The presence of two kinetically distinguishable binding sites for FDDNP and FENE suggests multiple binding sites for SPs and identifies the parameters that allow for the structural optimization of this family of probes for in vivo use. The high-affinity binding of the probes to multiple binding sites on fibrils are consistent with results obtained with digital autoradiography, immunohistochemistry, and confocal fluorescence microscopy using human brain specimens of AD patients.

Novel 18F-Labeled Arylquinoline Derivatives for Noninvasive Imaging of Tau Pathology in Alzheimer Disease

“…Tau imaging radiotracers need to cross the blood-brain barrier and to have a high binding affinity to NFTs with minimal nonspecific binding (18). 2-(1-(6-[(2-18 F-fluoroethyl)(methyl)amino]-2-naphthyl)ethylidene)malononitrile ( 18 F-FDDNP) is claimed as the only PET tracer that allows measurement of the amount of tau protein deposits in the human brain (19). However, 18 F-FDDNP was found to have lower binding affinity for protein fibrils than 11 C-Pittsburgh compound B ( 11 C-PiB) (20,21).…”

Quantum dots and prion proteins

“…Several research groups have launched programs to successfully identify the biomarkers for imaging Aβ plaques in the brain. [67][68][69] Even though computer tomography (CT) is not sensitive or specific in the evaluation of the disease, it may show atrophy at the advanced stage of the disease. Magnetic resonance imaging (MRI) is far more sensitive, especially with the addition of fluid attenuation inversion recovery (FLAIR) and diffusion weighted imaging (DWI).…”

Multiagent imaging of the brain

“…Among several probes developed to detect tau pathology in the brain, the radiotracer FDDNP (i.e., 2-(1-{6-[(2-[ 18 F]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile) has been shown to label senile plaques and NFTs in vitro [39]. PET with FDDNP has proved able to distinguish between cognitively normal, MCI and AD subjects [40].…”