title: Binding characteristics of radiofluorinated 6-dialkylamino-2-naphthylethylidene derivatives as positron emission tomography imaging probes for beta-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.
authors.affiliation: Division of Nuclear Medicine, Department of Molecular and Medical Pharmacology, Laboratory of Structural Biology and Molecular Medicine, University of California Los Angeles School of Medicine, Los Angeles, California 90095, USA.
authors.forename: E D
authors.initials: ED
authors.lastname: Agdeppa
authors.forename: V
authors.initials: V
authors.lastname: Kepe
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.forename: S
authors.initials: S
authors.lastname: Flores-Torres
authors.forename: N
authors.initials: N
authors.lastname: Satyamurthy
authors.forename: A
authors.initials: A
authors.lastname: Petric
authors.forename: G M
authors.initials: GM
authors.lastname: Cole
authors.forename: G W
authors.initials: GW
authors.lastname: Small
authors.forename: S C
authors.initials: SC
authors.lastname: Huang
authors.forename: J R
authors.initials: JR
authors.lastname: Barrio
mesh_terms: D000544:Alzheimer Disease / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D001345:Autoradiography; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D005456:Fluorescent Dyes / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009281:Naphthalenes / Q000737:chemistry* / Q000493:pharmacokinetics; D016874:Neurofibrillary Tangles / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D009570:Nitriles / Q000737:chemistry / Q000493:pharmacokinetics; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D058225:Plaque, Amyloid / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D011869:Radioligand Assay; D013379:Substrate Specificity; D014055:Tomography, Emission-Computed / Q000379:methods
chemical_list: C444522:1-(6-((2-fluoroethyl)(methyl)amino)naphthalen-2-yl)ethanone; C444520:2-(1-(6-((2-fluoroethyl)(methyl)amino)-2-naphthyl)ethylidene)malononitrile; D016229:Amyloid beta-Peptides; D005456:Fluorescent Dyes; D009281:Naphthalenes; D009570:Nitriles; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)