title: Interaction of the amyloid imaging tracer FDDNP with hallmark Alzheimer's disease pathologies.
abstract: The distinctive cortical uptake of the tracer (18)F-FDDNP (2-(1-{6-[(2-fluoroethyl(methyl)amino]-2-naphthyl}ethylidene)malononitrile) in Alzheimer's disease (AD) is believed to be because of its binding to both neurofibrillary tangles (NFTs) and highly fibrillar senile plaques. We therefore investigated the binding of a tracer concentration of (3)H-FDDNP to brain sections containing AD hallmark pathologies. Semi-adjacent sections were labelled with (3)H-PIB (Pittsburgh compound-B, 2-[4'-(methylamino)phenyl]-6-hydroxybenzothiazole) and (14)C-SB13 (4-N-methylamino-4'-hydroxystilbene) for comparison. Neocortical sections containing widespread senile plaques and cerebrovascular amyloid angiopathy, produced a sparse and weak labelling following incubation with (3)H-FDDNP. Furthermore, in sections containing NFTs, there was no overt labelling of the pathology by (3)H-FDDNP. In contrast, sections labelled with (3)H-PIB displayed extensive labelling of diffuse plaques, classical plaques, cerebrovascular amyloid angiopathy and NFTs. (14)C-SB13 produced a broadly similar binding pattern to PIB. Radioligand binding assays employing in vitro generated amyloid-beta peptide fibrils demonstrated a approximately 10-fold reduced affinity for (3)H-FDDNP (85.0 +/- 2.0 nM) compared with (3)H-PIB (8.5 +/- 1.3 nM). These data provide an alternative mechanistic explanation for the observed low cortical uptake of (18)F-FDDNP in AD; in that the ligand is only weakly retained by the hallmark neuropathology because of its low affinity for amyloid structures.
authors.affiliation: GlaxoSmithKline, R&D China, UK-Hub, Addenbrookes Hospital, Cambridge, UK.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Thompson
authors.forename: Liang
authors.initials: L
authors.lastname: Ye
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Morgenstern
authors.forename: Lucia
authors.initials: L
authors.lastname: Sue
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Beach
authors.forename: Duncan J
authors.initials: DJ
authors.lastname: Judd
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Shipley
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Libri
authors.forename: Andrew
authors.initials: A
authors.lastname: Lockhart
mesh_terms: D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000473:pathology; D005462:Fluorine Radioisotopes / Q000378:metabolism; D006801:Humans; D016874:Neurofibrillary Tangles / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D009570:Nitriles / Q000378:metabolism*; D058225:Plaque, Amyloid / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000473:pathology; D011849:Radioactive Tracers; D011877:Radionuclide Imaging
chemical_list: C444520:2-(1-(6-((2-fluoroethyl)(methyl)amino)-2-naphthyl)ethylidene)malononitrile; D005462:Fluorine Radioisotopes; D009570:Nitriles; D011849:Radioactive Tracers