Interaction of the amyloid imaging tracer FDDNP with hallmark Alzheimer's disease pathologies

• Published in: Journal of neurochemistry 2009-04, Vol.109 (2), p.623-630
• Main Authors: Thompson, Paul W, Ye, Liang, Morgenstern, Jennifer L, Sue, Lucia, Beach, Thomas G, Judd, Duncan J, Shipley, Nicholas J, Libri, Vincenzo, Lockhart, Andrew
• Format: Article
• Language: English
• Subjects: Adult and adolescent clinical studies; Alzheimer disease; Alzheimer Disease - diagnostic imaging; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; amyloid; amyloid β; Binding sites; Biochemistry; Biological and medical sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; FDDNP (2-(1-{6-[(2-fluoroethyl(methyl)amino]-2-naphthyl}ethylidene)malononitrile); Fluorine Radioisotopes - metabolism; Humans; image analysis; imaging; Medical imaging; Medical sciences; Neurofibrillary Tangles - diagnostic imaging; Neurofibrillary Tangles - metabolism; Neurofibrillary Tangles - pathology; Neurology; Nitriles - metabolism; Organic mental disorders. Neuropsychology; Pittsburgh compound-B (2-[4'-(methylamino)phenyl]-6-hydroxybenzothiazole); Plaque, Amyloid - diagnostic imaging; Plaque, Amyloid - metabolism; Plaque, Amyloid - pathology; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Radioactive Tracers; Radionuclide Imaging; SB13 (4-N-methylamino-4'-hydroxystilbene)
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2009.05996.x

The distinctive cortical uptake of the tracer ¹⁸F-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 ³H-FDDNP to brain sections containing AD hallmark pathologies. Semi-adjacent sections were labelled with ³H-PIB (Pittsburgh compound-B, 2-[4'-(methylamino)phenyl]-6-hydroxybenzothiazole) and ¹⁴C-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 ³H-FDDNP. Furthermore, in sections containing NFTs, there was no overt labelling of the pathology by ³H-FDDNP. In contrast, sections labelled with ³H-PIB displayed extensive labelling of diffuse plaques, classical plaques, cerebrovascular amyloid angiopathy and NFTs. ¹⁴C-SB13 produced a broadly similar binding pattern to PIB. Radioligand binding assays employing in vitro generated amyloid-β peptide fibrils demonstrated a ~10-fold reduced affinity for ³H-FDDNP (85.0 ± 2.0 nM) compared with ³H-PIB (8.5 ± 1.3 nM). These data provide an alternative mechanistic explanation for the observed low cortical uptake of ¹⁸F-FDDNP in AD; in that the ligand is only weakly retained by the hallmark neuropathology because of its low affinity for amyloid structures.