In vitro detection of (S)-naproxen and ibuprofen binding to plaques in the Alzheimer's brain using the positron emission tomography molecular imaging probe 2-(1-[6-[(2-[(18)F]fluoroethyl)(methyl)amino]-2-naphthyl]ethylidene)malononitrile.
Epidemiological studies have suggested that the chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the relative risk of Alzheimer's disease (AD). The possible neuroprotection by NSAIDs in AD is generally attributed to anti-inflammatory activity. An additional mode of drug action may involve anti-aggregation of beta-amyloid (Abeta) peptides by commonly used NSAIDs. We utilized in vitro competition assays, autoradiography, and fluorescence microscopy with AD brain specimens to demonstrate concentration-dependent decreases in the binding of the in vivo molecular imaging probe, 2-(1-[6-[(2-[(18)F]fluoroethyl)(methyl)amino]-2-naphthyl]ethylidene)malononitrile ([(18)F]FDDNP), against (S)-naproxen and (R)- and (S)-ibuprofen (but not diclofenac) to Abeta fibrils and ex vivo Abeta senile plaques. Conversely, in vitro amyloid dyes Congo Red and Thioflavine T were demonstrated in the same experiments not to bind to the FDDNP binding site. FDDNP and the NSAIDs that share the same binding site also exhibit anti-aggregation effects on Abeta peptides, suggesting that the shared binding site on Abeta fibrils and plaques may be a site of anti-aggregation drug action. Our results indicate for the first time the binding of select NSAIDs to plaques, specifically to the binding site of the molecular imaging probe [(18)F]FDDNP. Our understanding of the molecular requirements of FDDNP binding may help in the optimization of the Abeta anti-aggregation potency of experimental drugs. [(18)F]FDDNP has been used to image plaques in vivo with positron emission tomography (PET), and investigations into the influence of Abeta anti-aggregation on the risk-reduction effects of NSAIDs on AD could utilize [(18)F]FDDNP and PET in determining the occupancy rate of NSAIDs and experimental drugs in plaques in the living brain of AD patients.
Agdeppa
E D
ED
Division of Nuclear Medicine, Department of Molecular and Medical Pharmacology, Laboratory of Structural Biology and Molecular Medicine, The David Geffen School of Medicine at UCLA, Box 956948, Los Angeles, CA 90095, USA.
Kepe
V
V
Petri
A
A
Satyamurthy
N
N
Liu
J
J
Huang
S-C
SC
Small
G W
GW
Cole
G M
GM
Barrio
J R
JR
D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics*; D001345:Autoradiography / Q000379:methods; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007052:Ibuprofen / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D009288:Naproxen / Q000493:pharmacokinetics*; D009570:Nitriles; D058225:Plaque, Amyloid / Q000000981:diagnostic imaging; D019275:Radiopharmaceuticals; D014055:Tomography, Emission-Computed / Q000379:methods*
C444520:2-(1-(6-((2-fluoroethyl)(methyl)amino)-2-naphthyl)ethylidene)malononitrile; D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D009570:Nitriles; D019275:Radiopharmaceuticals; D009288:Naproxen; D007052:Ibuprofen