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- [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 -amyloid (A ) 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-[F]fluoroethyl)(methyl) amino]-2-naphthyl}ethylidene)malononitrile ([F]FDDNP), against (S)-naproxen and (R)and (S)-ibuprofen (but not diclofenac) to A fibrils and ex vivo A 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 A peptides, suggesting that the shared binding site on A 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 [F]FDDNP. Our understanding of the molecular requirements of FDDNP binding may help in the optimization of the A anti-aggregation potency of experimental drugs. [F]FDDNP has been used to image plaques in vivo with positron emission tomography (PET), and investigations into the influence of A anti-aggregation on the risk-reduction effects of NSAIDs on AD could utilize [F]FDDNP and PET in determining the occupancy rate of NSAIDs and experimental drugs in plaques in the living brain of AD patients. © 2003 IBRO. Published by Elsevier Science Ltd. All rights reserved.