2-Dialkylamino-6-acylmalononitrile substituted naphthalenes (DDNP analogs): novel diagnostic and therapeutic tools in Alzheimer's disease.

This article presents a comprehensive review of the in vitro and in vivo detection of neurofibrillary tangles (NFTs) and beta-amyloid senile plaques (SPs), neuropathological lesions found in the brains of the Alzheimer's disease (AD) patients, using FDDNP and its analogs. FDDNP and its analogs have excellent ability to bind to NFTs and SPs in vitro as shown by binding assays, confocal fluorescence microscopy with stained AD brain tissue and digital autoradiography with [18F]FDDNP. [18F]FDDNP-PET molecular imaging permits detection of these pathologies in living subjects. The discovery of a new binding site to Abeta(1-40) fibrils as a result of FDDNP binding also opens a therapeutic opportunity for early treatment of Alzheimer's disease. FDDNP shares a previously unrecognized common binding site on Abeta(1-40) fibrils and senile plaques with non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., naproxen and ibuprofen). Naproxen, ibuprofen and even FDDNP significantly inhibit aggregation of the Abeta(1-40) peptide in the micromolar range. This new binding site on Abeta(1-40) fibrils also offers a molecular template for design of anti-aggregation drugs without the secondary effects of NSAIDs. Therefore it is anticipated that a new vision for prevention, early diagnosis and treatment of Alzheimer's disease would be rapidly developing.