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

Department of Molecular and Medical Pharmacology, Laboratory of Structural Biology and Molecular Medicine, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Molecular Imaging & Biology (Impact Factor: 2.77). 11/2003; 5(6):404-17. DOI: 10.1016/j.mibio.2003.09.010
Source: PubMed


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.

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    • "Although fl uorescence based assays are widely used for searching for anti-amyloidogenic agents, only a limited number of dyes currently are used for such procedures. All of the main groups of compounds, i.e., those derived from thiofl avin T (Thio T)-PIB (Pittsburgh Compound B; N-methyl-4 ' -methylam- inophenyl-6-hydroxybenzathiazole) (Klunk et al. 2004), SB-13 (Verhoeff et al. 2004, Klunk et al. 2004), Congo red-BSB (bromo-2,5-bis-(3-hydroxycarbonyl- 4-hydroxy)styrylbenzene) (Schmidt et al. 2001) and aminonaphthalene-FDDNP (2-(1-(2-(N-(2-[18F]fl uoroethyl)-N-methylamino)naphthalene-6-yl)eth- ylidene)malononitrile) (Agdeppa et al. 2001), bind nonspecifi cally to AFs (Agdeppa et al. 2003, Ye et al. 2005). We examined previously a variety of substituted poly-and monomethine dyes as potential fl uorescent probes for AF detection and several cyanines with high specifi city and effi ciency were identifi ed (Volkova et al. 2008). "
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    ABSTRACT: Quantitative structure activity relationship (QSAR) studies were performed on a set of polymethine compounds to develop new fluorescent probes for detecting amyloid fibrils. Two different approaches were evaluated for developing a predictive model: part least squares (PLS) regression and an artificial neural network (ANN). A set of 60 relevant molecular descriptors were selected by performing principal component analysis on more than 1600 calculated molecular descriptors. Through QSAR analysis, two predictive models were developed. The final versions produced an average prediction accuracy of 72.5 and 84.2% for the linear PLS and the non-linear ANN procedures, respectively. A test of the ANN model was performed by using it to predict the activity, i.e., staining or non-staining of amyloid fibrils, using 320 compounds. The five candidates whose greatest activities were selected by the ANN model underwent confirmation of their predicted properties by empirical testing. The results indicated that the ANN model potentially is useful for facilitating prediction of activity of untested compounds as dyes for detecting amyloid fibrils.
    Biotechnic & Histochemistry 11/2013; 89(1). DOI:10.3109/10520295.2013.785593 · 1.44 Impact Factor
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    • "Cole et al, personal communication). Also, in humans FDDNP accumulation in hippocampus has been correlated with abundant tau tangle accumulation in this area [5], consistent with FDDNP labeling of tau-containing protein aggregates in brain specimens of various neurodegenerative diseases [4] [17]. In living patients FDDNP-PET succeeded in showing a pattern of neurofibrillary tangle distribution in patients with frontotemporal dementia [33], a disease with abundant brain neurofibrillary tangles without significant ␤-amyloid plaque deposition in the brain [34]. "
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    ABSTRACT: 2-(1-{6-[(2-[fluorine-18]fluoroethyl)(methyl)amino]-2-naphthyl}-ethylidene)malononitrile (FDDNP) is the first positron emission tomography (PET) molecular imaging probe to visualize Alzheimer's disease (AD) pathology in living humans. The most unique features of FDDNP are that (1) it is the only currently available radiotracer to image neurofibrillary tangles, beside amyloid aggregates, in living humans; and (2) it is also the only radiotracer to visualize AD pathology in the hippocampal region of living humans. In this article, we discuss FDDNP's unique ability to image tau pathology in living humans. Emphasizing tau pathology imaging capability using FDDNP in AD, as well as other tauopathies, is timely and beneficial considering that (1) post mortem histopathological studies using human specimens have consistently demonstrated that neurofibrillary tangles, compared with amyloid plaques, are better correlated with the disease severity and neuronal death; and (2) recently reported clinical trial failures of disease-modifying drugs in development, based on the amyloid-cascade hypothesis, suggest that some of the basic assumptions of AD causality warrant reassessment and redirection.
    Journal of Alzheimer's disease: JAD 01/2011; 26 Suppl 3(Suppl 3):135-45. DOI:10.3233/JAD-2011-0008 · 4.15 Impact Factor
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    • "From a clinical perspective, PET approaches are most promising. A variety of potential PET tracers for b-amyloid are currently in clinical evaluation and a number of PET studies have demonstrated the value of such tracers (Klunk et al., 2004; Agdeppa et al., 2003; Shoghi-Jadid et al., 2002; Verhoeff et al., 2004; Kudo, 2006). For rodent models of the disease, e.g. for studies in genetically engineered mice, fluorescent imaging in combination with stable fluorescent probes targeting b-amyloid peptides has been developed as an alternative (see Fig. 1; Bacskai et al., 2003; Hintersteiner et al., 2005; Sigurdson et al., 2007). "
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    ABSTRACT: Multimodal non-invasive neuroimaging in rodents constitutes an attractive tool for studying neurobiological processes in vivo. At present, imaging studies of brain anatomy and function as well as the investigation of structure-function relationships belong to the standard repertoire of neuroscientists. Molecular imaging adds a new perspective. The mapping of the receptor distribution and receptor occupancy can nowadays be complemented by specific readouts of receptor function either by visualizing the activity of signaling pathways or mapping the physiological consequences of receptor stimulation. Molecular information is obtained through the use of imaging probes that combine a target-specific ligand with a reporter moiety that generates a signal that can be detected from outside the body. For imaging probes targeting the central nervous system, penetration of the intact blood-brain barrier constitutes a major hurdle. Molecular imaging generates specific information and therefore has a large potential for disease phenotyping (diagnostics), therapy development and monitoring of treatment response. Molecular imaging is still in its infancy and major developments in imaging technology, probe design and data analysis are required in order to make an impact. Rodent molecular neuroimaging will play an important role in the development of these tools.
    European Journal of Neuroscience 11/2009; 30(10):1860-9. DOI:10.1111/j.1460-9568.2009.06987.x · 3.18 Impact Factor
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