Amyloid Imaging: From Benchtop to Bedside

Department of Medicinal Chemistry, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA.
Current Topics in Developmental Biology (Impact Factor: 4.68). 02/2005; 70:171-213. DOI: 10.1016/S0070-2153(05)70008-9
Source: PubMed


Tremendous efforts have been made in the search for a cure or effective treatment of Alzheimer's disease (AD) to develop therapies aimed at halting or reversing amyloid plaque deposition in the brain. This necessitates in vivo detection and quantification of amyloid plaques in the brain for efficacy evaluation of anti-amyloid therapies. For this purpose, a wide array of amyloid-imaging probes has been developed, mainly for in vivo studies based on positron emission tomography and single photon emission computed tomography. This review provides a full account of the development of amyloid-imaging agents. The in vitro binding properties and in vivo pharmacokinetic profiles of all amyloid-imaging agents so far reported are comprehensively and uniquely surveyed. Emphasis is placed on the development of small-molecule probes based on amyloid dyes, such as Congo red and thioflavin T. Compared to large biomolecules, these small-molecule probes have been systematically investigated through extensive structure activity relationship studies. Many of the probes show favorable properties for in vivo studies. As a result, three lead compounds, termed PIB (Pittsburgh-Compound B, [(11)C]6-OH-BTA-1), FDDNP (2-(1-[6-[(2-[(18)F]fluoroethyl)(methyl)amino]-2-naphthyl]ethylidene)malononitrile), and SB-13 (4-N-methylamino-4'-hydroxystilbene), have been identified and evaluated in human subjects. Preliminary studies have indicated that these lead compounds exhibit a characteristic retention in AD subjects that is consistent with the AD pathology, thus proving the concept that amyloid deposits in the brain can be readily detected and quantified in vivo. The progress to date paves the way for further investigation in various aspects of AD research. Once developed, these amyloid-imaging agents could be used as biomarkers to aid in early and definitive diagnosis of AD, facilitate drug discovery and development, and allow pathophysiological studies of the disease mechanism. Furthermore, the success in the development of amyloid-imaging agents helps with the development of imaging agents for in vivo studies of other AD pathologies in particular and of neurodegenerative disorders in general.

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    • "One widespread criterion for identification of amyloid assemblies relies upon specific association of benzothiazole fluorescent dye Thioflavin T (ThT) with fibrillar structures [8;9], followed by significantly enhanced fluorescence and shift of ThT excitation maximum from 340 to 450 nm [10]. High efficiency of ThT criterion stimulated considerable research activity aimed at improving ThT analytical sensitivity and specificity [11] [12] [13]. "
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    ABSTRACT: Two charged Thioflavin T (ThT) derivatives, referred to here as ICT2 and ICT3, showed higher fluorescence response, association constants and the blue-shifted emission maxima in the presence of lysozyme fibrils compared to insulin aggregates. In turn, the other two ThT derivatives, ICT4 and ICT5, possessed much weaker sensitivity to amyloid fibrils. Furthermore, a direct correlation was found between the “light-up” ability of the fibril-bound fluorophores and those observed in concentrated dichlormethane or glycerol solutions. To explain this behavior, the ground and lowest non-relaxed excited state properties of the dyes were evaluated with the 6-31G(d,p) basis set, using DFT and the CIS method. The excited state energy dependences along the torsion angle between the benzothiazole and phenyl moieties of the ICT4, ICT5 turned out to have three directly observed minima, corresponding to the locally excited (LE) and twisted intramolecular charge transfer (TICT) states. Thus, stronger stabilization of the ICT4, ICT5 LE states resulted in significantly greater quantum yield of these dyes in buffer solution and the absence of the “light-up” feature in the presence of insulin amyloid fibrils, compared to ICT2 and ICT3.
    Full-text · Article · Feb 2015 · Journal of Luminescence
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    • "One of the main obstacles is the blood–brain barrier (BBB), which efficiently ensures proper brain functioning and prevents brain penetration of harmful substances . Yet delivery of amyloid binding compounds into the brain is of vital importance in order to detect amyloid accumulation for diagnostic purposes [6] [7] [8] and to develop treatments that target cerebral amyloid [9] [10] [11]. "
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    ABSTRACT: Treatment of neurodegenerative disorders such as Alzheimer's disease is hampered by the blood-brain barrier (BBB). This tight cerebral vascular endothelium regulates selective diffusion and active transport of endogenous molecules and xenobiotics in to and out of the brain parenchyma. In this study, glutathione targeted PEGylated (GSH-PEG) liposomes were designed to deliver amyloid-targeting antibody fragments across the BBB into the brain. Two different formulations of GSH-PEG liposomes based on 1,2-Dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and egg-yolk phosphatidylcholine (EYPC) were produced. Both formulations encapsulate 15kDa amyloid beta binding llama single domain antibody fragments (VHH-pa2H). To follow the biodistribution of VHH-pa2H rather than the liposome, the antibody fragment was labelled with the radioisotope indium-111. To prolong the shelf life of the construct beyond the limit of radioactive decay, an active-loading method was developed to efficiently radiolabel the antibody fragments after encapsulation into the liposomes, with radiolabelling efficiencies of up to 68% after purification. The radiolabeled liposomes were administered via a single intravenous bolus injection to APPswe/PS1dE9 double transgenic mice, a mouse model of Alzheimer's disease, and their wildtype littermates. Both GSH-PEG DMPC and GSH-PEG EYPC liposomes significantly increased the standard uptake values (SUV) of VHH-pa2H in the blood of the animals compared to free VHH-pa2H. Encapsulation in GSH-PEG EYPC liposomes resulted in the highest increase in SUV in the brains of transgenic animals. Overall, these data provide evidence that GSH-PEG liposomes may be suitable for specific delivery of single domain antibody fragments over the BBB into the brain. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Feb 2015 · Journal of Controlled Release
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    • "Other methods have examined the relationship between small-nucleotide polymorphism loci in protein phosphatase B and calcium homeostasis modulator 1 (CALHM1), respectively , with AD quantitative biomarkers such as p-tau and Aí µí»½42 CSF or genome-wide association study with MRI brain structure degeneration localized in temporal, parietal, and hippocampal regions [73] [74] [75] [76] [77]. Histopathological aromatic dyes staining using Thioflavin S but especially Congo red is the gold standard for diagnosing amyloid plaques because it only binds aggregated í µí»½sheets [78] [79], and postmortem clinical diagnosis is still regarded as the gold standard for definitive diagnostic of AD. Other histopathological silver staining such as Bielschowsky, Bodian, or Gallyas and dyes staining such as Hematoxylin and eosin, cresyl violet, and luxol-fast blue as well as antibody specific to Aí µí»½, phosphorylated tau, alpha-synuclein, ubiquitin, and TAR DNA-binding protein 43 (TDP-43) are routinely employed during postmortem examinations [79] [80]. "
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    ABSTRACT: Sporadic Alzheimer's disease (AD) is an emerging chronic illness characterized by a progressive pleiotropic pathophysiological mode of actions triggered during the senescence process and affecting the elderly worldwide. The complex molecular mechanisms of AD not only are supported by cholinergic, beta-amyloid, and tau theories but also have a genetic basis that accounts for the difference in symptomatology processes activation among human population which will evolve into divergent neuropathological features underlying cognitive and behaviour alterations. Distinct immune system tolerance could also influence divergent responses among AD patients treated by immunotherapy. The complexity in nature increases when taken together the genetic/immune tolerance with the patient's brain reserve and with neuropathological evolution from early till advance AD clinical stages. The most promising diagnostic strategies in today's world would consist in performing high diagnostic accuracy of combined modality imaging technologies using beta-amyloid 42 peptide-cerebrospinal fluid (CSF) positron emission tomography (PET), Pittsburgh compound B-PET, fluorodeoxyglucose-PET, total and phosphorylated tau-CSF, and volumetric magnetic resonance imaging hippocampus biomarkers for criteria evaluation and validation. Early diagnosis is the challenge task that needs to look first at plausible mechanisms of actions behind therapies, and combining them would allow for the development of efficient AD treatment in a near future.
    Full-text · Article · Feb 2013 · The Scientific World Journal
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