In Vivo Optical Imaging of Amyloid Aggregates in Brain: Design of Fluorescent Markers

Nesterov, Evgueni E.; Skoch, Jesse; Hyman, Bradley T.; Klunk, William E.; Bacskai, Brian J.; Swager, Timothy M.

doi:10.1002/anie.200500845

Cited by 315 publications

(324 citation statements)

References 21 publications

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“…To this aim, ideal properties for a therapeutic and diagnostic small molecule should include (1) ability to change fluorescence properties upon binding to fibrils, (2) ability to absorb and emit light in the far red/near-infrared (NIR) region (ca. 600−800 nm), 7 where tissue scattering and absorption is lowest, 10 (3) large Stokes shift, (4) ability to modulate fibril aggregation, (5) minimum interference from human serum albumin (HSA) binding, (6) a small molecular size, which enables the small molecule to cross the BBB, and (7) low toxicity. [6][7][8][9]11 As a starting point, we noticed that several styryl derivatives, designed by Li et al to improve the pharmacokinetic properties of CR and ThT, were employed as AD imaging agents in vivo.…”

Section: * S Supporting Informationmentioning

confidence: 99%

“…600−800 nm), 7 where tissue scattering and absorption is lowest, 10 (3) large Stokes shift, (4) ability to modulate fibril aggregation, (5) minimum interference from human serum albumin (HSA) binding, (6) a small molecular size, which enables the small molecule to cross the BBB, and (7) low toxicity. [6][7][8][9]11 As a starting point, we noticed that several styryl derivatives, designed by Li et al to improve the pharmacokinetic properties of CR and ThT, were employed as AD imaging agents in vivo. 12 Interestingly, some of them were also found to be active against prion replication in infected cells.…”

Section: * S Supporting Informationmentioning

confidence: 99%

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confidence: 99%

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A Fluorescent Styrylquinoline with Combined Therapeutic and Diagnostic Activities against Alzheimer’s and Prion Diseases

Staderini

Aulić

Bartolini

et al. 2013

ACS Med. Chem. Lett.

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(E)-6-Methyl-4′-amino-2-styrylquinoline (3) is a small molecule with the proper features to potentially diagnose, deliver therapy and monitor response to therapy in protein misfolding diseases. These features include compound fluorescent emission in the NIR region and its ability to interact with both Aβ and prion fibrils, staining them with high selectivity. Styrylquinoline 3 also inhibits Aβ self-aggregation in vitro and prion replication in the submicromolar range in a cellular context. Furthermore, it is not toxic and is able to cross the blood brain barrier in vitro (PAMPA test).KEYWORDS: Aggregation, protein misfolding diseases, amyloid, fibrillation inhibitors P rotein misfolding diseases (PMD) include a broad range of human disorders characterized by a conformational change of normally expressed proteins, that convert from a physiological soluble monomeric form into oligomeric and fibrillar forms, rich in stable β-sheet regions. 1 These fibrillar aggregates play a pivotal role in neuronal dysfunction and survival, eventually leading to fatal disease. Alzheimer's (AD) and prion diseases (PrD) are prototypical examples of PMD. In these maladies, amyloid-β protein (Aβ) and cellular prion protein (PrP C ), respectively, change their conformations into β-sheet toxic isoforms. In the case of PrD, the toxic isoform known as scrapie prion protein (PrP Sc ) is also infectious. 2 In AD and PrD, the misfolded proteins have been regarded both as neuropathological hallmarks for diagnosis and as therapeutic targets. 2 While the so-called "amyloid hypothesis" in AD has been questioned, a recent interest has arisen in the possibility that all proteins causing neurodegeneration are prions. 2 If confirmed, this hypothesis would profoundly influence the development of diagnostic and therapeutic tools. 2 Many techniques have been employed to detect fibrillar aggregates, including positron emission tomography (PET) 3 and fluorescence spectroscopy. 4 PET is expensive and limited by the narrow isotope availability of the required probes. On the other hand, many fluorescent in vitro staining agents are available such as Congo Red (CR) and Thioflavin T (ThT) but they cannot translate into clinical diagnostic and therapeutic tools 4 because of their low specificity, poor sensitivity, inability to cross the blood brain barrier (BBB) and marked toxicity. 5 Because fluorescence spectroscopy has proven suitable for studying fibrillar aggregates also in vivo, 6−9 there is an urgent need for fluorescent sensors with improved properties.With these concepts in mind, we focused our attention on fluorescent compounds capable of staining Aβ and PrP Sc fibrils and, ideally, of simultaneously blocking their aggregation. To this aim, ideal properties for a therapeutic and diagnostic small molecule should include (1) ability to change fluorescence properties upon binding to fibrils, (2) ability to absorb and emit light in the far red/near-infrared (NIR) region (ca. 600−800 nm), 7 where tissue scattering and absorption is lowest...

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confidence: 99%

Section: * S Supporting Informationmentioning

confidence: 99%

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A Fluorescent Styrylquinoline with Combined Therapeutic and Diagnostic Activities against Alzheimer’s and Prion Diseases

Staderini

Aulić

Bartolini

et al. 2013

ACS Med. Chem. Lett.

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“…However, there have been fewer reports regarding the development of fluorescent probes than PET probes despite their significance, although AOI-987, 29 NIAD-4, 30 CRANAD-2, 32 ANCA-11, 35 and BMAOI 36 have been reported for the imaging of Aβ plaques.…”

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confidence: 99%

BODIPY-Based Molecular Probe for Imaging of Cerebral β-Amyloid Plaques

Ono

Watanabe

Kimura

et al. 2012

ACS Chem. Neurosci.

148

115

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We designed and synthesized a BODIPY-based probe (BAP-1) for the imaging of β-amyloid plaques in the brain. In binding experiments in vitro, BAP-1 showed excellent affinity for synthetic Aβ aggregates. β-Amyloid plaques in Tg2576 mouse brain were clearly visualized with BAP-1. In addition, the labeling of β-amyloid plaques was demonstrated in vivo in Tg2576 mice. These results suggest BAP-1 to be a useful fluorescent probe for the optical imaging of cerebral β-amyloid plaques in patients with Alzheimer's disease.

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“…Other molecules with interesting optical properties have been prepared using 2-stannylated thiophenes, such as the bithiophene 186, which is a fluorescent marker by in vivo optical imaging of amyloid aggregates in brain (Scheme 55). 340 This compound is obtained by Stille coupling of the stannylated bithiophene 183 and the O-silylated iodophenol 184 giving compound 185. Formylation of 185, followed by Knoevenagel condensation with malononitrile and final desilylation gave the final product 186.…”

Section: Scheme 53mentioning

confidence: 99%