A multimodal, β-amyloid-targeted contrast agent

Vithanarachchi, Sashiprabha M.; Allen, Matthew J.

doi:10.1039/c2cc36583a

Cited by 23 publications

(20 citation statements)

References 52 publications

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“…The ability of Gd-Cur to control metal-free and metal-induced Aβ aggregation pathways has not been reported, however. From our results and observations presented herein, together with the previous work [35], Gd-Cur, in comparison to Cur-S, is demonstrated to be a viable molecular scaffold that could be a foundation for the development of a theranostic agent, capable of indicating Aβ plaques and redirecting metal-triggered Aβ aggregation.…”

Section: Introductionsupporting

confidence: 66%

“…All reagents were purchased from commercial suppliers and used as received unless otherwise stated. The compounds Gd(III)(diethylenetriaminepentaacetate)-linked-2-(4-((1E,4Z,6E)-5-hydroxy-7-(4-hydroxy-3-methoxy-phenyl)-3oxohepta-1,4,6-trien-1-yl)-2-methoxy-phenoxy)-N-(2-(3-(ptolyl)thioureido)ethyl)acetamide (Gd-Cur) [35] and 2,2'-((((1E,3Z,6E)-3-hydroxy-5-oxohepta-1,3,6-triene-1,7-diyl) bis(2-methoxy-4,1-phenylene))bis(oxy))diacetate (Cur-S) [36] were prepared following previously reported methods. Aβ 40 (DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAI-IGLMVGGVV) and Aβ 42 (DAEFRHDSGYEVHHQKLVFF AEDVGSNKGAIIGLMVGGVVIA) were purchased from AnaSpec (Fremont, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

“…1), prepared by linkage of Gd(III)(DTPA) (Gd; Fig. 1; DTPA = diethylenetriamine pentaacetate; a clinically approved contrast agent) with Cur, was reported asa potential multimodal contrast agent to detect Aβ plaques in vitro, applicable to both magnetic resonance imaging (MRI) and fluorescence microscopy [35]. The ability of Gd-Cur to control metal-free and metal-induced Aβ aggregation pathways has not been reported, however.…”

Section: Introductionmentioning

confidence: 99%

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Inhibitory Activity of Curcumin Derivatives Towards Metal-Free and Metal-Induced Amyloid-β Aggregation

Kochi

Lee

Vithanarachchi

et al. 2015

CAR

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When Alzheimer's disease (AD) progresses, several pathological features arise including accumulation of misfolded protein aggregates [e.g., amyloid-β (Aβ) plaques], metal ion dyshomeostasis, and oxidative stress. These characteristics are recently suggested to be interconnected through a potential factor, metal-associated Aβ (metal-Aβ) species. The role of metal-Aβ species in AD pathogenesis remains unclear, however. To elucidate the contribution of metal-Aβ species to AD pathology, as well as to develop small molecules as chemical tools and/or theranostic (therapeutic and diagnostic) agents for this disease, curcumin (Cur), a natural product from turmeric, and its derivatives have been studied towards both metal-free and metal-induced Aβ aggregation. Although Cur has indicated anti-amyloidogenic activities and antioxidant properties, its biological use has been hindered due to low solubility and stability in physiologically relevant conditions. Herein, we report the reactivity of Cur and its derivatives (Gd-Cur, a potential multimodal Aβ imaging agent; Cur-S, a water soluble derivative of Cur that has substitution at the phenolic hydroxyls) with metal-free Aβ and metal-Aβ species. Our results and observations indicate that Gd-Cur could modulate Cu(II)-triggered Aβ aggregation more noticeably over metal-free or Zn(II)-induced analogues; however, Cur-S was not observed to noticeably modulate Aβ aggregation with and without metal ions. Overall, our studies present information that could aid in optimizing the molecular scaffold of Cur for the development of chemical tools or theranostics for metal-Aβ species.

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Section: Introductionsupporting

confidence: 66%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibitory Activity of Curcumin Derivatives Towards Metal-Free and Metal-Induced Amyloid-β Aggregation

Kochi

Lee

Vithanarachchi

et al. 2015

CAR

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“…-based probe. Besides a gadolinium(III) diethylenetriaminepentaacetic acid (DTPA)-curcumin conjugate reported recently [21], these are the first low molecular weight, potential MRI contrast agents bearing a specific unit that allows targeting of amyloid plaques. We describe the characterization of the most relevant physicochemical parameters for the use of these complexes as MRI probes for Ab detection.…”

Section: Introductionmentioning

confidence: 99%

Gd3+ complexes conjugated to Pittsburgh compound B: potential MRI markers of β-amyloid plaques

et al. 2013

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In an effort towards the visualization of β-amyloid (Aβ) plaques by T1-weighted magnetic resonance imaging for detection of Alzheimer's disease, we report the synthesis and characterization of stable, noncharged Gd(3+) complexes of three different 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid monoamide derivatives conjugated to Pittsburgh compound B, a well-established marker of Aβ plaques. The ligands L1, L2, and L3 differ in the nature and size of the spacer linking the macrocyclic chelator and the Pittsburgh compound B targeting moiety, which affects their lipophilicity, the octanol-water partition coefficients of the complexes ranging from -0.15 to 0.32. Given their amphiphilic behavior, the complexes form micelles in aqueous solution (critical micellar concentration 1.00-1.49 mM). The parameters determining the relaxivity, including the water exchange rate and the rotational correlation times, were assessed for the monomeric and the micellar form by a combined (17)O NMR and (1)H nuclear magnetic relaxation dispersion (NMRD) study. They are largely influenced by the aggregation state and the hydrophobic character of the linkers. The analysis of the rotational dynamics for the aggregated state in terms of local and global motions using the Lipari-Szabo approach indicates highly flexible, large aggregates. On binding of the complexes to human serum albumin or to the amyloid peptide Aβ1-40 in solution, they undergo a fourfold and a twofold relaxivity increase, respectively (40 MHz). Proton relaxation enhancement studies confirmed moderate interaction of Gd(L1) and Gd(L3) with human serum albumin, with KA values ranging between 250 and 910 M(-1).

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“…Curcumin was condensed via an amino-linker with an isothiocyanate derivative of Gadolinium III diethylenetriaminepentaacetate to yield an efficient contrast agent for MRI investigations. The agent interacted with A␤ aggregates producing changes in relaxation rate and fluorescence emission [216].…”

Section: Natural Productsmentioning

confidence: 99%

Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes. Disease-Modifying Drugs. Update 2014

Froestl

Pfeifer

Muhs

2014

JAD

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Scientists working in the field of Alzheimer's disease and, in particular, cognitive enhancers, are very productive. The review "Drugs interacting with Targets other than Receptors or Enzymes. Disease-modifying Drugs" was accepted in October 2012. In the last 20 months, new targets for the potential treatment of Alzheimer's disease were identified. Enormous progress was realized in the pharmacological characterization of natural products with cognitive enhancing properties. This review covers the evolution of research in this field through May 2014.

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A multimodal, β-amyloid-targeted contrast agent

Abstract: A multimodal, β-amyloid-targeted contrast agent was synthesized and studied in vitro. The agent has a higher relaxivity than a clinically approved contrast agent and interacts with β-amyloid aggregates producing changes in relaxation rate and fluorescence emission.

Cited by 23 publications

References 52 publications

Inhibitory Activity of Curcumin Derivatives Towards Metal-Free and Metal-Induced Amyloid-β Aggregation

Inhibitory Activity of Curcumin Derivatives Towards Metal-Free and Metal-Induced Amyloid-β Aggregation

Gd3+ complexes conjugated to Pittsburgh compound B: potential MRI markers of β-amyloid plaques

Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes. Disease-Modifying Drugs. Update 2014

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A multimodal, β-amyloid-targeted contrast agent

Abstract: A multimodal, β-amyloid-targeted contrast agent was synthesized and studied in vitro. The agent has a higher relaxivity than a clinically approved contrast agent and interacts with β-amyloid aggregates producing changes in relaxation rate and fluorescence emission.

Cited by 23 publications

References 52 publications

Inhibitory Activity of Curcumin Derivatives Towards Metal-Free and Metal-Induced Amyloid-&#946; Aggregation

Inhibitory Activity of Curcumin Derivatives Towards Metal-Free and Metal-Induced Amyloid-&#946; Aggregation

Gd3+ complexes conjugated to Pittsburgh compound B: potential MRI markers of β-amyloid plaques

Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes. Disease-Modifying Drugs. Update 2014

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Product

Resources

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Inhibitory Activity of Curcumin Derivatives Towards Metal-Free and Metal-Induced Amyloid-β Aggregation

Inhibitory Activity of Curcumin Derivatives Towards Metal-Free and Metal-Induced Amyloid-β Aggregation