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Design, synthesis, and testing of difluoroboron-derivatized curcumins as near-infrared probes for in vivo detection of amyloid-beta deposits.

ABSTRACT: Amyloid-beta (Abeta) deposits have been identified as key players in the progression of Alzheimer's disease (AD). Recent evidence indicates that the deposits probably precede and induce the neuronal atrophy. Therefore, methods that enable monitoring the pathology before clinical symptoms are observed would be beneficial for early AD detection. Here, we report the design, synthesis, and testing of a curcumin-derivatized near-infrared (NIR) probe, CRANAD-2. Upon interacting with Abeta aggregates, CRANAD-2 undergoes a range of changes, which include a 70-fold fluorescence intensity increase, a 90 nm blue shift (from 805 to 715 nm), and a large increase in quantum yield. Moreover, this probe also shows a high affinity for Abeta aggregates (K(d) = 38.0 nM), a reasonable log P value (log P = 3), considerable stability in serum, and a weak interaction with albumin. After intravenous injection of this probe, 19-month-old Tg2576 mice exhibited significantly higher relative signal than that of the control mice over the same period of time. In summary, CRANAD-2 meets all the requirements for a NIR contrast agent for the detection of Abeta plaques both in vitro and in vivo. Our data point toward the feasibility of monitoring the progress of the disease by NIR imaging with CRANAD-2. In addition, we believe that our probe could be potentially used as a tool for drug screening.

SUBMITTER: Ran C

PROVIDER: S-EPMC2784241 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Design, synthesis, and testing of difluoroboron-derivatized curcumins as near-infrared probes for in vivo detection of amyloid-beta deposits.

Ran Chongzhao C Xu Xiaoyin X Raymond Scott B SB Ferrara Brian J BJ Neal Krista K Bacskai Brian J BJ Medarova Zdravka Z Moore Anna A

Journal of the American Chemical Society 20091001 42

Amyloid-beta (Abeta) deposits have been identified as key players in the progression of Alzheimer's disease (AD). Recent evidence indicates that the deposits probably precede and induce the neuronal atrophy. Therefore, methods that enable monitoring the pathology before clinical symptoms are observed would be beneficial for early AD detection. Here, we report the design, synthesis, and testing of a curcumin-derivatized near-infrared (NIR) probe, CRANAD-2. Upon interacting with Abeta aggregates, ...[more]

PMID: 19807070

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Project description:Near-infrared (NIR) fluorescent imaging of both soluble and insoluble Aβ species in the brain of Alzheimer's disease (AD) is crucial for the early diagnosis and intervention of AD. To date, a variety of NIR fluorescent probes have been reported for the detection of Aβ species. Among these probes, CRANAD-58 was reported to have the capability to detect both soluble and insoluble Aβ species, which is vital to monitor the changes of Aβ species during the pathological course of the disease. Though CRANAD-58 has shown promise to noninvasively detect Aβ species in transgenic AD mice, the emission wavelength (~670 nm) is still too short for further applications. Therefore, new probes with longer emission wavelength and improved physiological properties are in highly demand. Herein, we report the design and engineering of nine donor-acceptor-donor molecules as "off-on" near-infrared fluorescent probes for in vivo imaging of both soluble and insoluble Aβ species in living AD mice owing to its improved in vitro properties and in vivo performance. Methods: We report a two-round strategy to develop nine "off-on" NIR fluorescence probes via structural modification of a curcumin analogue-based donor-acceptor-donor architecture. In round one, probes 1 and 2 were synthesized, and probe 2 was identified to be an optimum probe as it showed distinct "off-on" NIR fluorescence at > 690 nm upon binding to Aβ monomers, oligomers and aggregates. To further improve the in vivo performance, further structural modification of probe 2 into probes 3-9 was then conducted. The fluorescence response with Aβ species and histological staining in vitro and in vivo imaging of Aβ species in APP/PS1 transgenic AD mice and age-matched wild-type mice were performed. Results: We demonstrate that, compared to probe 2, probe 9 with improved physiological properties hold the fastest kinetics (~10 min) to produce not only higher brain fluorescence intensity in 10-month-old APP/PS1 transgenic AD mice, but also afford a higher discrepancy in brain fluorescence to discriminate AD mice from wild-type (WT) mice. Probe 9 also hold the ability to detect soluble Aβ species in 6-month-old APP/PS1 transgenic mice. Probe 9 was further applied for dynamic visualization of Aβ plaques in a skull-thinning 14-month-old APP/PS1 mouse, which revealed its immediate penetration into brain parenchyma and selective labeling of both parenchymal and angiopathic Aβ plaques. In addition, probe 9 possessed significantly high attenuation effect on the aggregation of Aβ monomers. Conclusion: Our results demonstrate the good potential of probe 9 for longitudinal NIR fluorescence imaging of soluble and insoluble Aβ species in APP/PS1 transgenic AD mice, which may act as a useful tool for early diagnosis and intervention of AD.

Dataset Information

Design, synthesis, and testing of difluoroboron-derivatized curcumins as near-infrared probes for in vivo detection of amyloid-beta deposits.

Publications

Design, synthesis, and testing of difluoroboron-derivatized curcumins as near-infrared probes for in vivo detection of amyloid-beta deposits.

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