ANCA: A Family of Fluorescent Probes that Bind and Stain Amyloid Plaques in Human Tissue

Tian

Proc. Natl. Acad. Sci. U.S.A.

et al. 2015

192

180

Near-infrared fluorescence (NIRF) molecular imaging has been widely applied to monitoring therapy of cancer and other diseases in preclinical studies; however, this technology has not been applied successfully to monitoring therapy for Alzheimer's disease (AD). Although several NIRF probes for detecting amyloid beta (Aβ) species of AD have been reported, none of these probes has been used to monitor changes of Aβs during therapy. In this article, we demonstrated that CRANAD-3, a curcumin analog, is capable of detecting both soluble and insoluble Aβ species. In vivo imaging showed that the NIRF signal of CRANAD-3 from 4-mo-old transgenic AD (APP/PS1) mice was 2.29-fold higher than that from age-matched wild-type mice, indicating that CRANAD-3 is capable of detecting early molecular pathology. To verify the feasibility of CRANAD-3 for monitoring therapy, we first used the fast Aβ-lowering drug LY2811376, a well-characterized beta-amyloid cleaving enzyme-1 inhibitor, to treat APP/PS1 mice. Imaging data suggested that CRANAD-3 could monitor the decrease in Aβs after drug treatment. To validate the imaging capacity of CRANAD-3 further, we used it to monitor the therapeutic effect of CRANAD-17, a curcumin analog for inhibition of Aβ cross-linking. The imaging data indicated that the fluorescence signal in the CRANAD-17-treated group was significantly lower than that in the control group, and the result correlated with ELISA analysis of brain extraction and Aβ plaque counting. It was the first time, to our knowledge, that NIRF was used to monitor AD therapy, and we believe that our imaging technology has the potential to have a high impact on AD drug development.Alzheimer's | amyloid | imaging | fluorescence | curcumin

Section: Discussionmentioning

confidence: 99%

“…Several NIRF probes for insoluble Aβs have been reported (37)(38)(39)(40)(41)(42)(43)(44)(45). It has been almost 10 y since the first report of NIRF imaging of Aβs by Hintersteiner et al in 2005 (41).…”

mentioning

confidence: 99%

Near-infrared fluorescence molecular imaging of amyloid beta species and monitoring therapy in animal models of Alzheimer’s disease

Tian

Proc. Natl. Acad. Sci. U.S.A.

et al. 2015

192

180

“…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.…”

mentioning

confidence: 99%

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

Ono

Watanabe

Kimura

et al. 2012

ACS Chem. Neurosci.

140

115

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.

“…In principle, an ideal fluorescent probe for Aβ should have the following properties [35][36][37][38] : (1) a high selectivity and a binding affinity for Aβ; (2) a high quantum yield and a significant change in fluorescence upon binding to Aβ; (3) a suitable emission wavelength greater than 450 nm to minimize background fluorescence from brain tissue, ideally between 650 nm and 900 nm for in vivo detection; (4) the ability to rapidly cross the blood-brain barrier (BBB); (5) a high metabolic stability; (6) fast washout kinetics from normal brain regions; (7) low toxicity; and (8) straightforward synthesis.…”

Section: What Makes An Ideal Aβ Fluorescent Probe?mentioning

confidence: 99%

“…One of these compounds, ANCA-11 (37), showed increased fluorescence upon binding to Aβ aggregates (7.7-fold) and the highest binding affinity (K d =1.4 μmol/L) among all compounds. In vitro tests indicated that all of the compounds could fluorescently stain amyloid deposits in human brain tissue from AD patients [35] . However, further improvement of the binding affinity and maximal emission wavelengths of these probes is needed.…”

Section: Other Probesmentioning

confidence: 99%

Advances in development of fluorescent probes for detecting amyloid-β aggregates

Ren

Tang

et al. 2016

Acta Pharmacol Sin

With accumulating evidence suggesting that amyloid-β (Aβ) deposition is a good diagnostic biomarker for Alzheimer's disease (AD), the discovery of active Aβ probes has become an active area of research. Among the existing imaging methods, optical imaging targeting Aβ aggregates (fibrils or oligomers), especially using near-infrared (NIR) fluorescent probes, is increasingly recognized as a promising approach for the early diagnosis of AD due to its real time detection, low cost, lack of radioactive exposure and high-resolution. In the past decade, a variety of fluorescent probes have been developed and tested for efficiency in vitro, and several probes have shown efficacy in AD transgenic mice. This review classifies these representative probes based on their chemical structures and functional modes (dominant solvent-dependent mode and a novel solvent-independent mode). Moreover, the pharmaceutical characteristics of these representative probes are summarized and discussed. This review provides important perspectives for the future development of novel NIR Aβ diagnostic probes.