New molecular imaging probes specific to A2 species including soluble A2 oligomers, insoluble fibrils and plaques, are indispensable for accurate and early detection of AD pathology, as well as for drug development and treatment monitoring. NIR (near infrared imaging), MRI (magnetic resonance imaging) and PET (positron emission tomography) are the imaging modalities that currently provide capabilities for imaging A2 species. Each of these modalities has its own advantages and weaknesses;multi-modality imaging, an emerging approach that combines information from more than one modality, provides fundamental improvements for 1) accurate detection to permit early diagnosis and spatial localization;2) unambiguous information about molecular activities of a target;3) easy translation from animal study to clinical trial. To date, multi-modality imaging efforts have been focused primarily on two objectives: 1) to achieve better co-registration for accurate spatial location by constructing hybrid imaging systems or using complicated registration algorithms;2) to achieve more accurate molecular-level information of the target by developing multi-modal imaging probes. Such probes would be particularly suitable for detection and monitoring of AD and other neurodegenerative diseases. Curcumin, the principal curcuminoid of the Indian curry, has been used for ex vivo detection of amyloid deposits. However, its rapid metabolism and limited penetration across blood-brain barrier (BBB) do not allow for its use as an in vivo imaging agent. In this application we propose to create a small library of curcumin derivatives with NIR properties for in vitro and in vivo preliminary screening, and adapt the selected candidates for modification with PET and 19F MR imaging reporters for NIR/MRI/PET imaging. We will further perform NIR/PET/19F MRI multi-modality imaging of AD pathology in transgenic animals in vivo. Finally, we will attempt to conduct a limited theragnostic study with AD therapeutics using the synthesized probes for monitoring of the therapeutic outcome. In addition, several very promising PET probes such as PiB (Pittsburg compound B) and AV-45 have displayed efficacy primarily for imaging insoluble A2 plaques;however, we still fall short of a probe for imaging the soluble A2 species, the likely toxic species at early AD pathological stage. Since curcumin derivatives synthesized in our preliminary studies showed appreciable binding to monomeric species, we will investigate this phenomenon further in this application. If successful, with an arsenal of probes for detection of both insoluble plaques and soluble A2 species, we believe that eventually we will be able to monitor the full course of amyloidosis pathology of Alzheimer's disease.

Public Health Relevance

The proposed research will be beneficial for the preclinical animal study and the drug development for Alzheimer's Disease, and will have potential capability for the early and accurate clinical diagnosis of Alzheimer's Disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Mentored Quantitative Research Career Development Award (K25)
Project #
5K25AG036760-05
Application #
8667383
Study Section
National Institute on Aging Initial Review Group (NIA)
Program Officer
Hsiao, John
Project Start
2010-06-01
Project End
2015-05-31
Budget Start
2014-06-15
Budget End
2015-05-31
Support Year
5
Fiscal Year
2014
Total Cost
$153,996
Indirect Cost
$11,246
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Yang, Jian; Yang, Jing; Liang, Steven H et al. (2016) Imaging hydrogen peroxide in Alzheimer's disease via cascade signal amplification. Sci Rep 6:35613
Zhang, Xueli; Tian, Yanli; Zhang, Can et al. (2015) Near-infrared fluorescence molecular imaging of amyloid beta species and monitoring therapy in animal models of Alzheimer's disease. Proc Natl Acad Sci U S A 112:9734-9
Zhang, Xueli; Tian, Yanli; Yuan, Peng et al. (2014) A bifunctional curcumin analogue for two-photon imaging and inhibiting crosslinking of amyloid beta in Alzheimer's disease. Chem Commun (Camb) 50:11550-3
Tian, Yanli; Zhang, Xueli; Li, Yuyan et al. (2014) Crown ethers attenuate aggregation of amyloid beta of Alzheimer's disease. Chem Commun (Camb) 50:15792-5
Zhang, Xueli; Tian, Yanli; Li, Zeng et al. (2013) Design and synthesis of curcumin analogues for in vivo fluorescence imaging and inhibiting copper-induced cross-linking of amyloid beta species in Alzheimer's disease. J Am Chem Soc 135:16397-409
Zhang, Xueli; Ran, Chongzhao (2013) Dual Functional Small Molecule Probes as Fluorophore and Ligand for Misfolding Proteins. Curr Org Chem 17:
Ran, Chongzhao; Moore, Anna (2012) Spectral unmixing imaging of wavelength-responsive fluorescent probes: an application for the real-time report of amyloid Beta species in Alzheimer's disease. Mol Imaging Biol 14:293-300
Ran, Chongzhao; Zhao, Wei; Moir, Robert D et al. (2011) Non-conjugated small molecule FRET for differentiating monomers from higher molecular weight amyloid beta species. PLoS One 6:e19362