4.8 Article

Smart Near-Infrared Fluorescence Probes with Donor-Acceptor Structure for in Vivo Detection of β-Amyloid Deposits

Journal

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 136, Issue 9, Pages 3388-3394

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/ja4052922

Keywords

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Funding

  1. Japan Society for the Promotion of Science (JSPS)
  2. Council for Science and Technology Policy (CSTP)
  3. National Natural Science Foundation of China [21201019]
  4. Research Fund for the Doctoral Program of Higher Education of China [20120003120013]
  5. China Scholarship Council (CSC)

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The deposition of beta-amyloid (A beta) plaques in the parenchymal and cortical brain is accepted as the main pathological hallmark of Alzheimer's disease (AD); however, early detection of AD still presents a challenge. With the assistance of molecular imaging techniques, imaging agents specifically targeting A beta plaques in the brain may lead to the early diagnosis of AD. Herein, we report the design, synthesis, and evaluation of a series of smart near-infrared fluorescence (NIRF) imaging probes with donor acceptor architecture bridged by a conjugated pi-electron chain for A beta plaques. The chemical structure of these NIRF probes is completely different from Congo Red and Thioflavin-T. Probes with a longer conjugated pi system (carbon carbon double bond) displayed maximum emission in PBS (>650 nm), which falls in the best range for NIRF probes. These probes were proved to have affinity to A beta plaques in fluorescent staining of brain sections from an AD patient and double transgenic mice, as well as in an in vitro binding assay using A beta(1-42) aggregates. One probe with high affinity (k(i) = 37 nM, K-d = 27 nM) was selected for in vivo imaging. It can penetrate the blood-brain barrier of nude mice efficiently and is quickly washed out of the normal brain. Moreover, after intravenous injection of this probe, 22-month-old APPswe/PSENI mice exhibited a higher relative signal than control mice over the same period of time, and ex vivo fluorescent observations confirmed the existence of A beta plaques. In summary, this probe meets most of the requirements for a NIRF contrast agent for the detection of A beta plaques both in vitro and in vivo.

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