Design, synthesis, and testing of difluoroboron-derivatized curcumins as near-infrared probes for in vivo detection of amyloid-beta deposits.
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.
Ran
Chongzhao
C
Molecular Imaging Laboratory, MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital/Harvard Medical School, Room 2301, Building 149, Charlestown, Massachusetts 02129, USA.
Xu
Xiaoyin
X
Raymond
Scott B
SB
Ferrara
Brian J
BJ
Neal
Krista
K
Bacskai
Brian J
BJ
Medarova
Zdravka
Z
Moore
Anna
A
D016229:Amyloid beta-Peptides / Q000032:analysis*; D000818:Animals; D001896:Boron Compounds / Q000032:analysis* / Q000138:chemical synthesis; D003474:Curcumin / Q000032:analysis* / Q000138:chemical synthesis; D017611:Fluorine Compounds / Q000032:analysis* / Q000138:chemical synthesis; D051379:Mice; D015335:Molecular Probes / Q000032:analysis* / Q000138:chemical synthesis; D015394:Molecular Structure; D019265:Spectroscopy, Near-Infrared
D016229:Amyloid beta-Peptides; D001896:Boron Compounds; D017611:Fluorine Compounds; D015335:Molecular Probes; D003474:Curcumin