Design, Synthesis, and Testing of Difluoroboron-Derivatized Curcumins as Near-Infrared Probes for in Vivo Detection of Amyloid-β Deposits

Abstract

Amyloid-β (Aβ) 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 the early AD detection. Here, we report the design, synthesis, and testing of a curcumin derivatized near infrared (NIR) probe CRANAD-2. Upon interacting with Aβ aggregates, CRANAD-2 undergoes a range of changes, which include a 70-fold fluorescence intensity increase, a 90 nm blue-shift (from 805 nm to 715 nm), and a large increase in quantum yield. Moreover, this probe also shows a high affinity for Aβ aggregates (Kd = 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 Aβ plaques both in vitro and in vivo. Our data point towards 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.

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

“…As a brainimaging probe, CRANAD-3 must meet several requirements that include proper lipophilicity (log P) and reasonable penetration of the brain-blood barrier (BBB) (47). We found that log P for CRANAD-3 was 2.50, which is reasonable for brain imaging.…”

“…In our previous studies, we showed that CRANAD-2, a curcumin-based NIRF imaging probe, can differentiate between 19-mo-old wild-type and transgenic mice by in vivo NIRF imaging (47). CRANAD-2 could be considered a "smart" probe because it displayed a significant increase in fluorescence intensity, an emission blue shift, a lifetime change, and quantum yield improvement upon interacting with insoluble Aβ aggregates (47). However, we found that CRANAD-2 was not able to detect soluble Aβ species (46).…”

A Fluorescent Styrylquinoline with Combined Therapeutic and Diagnostic Activities against Alzheimer’s and Prion Diseases

“…600−800 nm), 7 where tissue scattering and absorption is lowest, 10 (3) large Stokes shift, (4) ability to modulate fibril aggregation, (5) minimum interference from human serum albumin (HSA) binding, (6) a small molecular size, which enables the small molecule to cross the BBB, and (7) low toxicity. [6][7][8][9]11 As a starting point, we noticed that several styryl derivatives, designed by Li et al to improve the pharmacokinetic properties of CR and ThT, were employed as AD imaging agents in vivo. 12 Interestingly, some of them were also found to be active against prion replication in infected cells.…”

“…600−800 nm), 7 where tissue scattering and absorption is lowest, 10 (3) large Stokes shift, (4) ability to modulate fibril aggregation, (5) minimum interference from human serum albumin (HSA) binding, (6) a small molecular size, which enables the small molecule to cross the BBB, and (7) low toxicity. [6][7][8][9]11 …”

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

“…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.…”