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

TLDR

Amyloid‑β deposits are central to Alzheimer’s disease progression and appear to precede neuronal atrophy. The study aims to develop a method for early Alzheimer’s detection by monitoring pathology before clinical symptoms arise. The authors designed, synthesized, and tested a curcumin‑derivatized near‑infrared probe, CRANAD‑2, to bind Aβ aggregates. CRANAD‑2 exhibits a 70‑fold fluorescence increase, a 90‑nm blue shift, high affinity (Kd = 38 nM), suitable lipophilicity, serum stability, weak albumin binding, and produces significantly higher in‑vivo signals in Tg2576 mice, meeting the criteria for an NIR contrast agent and enabling disease monitoring and drug screening.

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 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 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 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.