BODIPY-based molecular probe for imaging of cerebral β-amyloid plaques

Abstract

We designed and synthesized a BODIPY-based probe (BAP-1) for the imaging of β-amyloid plaques in the brain. In binding experiments in vitro, BAP-1 showed excellent affinity for synthetic Aβ aggregates. β-Amyloid plaques in Tg2576 mouse brain were clearly visualized with BAP-1. In addition, the labeling of β-amyloid plaques was demonstrated in vivo in Tg2576 mice. These results suggest BAP-1 to be a useful fluorescent probe for the optical imaging of cerebral β-amyloid plaques in patients with Alzheimer's disease.

Keywords: Alzheimer’s disease; BODIPY; optical imaging; β-amyloid plaque.

Scheme 1. Synthetic Route for BAP-1

Reagents: (a) CHCl₃, POCl₃, BF₃OEt₂, Et₃N; (b) toluene, 4-dimethylaminobenzaldehyde, piperidine, and AcOH.

Figure 1

Fluorescence intensity of BAP-1 upon interaction with Aβ42 aggregates and BSA.

Figure 2

Plot of the fluorescence intensity (Em = 673 nm) as a function of the concentration of BAP-1 in the presence of Aβ42 aggregates (2.2 μM) in solutions.

Figure 3

Neuropathological staining of BAP-1 in a 10-μm section from a Tg2576 mouse brain (A) and a wild-type mouse brain (B). Labeled plaques were confirmed by staining of the adjacent section with thioflavin-S (C).

Figure 4

Fluorescence intensity after injection of BAP-1 into ddY mice with an IVIS spectrum.

Figure 5

Comparison of the fluorescence intensity in the brain after the injection of BAP-1 into a Tg2576 mouse (A) and wild-type mouse (B).

Figure 6

Ex vivo fluorescence observation of brain sections from a Tg2576 mouse (A) and wild-type mouse (B) after an injection of BAP-1. The presence of Aβ plaques in the section from the Tg2576 mouse was confirmed with immunohistochemical staining using a monoclonal Aβ antibody (C). Arrows show Aβ plaques stained by both BAP-1 (A) and immunohistochemical labeling (C).