Quinoline and benzimidazole derivatives: candidate probes for in vivo imaging of tau pathology in Alzheimer's disease

Abstract

Neurofibrillary tangles (NFTs), neuropil threads, and neuritic elements of senile plaques predominantly comprise hyperphosphorylated tau protein and represent pathological characteristics of Alzheimer's disease (AD). These lesions occur before the presentation of clinical symptoms and correlate with the severity of dementia. In vivo detection of these lesions would thus prove useful for preclinical diagnosis of AD and for tracking disease progression. The present study introduces three novel compounds, 4-[2-(2-benzoimidazolyl)ethenyl]-N,N-diethylbenzenamine (BF-126), 2-[(4-methylamino)phenyl]quinoline (BF-158), and 2-(4-aminophenyl)quinoline (BF-170), as candidate probes for in vivo imaging of tau pathology in the AD brain. When solutions of these compounds are injected intravenously into normal mice, these agents exhibit excellent brain uptake and rapid clearance from normal brain tissue. These compounds display relatively lower binding affinity to beta-amyloid fibrils and higher binding affinity to tau fibrils, compared with previously reported probe BF-168. In neuropathological examination using AD brain sections, BF-126, BF-158, and BF-170 clearly visualize NFTs, neuropil threads, and paired helical filament-type neuritis. Autoradiography using 11C-labeled BF-158 further demonstrated labeling of NFTs in AD brain sections. These findings suggest the potential usefulness of quinoline and benzimidazole derivatives for in vivo imaging of tau pathology in AD.

Figure 1.

A, Chemical structures of BF-126, BF-158, BF-168, BF-170, and [¹²⁵I]BF-180. B, Radiolabeling of BF-158. C, The %ID/g obtained in the brains of mice after intravenous administration of [¹¹C]BF-158.

Figure 2.

A-J, Neuropathological staining of brain sections from cases of AD (A-I), Pick's disease (J), and progressive supranuclear palsy (K). BF-126 (A), BF-158 (B), and BF-170 (C) clearly stained neurofibrillary tangles and neuropil threads. These stainings were consistent with tau immunostaining. In contrast, these compounds faintly stained amyloid plaques, which were clearly stained with thioflavin-S (TFS) in adjacent sections. D-G, Double staining with BF compounds and anti-tau antibody was performed in hippocampal brain sections. D, Cored plaque is clearly visualized by BF-168 using violet and blue filters. A merged image of BF-168 fluorescence using a blue filter and tau immunostaining (green) indicates that BF-168 does not recognize PHF-type neurites. The image of Aβ immunostaining in an adjacent section closely resembles BF-168 staining. BF-126 (E), BF-158 (F), and BF-170 (G) faintly stain the core and halo of amyloid plaque using a violet filter. However, images using a blue filter closely resemble tau immunostaining. E-I, A merged image indicates that these three compounds preferentially bind to PHF-type neurites (E-G). BF-170 (H), BF-158, and BF-126 (data not shown) did not stain any pathological structures in the section pretreated with formic acid, in contrast to the clear visualization of NFTs in non-pretreated brain sections (I). J, K, Staining of Pick bodies and globose tangles were compared with tau immunostaining in brain sections from cases of Pick's disease (J) and progressive supranuclear palsy (K). Neither Pick bodies (G; green) nor globose tangles (H; green) are detected in brain sections treated with BF-126 and BF-170. Scale bars: A-C, 25 μm; D-G, 50 μm; H-I, 400 μm; J-K, 100 μm

Figure 3.

A-C, Autoradiography of AD hippocampal brain section using [¹¹C]BF-158 (B) and immunostaining by anti-tau (A) and anti-Aβ (C) antibodies in adjacent sections. D-F, Close-up images of A, B, and C, respectively. D, E, Accumulation of [¹¹C]BF-158 (E, arrows) correlates well with tau immunostaining (D).