(E)-5-Styryl-1H-indole and (E)-6-Styrylquinoline Derivatives Serve as Probes for β-Amyloid Plaques

Yang Yang,Hong-Mei Jia,Bo-Li Liu

doi:10.3390/molecules17044252

Abstract

We report the synthesis and biological evaluation of novel (E)-5-styryl-1H-indole and (E)-6-styrylquinoline derivatives as probes for imaging β-amyloid (Aβ) plaques. These derivatives showed binding affinities for Aβ1–40 aggregates with Ki values varying from 4.1 to 288.4 nM. (E)-5-(4-iodostyryl)-1H-indole (8) clearly stained Aβ plaques in the brain sections of Alzheimer’s disease (AD) model mice (APP/PS1). Furthermore, autoradiography for [125I]8 displayed intense and specific labeling of Aβ plaques in the brain sections mentioned above with low background. In biodistribution experiments using normal mice [125I]8 showed high initial brain uptake followed by rapid washout (4.27 and 0.64% ID/g at 2 and 30 min post injection, respectively). These findings suggests that [123I]8 may be a potential SPECT imaging agent for detecting Aβ plaques in AD brain.

Highlights

Alzheimer’s disease (AD) is a kind of irreversible, progressive brain disease characterized by dementia, cognitive impairment and memory loss
Molecules 2012, 17 tomography) would be very useful for early diagnosis of AD and provide significant information to evaluate the efficacy of AD therapies [4,5]
We successfully developed a series of novel imaging agents for β-amyloid plaques based on the N-benzoylindole core which showed high binding affinities with Ki values in the nM range [18]

Summary

Introduction

Alzheimer’s disease (AD) is a kind of irreversible, progressive brain disease characterized by dementia, cognitive impairment and memory loss. We successfully developed a series of novel imaging agents for β-amyloid plaques based on the N-benzoylindole core which showed high binding affinities with Ki values in the nM range [18]. Watanabe et al have developed phenylindoles for image β-amyloid in brain, these derivatives demonstrated high binding affinities to Aβ1–42 aggregates [20]. Following these successful results, we applied highly conjugated (E)-5-styryl-1H-indole as a core structure for Aβ imaging agents to explore more useful candidates with favorable pharmacokinetics as. Reported are the synthesis and biological evaluation of novel (E)-5-styryl-1H-indole and (E)-6-styrylquinoline derivatives and especially, two radioiodinated derivatives as potential SPECT tracers for imaging β-amyloid plaques in the brain

Chemistry and Radiochemistry

In Vitro Binding Studies Using the Aggregated Aβ1–40

In Vitro Labeling of Brain Sections from Transgenic Mouse by Autoradiography

In Vivo Biodistribution Studies

General

General procedure for preparing 14–19

Preparation of Radioiodinated Ligands

Partition Coefficient Determination

In Vivo Biodistribution in Normal Mice

Conclusions