Fluselenamyl: A Novel Benzoselenazole Derivative for PET Detection of Amyloid Plaques (Aβ) in Alzheimer's Disease.

G S M Sundaram,Jin-Moo Lee,Richard Laforest,Julie L Prior,John Cirrito,Nigel J Cairns,Paul T Kotzbauer,Ping Yan,Nigam P Rath,Dhruva D Dhavale,Vijay Sharma

doi:10.1038/srep35636

Abstract

Fluselenamyl (5), a novel planar benzoselenazole shows traits desirable of enabling noninvasive imaging of Aβ pathophysiology in vivo; labeling of both diffuse (an earlier manifestation of neuritic plaques) and fibrillar plaques in Alzheimer’s disease (AD) brain sections, and remarkable specificity for mapping Aβ compared with biomarker proteins of other neurodegenerative diseases. Employing AD homogenates, [18F]-9, a PET tracer demonstrates superior (2–10 fold higher) binding affinity than approved FDA tracers, while also indicating binding to high affinity site on Aβ plaques. Pharmacokinetic studies indicate high initial influx of [18F]-9 in normal mice brains accompanied by rapid clearance in the absence of targeted plaques. Following incubation in human serum, [18F]-9 indicates presence of parental compound up to 3h thus indicating its stability. Furthermore, in vitro autoradiography studies of [18F]-9 with AD brain tissue sections and ex vivo autoradiography studies in transgenic mouse brain sections show cortical Aβ binding, and a fair correlation with Aβ immunostaining. Finally, multiphoton- and microPET/CT imaging indicate its ability to penetrate brain and label parenchymal plaques in transgenic mice. Following further validation of its performance in other AD rodent models and nonhuman primates, Fluselenamyl could offer a platform technology for monitoring earliest stages of Aβ pathophysiology in vivo.

Highlights

TM intensely studied, [18F]-AV-4516, [18F]-Flutemetamol (Vizamyl)[17,18] and [18F]-Florbetaben (Neuraceq )[19,20,21] have been recently approved by FDA for Aβimaging
To further supplement the existing armamentarium of FDA approved Aβimaging agents, earlier we have shown that a heterocyclic fluorescent molecule is capable of traversing the blood brain barrier (BBB) to label Aβplaques in brains of APP+/−/PS1+/− mice and indicates sensitivity for detecting diffuse plaques in autopsy confirmed Alzheimer’s disease (AD) human tissues[25,26]
We report synthesis, characterization and crystal structure of (Z)-5(2-(5-(2-fluoroethoxy)benzo[d][1,3]selenazol-2-yl)vinyl)-N,N-dimethylpyrimidin-2-amine (Fluselenamyl: 5), F-18 labeled radiotracer ([18F]-9), and perform its preclinical validation to evaluate its potential to serve as an Aβ-targeted PET radiopharmaceutical for monitoring plaque burden in AD

Summary

Introduction

TM intensely studied, [18F]-AV-4516, [18F]-Flutemetamol (Vizamyl)[17,18] and [18F]-Florbetaben (Neuraceq )[19,20,21] have been recently approved by FDA for Aβimaging. The PET counterpart showed high first pass extraction into the brains of normal mice and Aβlabeling in brain frontal cortex of APP+/−/PS1+/− mice, its binding affinity to AD homogenates was 5–10 fold inferior compared with two FDA approved agents[27]. This template scaffold of our first generation agent comprised a benzothiazole moiety, a pharmacologically active constituent with widespread medicinal chemistry applications. Fluselenamyl demonstrates potent binding to Aβfibrils, autopsy confirmed AD homogenates, traverses the blood brain barrier (BBB) to detect Aβplaques in a transgenic mice model, and is highly specific for probing Aβplaques in AD

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Conclusion