Hilt Silvia, Tang Tang, Walton Jeffrey H, Budamagunta Madhu, Maezawa Izumi, Kálai Tamás, Hideg Kálmán, Singh Vikrant, Wulff Heike, Gong Qizhi, Jin Lee-Way, Louie Angelique, Voss John C
Department of Biochemistry & Molecular Medicine, University of California Davis, Sacramento, CA, USA.
Department of Chemistry, University of California Davis, Davis, CA, USA.
J Alzheimers Dis. 2017;55(4):1667-1681. doi: 10.3233/JAD-160279.
Alzheimer's disease (AD) is characterized by depositions of the amyloid-β (Aβ) peptide in the brain. The disease process develops over decades, with substantial neurological loss occurring before a clinical diagnosis of dementia can be rendered. It is therefore imperative to develop methods that permit early detection and monitoring of disease progression. In addition, the multifactorial pathogenesis of AD has identified several potential avenues for AD intervention. Thus, evaluation of therapeutic candidates over lengthy trial periods also demands a practical, noninvasive method for measuring Aβ in the brain. Magnetic resonance imaging (MRI) is the obvious choice for such measurements, but contrast enhancement for Aβ has only been achieved using Gd(III)-based agents. There is great interest in gadolinium-free methods to image the brain. In this study, we provide the first demonstration that a nitroxide-based small-molecule produces MRI contrast in brain specimens with elevated levels of Aβ. The molecule is comprised of a fluorene (a molecule with high affinity for Aβ) and a nitroxide spin label (a paramagnetic MRI contrast species). Labeling of brain specimens with the spin-labeled fluorene produces negative contrast in samples from AD model mice whereas no negative contrast is seen in specimens harvested from wild-type mice. Injection of spin-labeled fluorene into live mice resulted in good brain penetration, with the compound able to generate contrast 24-h post injection. These results provide a proof of concept method that can be used for early, noninvasive, gadolinium-free detection of amyloid plaques by MRI.
阿尔茨海默病（AD）的特征是大脑中存在淀粉样β（Aβ）肽沉积。该疾病过程会持续数十年，在能够做出痴呆症临床诊断之前就会发生大量神经功能丧失。因此，开发能够早期检测和监测疾病进展的方法势在必行。此外，AD的多因素发病机制已经确定了几种AD干预的潜在途径。因此，在漫长的试验期内评估候选治疗药物也需要一种实用的、非侵入性的方法来测量大脑中的Aβ。磁共振成像（MRI）显然是进行此类测量的选择，但仅使用基于钆（III）的试剂才能实现Aβ的对比增强。人们对无钆的大脑成像方法非常感兴趣。在本研究中，我们首次证明了一种基于氮氧化物的小分子在Aβ水平升高的脑标本中产生MRI对比。该分子由芴（一种对Aβ具有高亲和力的分子）和氮氧化物自旋标记物（一种顺磁性MRI对比剂）组成。用自旋标记的芴标记脑标本会在AD模型小鼠的样本中产生负对比，而在从野生型小鼠采集的标本中则未观察到负对比。将自旋标记的芴注射到活小鼠体内可实现良好的脑内渗透，该化合物在注射后24小时能够产生对比。这些结果提供了一种概念验证方法，可用于通过MRI对淀粉样斑块进行早期、非侵入性、无钆检测。
