In vivo optical Imaging of amyloid aggregates in brain: Design of fluorescent markers
In vivo optical Imaging of amyloid aggregates in brain: Design of fluorescent markers
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DOI：
10.1002/anie.200500845
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发表时间：
2005-01-01
影响因子：
16.6
通讯作者：
Swager, TM
中科院分区：
文献类型：
--
作者：
Nesterov, EE;Skoch, J;Swager, TM
神经影像学正在成为一种在临床前和早期临床阶段无创识别和监测神经退行性疾病的方法。[1]阿尔茨海默病（Alzheimer’s disease，AD）是美国第四大致死性神经退行性疾病，也是获得性痴呆的最常见原因。[2]AD的早期检测对于了解和临床治疗这种疾病以及预防其进展至关重要。AD的特征性特征是患者大脑中淀粉样蛋白-β斑块和神经元缠结的沉积，[3]这与疾病平行，但只能在死亡后通过尸检确定诊断。该领域的一个重大进展是开发了能够进入大脑并特异性靶向斑块和缠结的放射性标记的小分子试剂，用于正电子发射断层扫描（PET）和单光子发射计算机断层扫描（SPECT）成像。[1]这些方法的主要限制是需要用短寿命同位素标记标记物，例如PET的半衰期约为20分钟的11 C。一种有吸引力的非侵入性替代方法是使用特定的远红外（近红外）荧光造影剂的体内光学成像。这些造影剂利用波长和光散射之间的逆四次方关系，从而允许更长波长的光穿透直接脑成像所需的活组织。[4a]长波长检测方法也受益于生物物质在600 nm以上的低自发荧光。[4]成功的AD光学标记物的要求是：1）吸收和发射的合适波长间隔（600- 800 nm），2）静脉注射后快速进入大脑的能力，以及3）特异性标记淀粉样蛋白-β沉积物并快速清除未结合的染料。光学成像的另一个独特优点是，可以在标记物的结合和未结合形式之间获得生物物理/光学性质的显著差异（要求4）。这将允许成像对比度的显著增加，这不能用基于放射性配体的技术来利用。在已知的淀粉样蛋白染色化合物中，刚果红（CR）在历史上提供了染色淀粉样蛋白斑块的最标准化的方法，并且由于结合是特异性的，因此仍然用于AD脑的死后组织学分析。[5]硫磺素T（ThT）是用于分析聚集的淀粉样蛋白的另一种染料。它的结合比CR稍弱，但通过显示绿色荧光弥补了这一缺陷，该荧光在与淀粉样蛋白斑块结合时变得比CR亮1000倍以上。[6]了解是什么使这些简单的分子对老年斑如此特异，是合理设计改进标记物的起点。研究[7]表明，CR与淀粉样蛋白-β聚集体特异性结合的起源是由于带负电荷的CR s磺酸基团与反平行蛋白中带正电荷的氨基酸残基之间的静电相互作用的组合
Neuroimaging is emerging as a way to noninvasively identify and monitor neurodegenerative diseases during the preclinical and early clinical stages.[1] Alzheimer s disease (AD) stands out among the neurodegenerative diseases as the fourth leading cause of death in the United States and the most common cause of acquired dementia.[2] Early detection of AD is imperative in enabling the understanding and clinical treatment of this disorder, as well as in preventing its progression. The characteristic signature of AD is the deposition of amyloid-β plaques and neurofibrillary tangles in the patient s brain,[3] which parallel the disease but can only be diagnosed with certainty after death by an autopsy. A significant advance in the field has been the development of radiolabeled small-molecule agents capable of entering the brain and specifically targeting plaques and tangles for imaging with positron emission tomography (PET) and single-photon emission computerized tomography (SPECT).[1] A major limitation of these methods is the requirement for the markers to be labeled with short-lived isotopes, such as 11C with a half-life of about 20 min for PET. An attractive noninvasive alternative is in vivo optical imaging using specific far-red (near-IR) fluorescent contrast agents. These contrast agents make use of the inverse fourth-power relationship between the wavelength and light scattering, thus allowing the longer-wavelength light penetration through the living tissues necessary for direct brain imaging.[4a] Long-wavelength detection methods also benefit from the low auto-fluorescence of biological matter beyond 600 nm.[4] The requirements for a successful optical marker of AD are: 1) a suitable wavelength interval of absorption and emission (600–800nm), 2) the ability to rapidly enter the brain after intravenous injection, and 3) specific labeling of the amyloid-β deposits with rapid clearing of the unbound dye. Another unique advantage of optical imaging is the possibility to attain substantial differences in the photophysical/optical properties between the bound and unbound forms of the marker (requirement 4). This would allow a significant increase in imaging contrast which cannot be exploited with techniques based on radioligands. Among the known amyloid-staining compounds, Congo Red (CR) provides historically the most standardized way of staining amyloid plaques, and is still employed in post mortem histological analysis of AD brain, as the binding is specific.[5] Thioflavin T (ThT) is another dye to use in analysis of aggregated amyloid proteins. It binds slightly weaker than CR, but makes up for this deficiency by exhibiting a green fluorescence, that becomes more than 1000 times brighter upon binding to amyloid plaques.[6] The understanding of what makes these simple molecules so specific to senile plaques is the starting point for the rational design of improved markers. Studies [7] suggest that the origin of the specific binding of CR to amyloid-β aggregates is due to the combination of electrostatic interactions between the negatively charged CR s sulfonate groups with the positively charged amino acid residues in the antiparallel protein