Abeta-Targeted Fluorinated Liposomes for 19F MRI Detection of Abeta Pathologies in APP/PSEN1 Mice

 描述(申请人提供)：阿尔茨海默病(AD)是65岁以上老年人痴呆症的主要原因，今年美国的痴呆症患病率估计为520万。2010年，83494名美国人死于阿尔茨海默病，今年估计还会有7万人死于阿尔茨海默病，目前仍没有治愈方法。经验数据有力地表明，淀粉样蛋白(Aβ，Aβ)沉积和血脑屏障受损可能比疾病的临床表现早20多年。因此，在体内定量Aβ的方法被医学研究界作为早期检测的一种手段而积极研究。我们的长期目标是开发一种磁共振成像造影剂，用于在体内显示Aβ斑块。我们最近发现，荧光Aβ靶向脂质体穿过血脑屏障，并在APP/PSEN1鼠的大脑中积极标记Aβ病理。在第二代配方中，我们将类似的颗粒加载到Gd造影剂中，并获得了MRI数据，证实它们穿过了Tg2576小鼠的血脑屏障。然而，由于质子核磁共振成像中存在的背景信号，这种试剂的对比度噪声比不允许对图像进行明确的解释。19F MRI为解决这一问题提供了一种替代方案，因为软组织中没有内源性19F MRI可检测到的信号。目前的1H MRI硬件只需稍加改动即可用于19F MRI，19F是一种稳定的原子，具有100%的自然丰度，易于获得，无放射性，价格低廉。不幸的是，目前用于生物医学应用的几乎所有基于19F的试剂都使用全氟碳化合物(PFC)，这种化合物在水中的溶解度很低，不符合水核脂质体制剂的要求。我们设计并合成了两个具有这种能力的新型亲水氟化分子。在这项应用中，我们建议制备一种以β为靶向的脂质体配方，将其中一个分子作为19F对比有效载荷，并探索其作为一种工具的潜力，以非侵入性地定义和量化纵向累积 用19F MRI检测淀粉样斑块(使用5、7、9和12个月大的APP/PSEN1小鼠)。这项工作的完成将带来一个潜在的新型MRI平台，用于体内淀粉样斑块负荷的非侵入性检测和量化，并可能成为其他分子成像应用的造影剂。

 DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the leading cause of dementia in individuals over the age of 65 and the prevalence in the United States this year is estimated at 5.2 million. 83,494 Americans died from the disease in 2010 and an estimated 70,000 more will die from AD this year, and it remains without a cure. Empirical data strongly suggest that amyloid-β (Aβ) deposition and blood-brain barrier (BBB) compromise may precede clinical manifestation of the disease by over 20 years. Methods to quantify Aβ in vivo are therefore actively investigated by the medical research community as a means of early detection. Our long term goal is to develop a magnetic resonance imaging (MRI) contrast agent for visualization of Aβ plaques in vivo. We recently showed that fluorescent Aβ-targeted liposomes cross the BBB and avidly label Aβ pathologies in the brains of APP/PSEN1 mice. In a second generation formulation, we loaded similar particles with a gadolinium contrast agent and obtained MRI data which confirm that they cross the BBB of Tg2576 mice. However, the contrast-to-noise ratio of this agent does not allow unequivocal interpretation of images due to the background signal that exists in proton-based MRI. 19F MRI presents an alternative to address this problem because there is no endogenous 19F MRI detectable signal in soft tissue. Current 1H MRI hardware can be used for 19F MRI with little modification and 19F is a stable atom with 100% natural abundance, easily available, non-radioactive, and inexpensive. Unfortunately, almost all 19F-based agents currently under use for biomedical applications utilize perfluorocarbons (PFCs) which have low aqueous solubility and not amenable to aqueous core liposome formulations protocols. We have designed and synthesized two new hydrophilic fluorinated molecules with this capacity. In this application, we propose to prepare a Aβ-targeted liposome formulation bearing one of the molecules as a 19F contrast payload and explore its potential as a tool to define and quantify noninvasively, the longitudinal accumulation of amyloid plaques (using 5, 7, 9 and 12-month old APP/PSEN1 mice) by 19F MRI. Completion of this work will result in a potential novel MRI platform for noninvasive detection and quantification of amyloid plaque burden in vivo and a potential contrast agent to other molecular imaging applications.