Leung Kam
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD
Alzheimer's disease (AD) is a form of dementia with a gradual memory loss and a progressive decline in mental functions overtime (1, 2). It is characterized pathologically by neuronal loss, extracellular senile plaques (aggregates of amyloid-beta peptides consisting of 40 to 42 amino acids) and intracellular neurofibrillary tangles (filaments of microtubule-binding hyper-phosphorylated protein tau) in the brain, especially in the hippocampus and associative regions of the cortex (3, 4). β-amyloid peptides and tau protein are implicated as the main causes of neuronal degeneration and cell death (5, 6). Early diagnosis of AD is important for treatment consideration and disease management (7). Various β-amyloid imaging agents have been developed for magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), and positron emission tomography (PET) (8-13). The binding of different derivatives of Congo red, thioflavin, stibene, and aminonaphthalene has been studied in human post-mortem brain tissue and in transgenic mice. Out of these analogues, 2-(1-(6-[(2-[F]fluoroethyl)(methyl)amino]-2-naphthyl)ethylidene)malono nitrile ([F]FDDNP) was studied in humans, showing more binding in the brains of patients with AD than in those of healthy people (14). However, [F]FDDNP showed low signal-to-noise ratios for PET imaging, because it is highly lipophilic. -methyl-[C]-2-(4’-methylaminophenyl)-6-hydroxybenzothiasole, a β-amyloid binding compound based on a series of neutral thioflavin-T derivatives (15), was radiolabeled with the positron-emitting radionuclide C ([C]6-OH-BTA-1 or [C]PIB). [C]6-OH-BTA-1 was found to be a promising imaging agent for the senile plaques in the brain (16). Zhang et al. (17) reported the development of a series of fluorinated polyethylene glycol (PEG) units (n = 2-5) for PET imaging of β-amyloid plaques in the brain. Two of them, [F]{4-[2-(4-{2-(2[2-(2-Fluoro-ethoxy)-ethoxyl]-ethoxy}-phenyl)-vinyl]-phenyl}-methyl-amine ([F]BAY94-9172, [F]AV-1) (18) and ()-4-(2-(6-(2-(2-(2-([F]-fluoroethoxy)ethoxy)ethoxy)pyridin-3-yl)vinyl)--methyl benzenamine ([F]AV-45) (19), are being evaluated in clinical trials.
阿尔茨海默病（AD）是一种痴呆症，会逐渐出现记忆力丧失，且随着时间推移心理功能会逐渐衰退（1, 2）。其病理特征为大脑中神经元丧失、细胞外老年斑（由40至42个氨基酸组成的β-淀粉样肽聚集体）和细胞内神经原纤维缠结（微管结合的高度磷酸化tau蛋白细丝），尤其是在海马体和皮质联合区域（3, 4）。β-淀粉样肽和tau蛋白被认为是神经元变性和细胞死亡的主要原因（5, 6）。AD的早期诊断对于治疗考量和疾病管理很重要（7）。已开发出多种用于磁共振成像（MRI）、单光子发射计算机断层扫描（SPECT）和正电子发射断层扫描（PET）的β-淀粉样蛋白成像剂（8 - 13）。已在人类尸检脑组织和转基因小鼠中研究了刚果红、硫黄素、芪和氨基萘的不同衍生物的结合情况。在这些类似物中，2-(1-(6-[(2-[F]氟乙基)(甲基)氨基]-2-萘基)亚乙基)丙二腈（[F]FDDNP）已在人体中进行研究，结果显示其在AD患者大脑中的结合比健康人更多（14）。然而，[F]FDDNP在PET成像中显示出低信噪比，因为它具有高度亲脂性。基于一系列中性硫黄素-T衍生物的β-淀粉样蛋白结合化合物 -甲基-[C]-2-(4’-甲基氨基苯基)-6-羟基苯并噻唑，用发射正电子的放射性核素C进行放射性标记（[C]6-OH-BTA-1或[C]PIB）。已发现[C]6-OH-BTA-1是一种用于大脑中老年斑的有前景的成像剂（16）。张等人（17）报道了一系列用于大脑β-淀粉样斑PET成像的氟化聚乙二醇（PEG）单元（n = 2 - 5）的开发。其中两种，[F]{4-[2-(4-{2-(2[2-(2-氟乙氧基)-乙氧基]-乙氧基}-苯基)-乙烯基]-苯基}-甲胺（[F]BAY94-9172，[F]AV-1）（18）和（）-4-(2-(6-(2-(2-(2-([F]-氟乙氧基)乙氧基)乙氧基)吡啶-3-基)乙烯基)--甲基苯甲胺（[F]AV-45）（19），正在临床试验中进行评估。
