Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Eur J Nucl Med Mol Imaging. 2013 Apr;40(4):580-93. doi: 10.1007/s00259-012-2322-6. Epub 2013 Jan 17.
The aim of this study was to evaluate AZD2995 side by side with AZD2184 as novel PET radioligands for imaging of amyloid-β in Alzheimer's disease (AD).
In vitro binding of tritium-labelled AZD2995 and AZD2184 was studied and compared with that of the established amyloid-β PET radioligand PIB. Subsequently, a first-in-human in vivo PET study was performed using [(11)C]AZD2995 and [(11)C]AZD2184 in three healthy control subjects and seven AD patients.
AZD2995, AZD2184 and PIB were found to share the same binding site to amyloid-β. [(3)H]AZD2995 had the highest signal-to-background ratio in brain tissue from patients with AD as well as in transgenic mice. However, [(11)C]AZD2184 had superior imaging properties in PET, as shown by larger effect sizes comparing binding potential values in cortical regions of AD patients and healthy controls. Nevertheless, probably due to a lower amount of nonspecific binding, the group separation of the distribution volume ratio values of [(11)C]AZD2995 was greater in areas with lower amyloid-β load, e.g. the hippocampus.
Both AZD2995 and AZD2184 detect amyloid-β with high affinity and specificity and also display a lower degree of nonspecific binding than that reported for PIB. Overall [(11)C]AZD2184 seems to be an amyloid-β radioligand with higher uptake and better group separation when compared to [(11)C]AZD2995. However, the very low nonspecific binding of [(11)C]AZD2995 makes this radioligand potentially interesting as a tool to study minute levels of amyloid-β. This sensitivity may be important in investigating, for example, early prodromal stages of AD or in the longitudinal study of a disease modifying therapy.
本研究旨在评估 AZD2995 和 AZD2184 作为新型 PET 放射性配体在阿尔茨海默病（AD）中淀粉样蛋白-β成像的作用。
研究并比较了氚标记的 AZD2995 和 AZD2184 的体外结合情况，并与已建立的淀粉样蛋白-β PET 放射性配体 PIB 进行了比较。随后，在 3 名健康对照者和 7 名 AD 患者中进行了首次人体体内 PET 研究，使用 [(11)C]AZD2995 和 [(11)C]AZD2184。
AZD2995、AZD2184 和 PIB 被发现与淀粉样蛋白-β具有相同的结合部位。[(3)H]AZD2995 在 AD 患者和转基因小鼠的脑组织中具有最高的信号背景比。然而，[(11)C]AZD2184 在 PET 中具有更好的成像特性，表现在 AD 患者和健康对照者皮质区域的结合潜力值的效应大小较大。尽管如此，可能由于非特异性结合量较低，[(11)C]AZD2995 的分布容积比值的组间分离在淀粉样蛋白-β负荷较低的区域（如海马体）更大。
AZD2995 和 AZD2184 均以高亲和力和特异性检测淀粉样蛋白-β，并且与 PIB 报道的相比，显示出较低程度的非特异性结合。总体而言，与 [(11)C]AZD2995 相比，[(11)C]AZD2184 似乎是一种具有更高摄取率和更好组间分离的淀粉样蛋白-β放射性配体。然而，[(11)C]AZD2995 的非常低的非特异性结合使其成为一种研究淀粉样蛋白-β微量水平的潜在工具。这种敏感性在研究 AD 的早期前驱期或疾病修饰治疗的纵向研究中可能很重要。
