Liu Jianrong, Maisonial-Besset Aurélie, Wenzel Barbara, Canitrot Damien, Baufond Ariane, Chezal Jean-Michel, Brust Peter, Moreau Emmanuel
Univ. Clermont Auvergne, INSERM, UMR 1240, IMOST, F-63005 Clermont-Ferrand, France.
Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Dept. of Neuroradiopharmaceuticals, Permoserstrasse 15, 04318 Leipzig, Germany.
Eur J Med Chem. 2017 Aug 18;136:548-560. doi: 10.1016/j.ejmech.2017.03.091. Epub 2017 Apr 19.
The increasing incidence of Alzheimer's disease (AD) worldwide is a major public health problem. Current treatments provide only palliative solutions with significant side effects. Therefore, new efficient treatment options and novel early diagnosis tools are urgently needed. Recently, strong pre-clinical evidences suggested that phosphodiesterase 5 (PDE5) may be clinically relevant both as biomarker and drug-target in AD. In this study, we intended to develop a new radiofluorinated tracer for the visualisation of PDE5 in brain using PET imaging. Based on currently known PDE5 inhibitors, a series of novel fluorinated compounds bearing a quinoline core have been synthesised via multi-steps reaction pathways. Their affinity for PDE5 and selectivity over other PDE families have been investigated. According to the data collected from this in vitro screening, fluorinated derivatives 24a, b bearing a fluoroethoxy group at the C-3 position of the quinoline core appeared to be the most promising structures and will be further radiolabelled with fluorine-18 for in vitro and in vivo evaluations as PET radiotracer for neuroimaging of PDE5.
全球范围内阿尔茨海默病（AD）发病率的不断上升是一个重大的公共卫生问题。目前的治疗方法仅提供具有显著副作用的姑息性解决方案。因此，迫切需要新的有效治疗方案和新颖的早期诊断工具。最近，有力的临床前证据表明，磷酸二酯酶5（PDE5）在AD中作为生物标志物和药物靶点可能都具有临床相关性。在本研究中，我们旨在开发一种新的放射性氟化示踪剂，用于通过正电子发射断层扫描（PET）成像在大脑中可视化PDE5。基于目前已知的PDE5抑制剂，通过多步反应途径合成了一系列带有喹啉核心的新型氟化化合物。研究了它们对PDE5的亲和力以及对其他PDE家族的选择性。根据从该体外筛选收集的数据，在喹啉核心的C-3位带有氟乙氧基的氟化衍生物24a、b似乎是最有前景的结构，将进一步用氟-18进行放射性标记，以作为用于PDE5神经成像的PET放射性示踪剂进行体外和体内评估。
