Institute of Pharmaceutical Sciences, ETH Zürich, 8093, Zürich, Switzerland.
Neuromuscular Diseases Unit/ALS Clinic, Kantonsspital St. Gallen, 9007, St. Gallen, Switzerland.
Eur J Med Chem. 2015 Mar 6;92:554-64. doi: 10.1016/j.ejmech.2015.01.028. Epub 2015 Jan 13.
Our goal is to develop a highly specific and selective PET brain tracer for imaging CB2 expression in patients with neuroinflammatory diseases. Based on our previous findings on a carbon-11 labeled 4-oxo-quinoline structure, designated KD2, further structural optimizations were performed, which led to the discovery of N-(1-adamantyl)-1-(2-ethoxyethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxamide (RS-016). Compared to KD2, RS-016 exhibits a higher binding affinity towards CB2 (Ki = 0.7 nM) with a selectivity over CB1 of >10,000 and lower lipophilicity (logD7.4 = 2.78). [(11)C]RS-016 was obtained in ≥99% radiochemical purity and up to 850GBq/μmol specific radioactivity at the end of synthesis. In vitro autoradiography on rodent spleen tissue showed high specific binding to CB2. [(11)C]RS-016 was stable in vitro in rodent and human plasma over 40 min, whereas 47% intact compound was found in vivo in rat blood plasma 20 min post injection (p.i.). High specific binding to CB2 was observed in murine spleen tissues and postmortem ALS patient spinal cord tissues in vitro autoradiography, ex vivo biodistribution data confirmed the high and specific uptake of [(11)C]RS-016 in spleen region in rats. In vivo specificity of [(11)C]RS-016 could also be shown in brain by PET imaging using a murine neuroinflammation model, which has higher CB2 receptor expression level in the brain induced by lipopolysaccharide (LPS) application.
我们的目标是开发一种高特异性和选择性的 PET 脑示踪剂，用于成像神经炎症性疾病患者的 CB2 表达。基于我们之前对一种碳-11 标记的 4-氧代喹啉结构（命名为 KD2）的研究结果，我们进行了进一步的结构优化，发现了 N-(1-金刚烷基）-1-(2-乙氧基乙基）-8-甲氧基-4-氧代-1,4-二氢喹啉-3-甲酰胺（RS-016）。与 KD2 相比，RS-016 对 CB2 的结合亲和力更高（Ki=0.7 nM），对 CB1 的选择性大于 10,000，亲脂性更低（logD7.4=2.78）。[（11）C]RS-016 在合成结束时以≥99%的放射性化学纯度和高达 850GBq/μmol 的比放射性获得。在啮齿动物脾脏组织的体外放射自显影中，观察到对 CB2 的高特异性结合。[（11）C]RS-016 在啮齿动物和人血浆中在 40 分钟内稳定，而在注射后 20 分钟的大鼠血浆中发现 47%的完整化合物。在体外放射自显影中，在鼠脾脏组织和尸检 ALS 患者脊髓组织中观察到对 CB2 的高特异性结合，在大鼠中，外显分布数据证实了[（11）C]RS-016 在脾脏区域的高特异性摄取。在 LPS 应用诱导脑内 CB2 受体表达水平较高的小鼠神经炎症模型中，也可以通过 PET 成像显示[（11）C]RS-016 的体内特异性。
