Oi Norihito, Tokunaga Masaki, Suzuki Michiyuki, Nagai Yuji, Nakatani Yosuke, Yamamoto Noboru, Maeda Jun, Minamimoto Takafumi, Zhang Ming-Rong, Suhara Tetsuya, Higuchi Makoto
Tsukuba Research Laboratories, Eisai Co., Ltd. , 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
Molecular Imaging Center, National Institute of Radiological Sciences , 4-9-1 Anagawa, Inage-ku, Chiba, Chiba 263-8555, Japan.
J Med Chem. 2015 Nov 12;58(21):8444-62. doi: 10.1021/acs.jmedchem.5b00712. Epub 2015 Nov 2.
We document the development of PET probes for central AMPA receptors and their application to in vivo animal imaging. An initial screening of perampanel derivatives was performed to identify probe candidates. Despite the high autoradiographic contrast yielded by several radioligands, rat PET scans did not support their in vivo suitability. Further focused derivatization and a second screening by ex vivo LC-MS measurements led to the selection of 2-[1-(3-methylaminophenyl)-2-oxo-5-(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl]benzonitrile, 21a, and its analogues as candidates. [(11)C]21a was shown by autoradiography to specifically bind to the neocortex and hippocampus, consistent with AMPA receptor localization. PET imaging with [(11)C]21a demonstrated moderate uptake of radioactivity in rat and monkey brains, with the retention of radiosignals being consistent with that from the autoradiogram data, and the uptake was blocked by pretreatment with unlabeled 21a in a dose-dependent manner. The current approach has facilitated the discovery of a PET probe potentially suitable for translational research and development focused on AMPA receptors.
我们记录了用于中枢α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体的正电子发射断层扫描（PET）探针的研发及其在体内动物成像中的应用。对吡仑帕奈衍生物进行了初步筛选以确定候选探针。尽管几种放射性配体产生了高放射自显影对比度，但大鼠PET扫描并不支持它们在体内的适用性。进一步的聚焦衍生化以及通过体外液相色谱-质谱（LC-MS）测量进行的第二次筛选导致选择了2-[1-(3-甲氨基苯基)-2-氧代-5-(嘧啶-2-基)-1,2-二氢吡啶-3-基]苄腈（21a）及其类似物作为候选物。放射自显影显示[(11)C]21a特异性结合到新皮质和海马体，这与AMPA受体的定位一致。用[(11)C]21a进行的PET成像显示大鼠和猴脑中放射性有适度摄取，放射性信号的保留与放射自显影数据一致，并且摄取被未标记的21a预处理以剂量依赖方式阻断。当前方法促进了一种可能适用于专注于AMPA受体的转化研究和开发的PET探针的发现。
