Synthesis, characterization, and first successful monkey imaging studies of metabotropic glutamate receptor subtype 5 (mGluR5) PET radiotracers
Synthesis, characterization, and first successful monkey imaging studies of metabotropic glutamate receptor subtype 5 (mGluR5) PET radiotracers
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DOI：
10.1002/syn.20147
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发表时间：
2005-06-15
期刊：
影响因子：
2.3
通讯作者：
Burns, HD
中科院分区：
文献类型：
--
作者：
Hamill, TG;Krause, S;Burns, HD
三种代谢型谷氨酸受体亚型5（mGluR 5）PET示踪剂已被标记的碳-11或氟-18和其在恒河猴的体外和体内的行为进行了表征。这些示踪剂中的每一种都具有对mGluR 5的高亲和力（0.08-0.23 nM vs.大鼠mGluR 5）和中等亲脂性（log P 2.8-3.4）的共同特征。使用Suzuki或Stille偶联反应与[C-11]MeI合成化合物1b。化合物2b和3b通过使用3-氯苯甲腈前体的SNAr反应合成。使用2b和3b对恒河猴脑切片进行的放射自显影研究显示，皮质、尾状核、壳核、杏仁核、海马、大多数丘脑核中存在特异性结合，而小脑中的结合较低。对猴子的PET成像研究表明，所有三种示踪剂都很容易进入大脑，并在所有灰质区域（包括小脑）提供mGluR 5特异性信号。放射自显影研究和饱和结合实验证实了在小脑中观察到的特异性信号，这些实验表明示踪剂在恒河猴小脑中结合。使用未标记化合物进行的体外代谢研究表明，1a、2a和3a在人肝微粒体中的代谢速度比在猴肝微粒体中慢。体内代谢研究表明，3b在恒河猴血浆中的寿命较长，仅观察到另一种极性更强的代谢物。(c)2005 Wiley-Liss，Inc.
Three metabotropic glutamate receptor subtype 5 (mGluR5) PET tracers have been labeled with either carbon-11 or fluorine-18 and their in vitro and in vivo behavior in rhesus monkey has been characterized. Each of these tracers share the common features of high affinity for mGluR5 (0.08-0.23 nM vs. rat mGluR5) and moderate lipophilicity (log P 2.8-3.4). Compound 1b was synthesized using a Suzuki or Stille coupling reaction with [C-11]MeI. Compounds 2b and 3b were synthesized by a SNAr reaction using a 3-chlorobenzonitrile precursor. Autoradiographic studies in rhesus monkey brain slices using 2b and 3b showed specific binding in cortex, caudate, putamen, amygdala, hippocampus, most thalamic nuclei, and lower binding in the cerebellum. PET imaging studies in monkey showed that all three tracers readily enter the brain and provide an mGluR5-specific signal in all gray matter regions, including the cerebellum. The specific signal observed in the cerebellum was confirmed by the autoradiographic studies and saturation binding experiments that showed tracer binding in the cerebellum of rhesus monkeys. In vitro metabolism studies using the unlabeled compounds showed that 1a, 2a, and 3a are metabolized slower by human liver microsomes than by monkey liver microsomes. In vivo metabolism studies showed 3b to be long-lived in rhesus plasma with only one other more polar metabolite observed. (c) 2005 Wiley-Liss, Inc.