Synthesis and evaluation of N-(methylthiophenyl)picolinamide derivatives as PET radioligands for metabotropic glutamate receptor subtype 4.
Synthesis and evaluation of N-(methylthiophenyl)picolinamide derivatives as PET radioligands for metabotropic glutamate receptor subtype 4.
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N-(甲硫基苯基)吡啶酰胺衍生物作为代谢型谷氨酸受体亚型 4 的 PET 放射性配体的合成和评价。
DOI：
10.1016/j.bmcl.2015.11.015
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发表时间：
2016
影响因子：
2.7
通讯作者：
Brownell,Anna-Liisa
中科院分区：
文献类型：
--
作者：
Kil,Kun-Eek;Poutiainen,Pekka;Zhang,Zhaoda;Zhu,Aijun;Kuruppu,Darshini;Prabhakar,Shilpa;Choi,Ji-Kyung;Tannous,BakhosA;Brownell,Anna-Liisa
近年来，由于mglu4激活在治疗多种脑部疾病（如帕金森病（PD））中的潜在益处，mglu4受到了广泛的研究关注。一个特定的mGlu4PET放射配体可能是了解mglu4在健康和疾病状况中的作用以及开发新药的重要工具。在这项研究中，我们合成了四个新的wn -（甲基噻吩基）吡啶酰胺衍生物11 - 14。其中，11和14对mglu4具有较高的体外结合亲和力，ic50值分别为3.4 nM和3.1 nM，且具有合适的理化参数。化合物11对其他mGluRs也表现出较好的代谢稳定性和选择性。[11C]11和[11C]14用[11C]CH3I对噻吩前体20和20c进行[11C]甲基化，放射化学产率分别为19.0%和34.8%，合成末比活性分别为496±138 GBq/μmol （n= 6）和463±263 GBq/μmol （n= 4）。PET研究表明，[11C]11在脑内积累快，摄取高，洗脱慢，对比度比[11C]2好25%，表明与[11C]2相比，mglu4作为PET示踪剂的成像特性有所改善。因此，[11C]11将成为研究mglu4在不同生物学应用中的一个有用的放射性配体。
In recent years, mGlu4has received great research attention because of the potential benefits of mGlu4activation in treating numerous brain disorders, such as Parkinson’s disease (PD). A specific mGlu4PET radioligand could be an important tool in understanding the role of mGlu4in both healthy and disease conditions, and also for the development of new drugs. In this study, we synthesized four newN-(methylthiophenyl)picolinamide derivatives11–14. Of these ligands,11and14showed high in vitro binding affinity for mGlu4with IC50values of 3.4 nM and 3.1 nM, respectively, and suitable physicochemical parameters. Compound11also showed enhanced metabolic stability and good selectivity to other mGluRs. [11C]11and [11C]14were radiolabeled using the [11C]methylation of the thiophenol precursors20aand20cwith [11C]CH3I in 19.0% and 34.8% radiochemical yields (RCY), and their specific activities at the end of synthesis (EOS) were 496 ± 138 GBq/μmol (n= 6) and 463 ± 263 GBq/μmol (n= 4), respectively. The PET studies showed that [11C]11accumulated fast into the brain and had higher uptake, slower washout and 25% better contrast than [11C]2, indicating improved imaging characteristics as PET radiotracer for mGlu4compared to [11C]2. Therefore, [11C]11will be a useful radioligand to investigate mGlu4in different biological applications.