Synthesis and evaluation of N-(methylthiophenyl)picolinamide derivatives as PET radioligands for metabotropic glutamate receptor subtype 4

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• 作者：Kun-Eek Kil^a ; Pekka Poutiainen^a ; Zhaoda Zhang^a ; Aijun Zhu^a ; Darshini Kuruppu^b ; Shilpa Prabhakar^c ; Ji-Kyung Choi^a ; Bakhos A. Tannous^c ; Anna-Liisa Brownell^a ; ^{abrownell@mgh.harvard.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：PET ; Metabotropic glutamate receptor subtype 4 (mGlu4) ; Positive allosteric modulator (PAM)
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 January 2016
• 年：2016
• 卷：26
• 期：1
• 页码：133-139
• 全文大小：2001 K

文摘

In recent years, mGlu₄ has received great research attention because of the potential benefits of mGlu₄ activation in treating numerous brain disorders, such as Parkinson’s disease (PD). A specific mGlu₄ PET radioligand could be an important tool in understanding the role of mGlu₄ in both healthy and disease conditions, and also for the development of new drugs. In this study, we synthesized four new N-(methylthiophenyl)picolinamide derivatives class="boldFont">11–class="boldFont">14. Of these ligands, class="boldFont">11 and class="boldFont">14 showed high in vitro binding affinity for mGlu₄ with IC₅₀ values of 3.4 nM and 3.1 nM, respectively, and suitable physicochemical parameters. Compound class="boldFont">11 also showed enhanced metabolic stability and good selectivity to other mGluRs. [¹¹C]class="boldFont">11 and [¹¹C]class="boldFont">14 were radiolabeled using the [¹¹C]methylation of the thiophenol precursors class="boldFont">20a and class="boldFont">20c with [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]class="boldFont">11 accumulated fast into the brain and had higher uptake, slower washout and 25% better contrast than [¹¹C]class="boldFont">2, indicating improved imaging characteristics as PET radiotracer for mGlu₄ compared to [¹¹C]class="boldFont">2. Therefore, [¹¹C]class="boldFont">11 will be a useful radioligand to investigate mGlu₄ in different biological applications.