二苯并噻吩衍生物用于正电子发射断层扫描成像α7-烟碱型乙酰胆碱受体。

Derivatives of dibenzothiophene for positron emission tomography imaging of α7-nicotinic acetylcholine receptors.

机构信息

Russell H. Morgan Department of Radiology and Radiological Sciences, Division of Nuclear Medicine, The Johns Hopkins University School of Medicine , 600 North Wolfe Street, Baltimore, Maryland 21287-0816, United States.

出版信息

J Med Chem. 2013 Oct 10;56(19):7574-89. doi: 10.1021/jm401184f. Epub 2013 Sep 19.

A new series of derivatives of 3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)dibenzo[b,d]thiophene 5,5-dioxide with high binding affinities and selectivity for α7-nicotinic acetylcholine receptors (α7-nAChRs) (Ki = 0.4-20 nM) has been synthesized for positron emission tomography (PET) imaging of α7-nAChRs. Two radiolabeled members of the series [(18)F]7a (Ki = 0.4 nM) and [(18)F]7c (Ki = 1.3 nM) were synthesized. [(18)F]7a and [(18)F]7c readily entered the mouse brain and specifically labeled α7-nAChRs. The α7-nAChR selective ligand 1 (SSR180711) blocked the binding of [(18)F]7a in the mouse brain in a dose-dependent manner. The mouse blocking studies with non-α7-nAChR central nervous system drugs demonstrated that [(18)F]7a is highly α7-nAChR selective. In agreement with its binding affinity the binding potential of [(18)F]7a (BPND = 5.3-8.0) in control mice is superior to previous α7-nAChR PET radioligands. Thus, [(18)F]7a displays excellent imaging properties in mice and has been chosen for further evaluation as a potential PET radioligand for imaging of α7-nAChR in non-human primates.

已经合成了一系列具有高亲和力和选择性的 3-(1,4-二氮杂双环[3.2.2]壬烷-4-基)二苯并[b,d]噻吩 5,5-二氧化物衍生物，用于α7-烟碱型乙酰胆碱受体（α7-nAChRs）的正电子发射断层扫描（PET）成像。该系列中的两种放射性标记成员[18F]7a（Ki = 0.4 nM）和[18F]7c（Ki = 1.3 nM）已被合成。[18F]7a 和 [18F]7c 很容易进入小鼠大脑并特异性标记 α7-nAChRs。α7-nAChR 选择性配体 1（SSR180711）以剂量依赖性方式阻断[18F]7a 在小鼠大脑中的结合。用非-α7-nAChR 中枢神经系统药物进行的小鼠阻断研究表明，[18F]7a 具有高度的 α7-nAChR 选择性。与结合亲和力一致，[18F]7a 在对照小鼠中的结合潜能（BPND = 5.3-8.0）优于以前的 α7-nAChR PET 放射性配体。因此，[18F]7a 在小鼠中显示出优异的成像特性，已被选为进一步评估作为非人类灵长类动物中 α7-nAChR 成像的潜在 PET 放射性配体。