Kil Kun-Eek, Zhu Aijun, Zhang Zhaoda, Choi Ji-Kyung, Kura Sreekanth, Gong Chunyu, Brownell Anna-Liisa
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital , Charlestown, Massachusetts 02129, United States.
ACS Med Chem Lett. 2014 Apr 6;5(6):652-6. doi: 10.1021/ml500007z. eCollection 2014 Jun 12.
mGlu5 play an important role in physiology and pathology to various central nervous system (CNS) diseases. Several positron emission tomography (PET) radiotracers have been developed to explore the role of mGlu5 in brain disorders. However, there are no single photon emission computed tomography (SPECT) radioligands for mGlu5. Here we report development of [(123)I]IPEB ([(123)I]1) and [(123)I]IMPEB ([(123)I]2) as mGlu5 radioligands for SPECT. [(123)I]1 and [(123)I]2 were produced by copper(I) mediated aromatic halide displacement reactions. The SPECT imaging using mouse models demonstrated that [(123)I]1 readily entered the brain and accumulated specifically in mGlu5-rich regions of the brain such as striatum and hippocampus. However, in comparison to the corresponding PET tracer [(18)F]FPEB, [(123)I]1 showed faster washout from the brain. The binding ratios of the striatum and the hippocampus compared to the cerebellum for [(123)I]1 and [(18)F]FPEB were similar despite unfavorable pharmacokinetics of [(123)I]1. Further structural optimization of 1 may lead to more viable SPECT radiotracers for the imaging of mGlu5.
代谢型谷氨酸受体5（mGlu5）在各种中枢神经系统（CNS）疾病的生理和病理过程中发挥着重要作用。已经开发了几种正电子发射断层扫描（PET）放射性示踪剂来探索mGlu5在脑部疾病中的作用。然而，目前尚无用于mGlu5的单光子发射计算机断层扫描（SPECT）放射性配体。在此，我们报告了作为用于SPECT的mGlu5放射性配体的[（123）I]IPEB（[（123）I]1）和[（123）I]IMPEB（[（123）I]2）的研发情况。[（123）I]1和[（123）I]2是通过铜（I）介导的芳基卤化物取代反应制备的。使用小鼠模型进行的SPECT成像表明，[（123）I]1很容易进入大脑，并特异性地聚集在大脑中富含mGlu5的区域，如纹状体和海马体。然而，与相应的PET示踪剂[（18）F]FPEB相比，[（123）I]1从大脑中的洗脱速度更快。尽管[（123）I]1的药代动力学不理想，但[（123）I]1和[（18）F]FPEB的纹状体和海马体与小脑的结合率相似。对1进行进一步的结构优化可能会产生更可行的用于mGlu5成像的SPECT放射性示踪剂。
