Korff Marvin, Chaudhary Ahmad, Li Yinlong, Zhou Xin, Zhao Chunyu, Rong Jian, Chen Jiahui, Xiao Zhiwei, Elghazawy Nehal H, Sippl Wolfgang, Davenport April T, Daunais James B, Wang Lu, Abate Carmen, Ahmed Hazem, Crowe Ron, Schmidt Thomas J, Liang Steven H, Ametamey Simon M, Wünsch Bernhard, Haider Achi
Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, Atlanta, Georgia 30322, United States.
Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Universität Münster, Corrensstraße 48, Münster D-48149, Germany.
J Med Chem. 2023 Dec 14;66(23):16018-16031. doi: 10.1021/acs.jmedchem.3c01441. Epub 2023 Nov 18.
GluN2B subunit-containing methyl-d-aspartate (NMDA) receptors have been implicated in various neurological disorders. Nonetheless, a validated fluorine-18 labeled positron emission tomography (PET) ligand for GluN2B imaging in the living human brain is currently lacking. The aim of this study was to develop a novel synthetic approach that allows an enantiomerically pure radiosynthesis of the previously reported PET radioligands ()[F]OF-NB1 and ()[F]OF-NB1 as well as to assess their and performance characteristics for imaging the GluN2B subunit-containing NMDA receptor in rodents. A novel synthetic approach was successfully developed, which allows for the enantiomerically pure radiosynthesis of ()[F]OF-NB1 and ()[F]OF-NB1 and the translation of the probe to the clinic. While both enantiomers were selective over sigma2 receptors and , ()[F]OF-NB1 showed superior GluN2B subunit specificity by autoradiography and higher volumes of distribution in the rodent brain by small animal PET studies.
含GluN2B亚基的N-甲基-D-天冬氨酸（NMDA）受体与多种神经疾病有关。然而，目前尚缺乏一种经验证的用于在活体人脑中进行GluN2B成像的氟-18标记正电子发射断层扫描（PET）配体。本研究的目的是开发一种新颖的合成方法，以实现对先前报道的PET放射性配体（）[F]OF-NB1和（）[F]OF-NB1进行对映体纯的放射性合成，并评估它们在啮齿动物中对含GluN2B亚基的NMDA受体成像的亲和力和性能特征。成功开发了一种新颖的合成方法，该方法能够实现（）[F]OF-NB1和（）[F]OF-NB1的对映体纯放射性合成，并将该探针推进到临床阶段。虽然两种对映体对σ2受体均具有选择性，且（）[F]OF-NB1通过放射自显影显示出对GluN2B亚基具有更高的特异性，并且通过小动物PET研究发现在啮齿动物脑中具有更高的分布容积。
