Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital , Charlestown, Massachusetts 02129, United States.
Chemical Biology and Imaging, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven , BE-3000 Leuven, Belgium.
ACS Chem Neurosci. 2018 Feb 21;9(2):298-305. doi: 10.1021/acschemneuro.7b00327. Epub 2017 Nov 14.
As one of the major excitatory ion channels in the brain, NMDA receptors have been a leading research target for neuroscientists, physicians, medicinal chemists, and pharmaceutical companies for decades. Molecular imaging of NMDA receptors by means of positron emission tomography (PET) with [F]GE-179 quickly progressed to clinical PET studies, but a thorough understanding of its binding specificity has been missing and has thus limited signal interpretation. Here a preclinical study with [F]GE-179 in rodents and nonhuman primates (NHPs) is presented in an attempt to characterize [F]GE-179 signal specificity. Rodent PET/CT was used to study drug occupancy and functional manipulation in rats by pretreating animals with NMDA targeted blocking/modulating drug doses followed by a single bolus of [F]GE-179. Binding competition with GE-179, MK801, PCP, and ketamine, allosteric inhibition by ifenprodil, and brain activation with methamphetamine did not alter the [F]GE-179 brain signal in rats. In addition, multimodal imaging with PET/MRI in NHPs was used to evaluate changes in radiotracer binding as a function of pharmacological challenges. Drug-induced hemodynamic changes were monitored simultaneously using functional MRI (fMRI). Comparisons of baseline and signal after drug challenge in NHPs demonstrated that the [F]GE-179 signal cannot be manipulated in a predictable fashion in vivo. fMRI data acquired simultaneously with PET data supported this finding and provided evidence that radiotracer delivery is not altered by blood flow changes. In conclusion, the [F]GE-179 brain signal is not readily interpretable in the context of NMDA receptor binding on the basis of the results shown in this study.
作为大脑中主要的兴奋性离子通道之一，NMDA 受体已成为神经科学家、医生、药物化学家以及制药公司数十年来的主要研究目标。正电子发射断层扫描（PET）用 [F]GE-179 对 NMDA 受体进行分子成像迅速发展为临床 PET 研究，但对其结合特异性的全面了解一直缺失，从而限制了信号解释。本研究通过在啮齿动物和非人类灵长类动物（NHP）中进行 [F]GE-179 的临床前研究，试图对 [F]GE-179 信号特异性进行描述。通过用 NMDA 靶向阻滞/调节药物剂量预处理动物，然后单次推注 [F]GE-179，进行了啮齿动物 PET/CT 研究，以研究药物占有率和功能操作。用 GE-179、MK801、PCP 和氯胺酮进行结合竞争，用ifenprodil 进行变构抑制，以及用 methamphetamine 进行脑激活，均未改变大鼠中 [F]GE-179 的脑信号。此外，使用 PET/MRI 在 NHP 中进行多模态成像，以评估放射性示踪剂结合作为药理学挑战的函数而发生的变化。使用功能磁共振成像（fMRI）同时监测药物诱导的血液动力学变化。与基线相比，在 NHP 中进行药物挑战后的信号比较表明，[F]GE-179 信号不能以可预测的方式在体内进行操作。与 PET 数据同时采集的 fMRI 数据支持这一发现，并提供了放射性示踪剂输送没有因血流变化而改变的证据。总之，根据本研究的结果，[F]GE-179 脑信号在 NMDA 受体结合的背景下不易解释。
