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 [¹⁸F]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 [¹⁸F]GE-179 in rodents and nonhuman primates (NHPs) is presented in an attempt to characterize [¹⁸F]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 [¹⁸F]GE-179. Binding competition with GE-179, MK801, PCP, and ketamine, allosteric inhibition by ifenprodil, and brain activation with methamphetamine did not alter the [¹⁸F]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 [¹⁸F]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 [¹⁸F]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.

中文翻译：

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体内[ ¹⁸ F] GE-179脑信号在啮齿动物和非人类灵长类动物中未显示具有药物挑战的NMDA特异性调节。

NMDA受体作为大脑中主要的兴奋性离子通道之一，几十年来一直是神经科学家，医师，药物化学家和制药公司的主要研究目标。借助[ ¹⁸ F] GE-179的正电子发射断层扫描（PET）对NMDA受体进行分子成像的研究迅速发展为临床PET研究，但是对其结合特异性的透彻了解已经缺失，因此限制了信号解释。在这里，我们进行了一项针对[ ¹⁸ F] GE-179在啮齿动物和非人类灵长类动物（NHPs）中的临床前研究，以试图表征[ ¹⁸F] GE-179信号特异性。通过用NMDA靶向阻断/调节药物剂量预处理动物，然后单次推注[ ¹⁸ F] GE-179，将啮齿类动物PET / CT用于研究大鼠中的药物占用和功能操纵。与GE-179，MK801，PCP和氯胺酮的结合竞争，艾芬地尔的变构抑制作用以及甲基苯丙胺的脑激活并未改变大鼠的[ ¹⁸ F] GE-179脑信号。此外，在NHP中使用PET / MRI进行多峰成像，以评估放射性示踪剂结合的变化与药理学挑战的关系。使用功能性MRI（fMRI）同时监测药物引起的血液动力学变化。比较NHP中药物攻击后的基线和信号，发现[ ¹⁸在体内无法以可预测的方式操纵F] GE-179信号。与PET数据同时采集的fMRI数据支持了这一发现，并提供了血流变化不会改变放射性示踪剂传递的证据。总之，根据本研究显示的结果，在NMDA受体结合的情况下[ ¹⁸ F] GE-179脑信号不容易解释。