In vivo [18F]GE-179 brain signal does not show NMDA-specific modulation with drug challenges in rodents and non-human primates

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 non-human primates 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 drug/dose followed by a single bolus of [18F]GE-179. Binding competition with GE-179, MK801, PCP and ketamine, allosteric inhibition by ifenprodil as well as brain activation with methamphetamine did not alter the [18F]GE-179 brain signal in rats. In addition, multimodal imaging with PET/MRI in non-human primates (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. 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 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 based on the results shown in this study.

Publication year:2018

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BOF-publication weight:2

CSS-citation score:2

Authors:International

Authors from:Higher Education

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