In Vivo [¹⁸F]GE-179 Brain Signal Does Not Show NMDA-Specific Modulation with Drug Challenges in Rodents and Nonhuman Primates

Abstract

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.

Evaluation of the Novel PET Tracer [11C]HACH242 for Imaging the GluN2B NMDA Receptor in Non-Human Primates

“…Future attempts at visualising the GluN2B binding site of the NMDA receptor are preferably performed in awake primates or humans to exclude potential CBF effects of anaesthetics. Simultaneous [ 11 C]HACH242 PET and fMRI could elucidate the relationship between NMDA receptor blockers, blood flow and radiotracer binding [27].…”

“…In addition, GluN2Bselective antagonists can divide into two distinct classes according to binding pose, resulting in strikingly different ligand orientation and receptor interactions [31]. Taken together, there are various receptor interactions and biophysical factors that affect in vivo binding properties of NMDA receptor radioligands, which remain to be tested, for example using bolus-plus-infusion PET experiments in awake primates while monitoring hemodynamic changes [27].…”

Development of an automated, GMP compliant FASTlab™ radiosynthesis of [18F]GE‐179 for the clinical study of activated NMDA receptors

“…1 H NMR (400 MHz, CDCl 3 ) δ 7.23 (d, 1H), 6.96 (dm, 1H), 6.87 (t, 1H), 6.75 (dt, 1H), 6.01 (broad, s, 1H), and 2.48 (s, 3H). 13…”

“…Our group have previously reported the design and evaluation of [ 18 F] GE‐179 , which has been identified as a lead candidate to progress to clinical studies to assess its potential as a PET tracer for imaging activated NMDA receptors . The reported precursor synthesis and radiosynthesis were appropriate to support a biological screening program for the identification of the lead compound, however, the manufacture of a GMP quality product was required for clinical studies .…”

“…Our group have previously reported the design and evaluation of [ 18 F]GE-179, 9 which has been identified as a lead candidate to progress to clinical studies to assess its potential as a PET tracer for imaging activated NMDA receptors. [10][11][12][13][14] The reported precursor synthesis and radiosynthesis were appropriate to support a biological screening program for the identification of the lead compound, however, the manufacture of a GMP quality product was required for clinical studies. 15 The original radiosynthesis 9 was suitable for the preparation of [ 18 F]GE-179 for pre-clinical studies but was not suitable for delivering a GMP quality product for clinical studies with high starting radioactivity (up to 80 GBq).…”