A new positron emission tomography (PET) tracer may aid in the study of various neurologic diseases, including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis (MS). The radiopharmaceutical is suitable for in vivo imaging of N-methyl-D-aspartate (NMDA) GluN1/GluN2B receptors, Swiss and German researchers have found. They published their findings in The Journal of Nuclear Medicine.
“The significance of the work lies in the fact that we have for the first time developed a useful PET radioligand that can be applied to image the GluN2B receptor subunit of the NMDA receptor complex in humans,” said co-investigator Simon M. Ametamey, PhD, Institute of Pharmaceutical Sciences, ETH Zurich, Switzerland.
“The availability of such a PET radioligand would not only help to better understand the role of NMDA receptors in the pathophysiology of the many brain diseases in which the NMDA receptor is implicated, but it would also help to select appropriate doses of clinically relevant GluN2B receptor candidate drugs. Administering the right dose of the drugs to patients will help minimize side effects and lead to improvement in the efficacy of the drugs,” he added.
Dr. Ametamey and colleagues have developed the new PET radioligand, 11C-Me-NB1, to image these receptors and examined whether this imaging agent can be used to investigate crosstalk involving the GluN1/GluN2B receptors in rats and to investigate the dose and effectiveness of eliprodil, which blocks the NMDA GluN2B receptor.
Use of PET scans with 11C-Me-NB1 showed that NMDA GluN1/GluN2B receptors are fully occupied at a 1 mg/kg dose of the GluN2B NTD modulator eliprodil, a dose reported to have neuroprotective effects. The new radioligand also enabled imaging of receptor crosstalk between Sigma-1 receptors, which modulate calcium signaling, and GluN2B-containing NMDA receptors.
Successful imaging of N-terminal domain (NTD) binding sites with the new PET tracer may eventually allow for noninvasive monitoring of the density of GluN2B/GluN1A receptors in neuronal diseases, as well as enable the study of receptor occupancy during therapeutic interventions, the investigators concluded.
“Our receptor-occupancy study suggests that the published neuroprotective effects of eliprodil in rats required complete occupancy of the NTD binding sites,” wrote these researchers. “11C-Me-NB1 PET is sensitive to drug-induced receptor cross talk.”
11C-Me-NB1 joins the list of existing PET radiopharmaceuticals used in imaging studies to investigate and understand underlying causes of these brain disorders.
Future imaging studies using 11C-Me-NB1 “would throw more light on the involvement of NMDA receptors, specifically the GluN2B receptors, in normal physiological processes such as learning and memory, as well as accelerate the development of GluN2B candidate drugs currently under development,” Dr. Ametamey concluded.
This work was supported by the Swiss National Science Foundation.