Toward a Small-Molecule Antagonist Radioligand for Positron Emission Tomography Imaging of the Mu Opioid Receptor

The opioid crisis is a catastrophic health emergency catalyzed by the misuse of opioids that target and activate the mu opioid receptor. Many traditional radioligands used to study the mu opioid receptor are often tightly regulated owing to their abuse and respiratory depression potential. Of those that are not regulated, a lack of opioid receptor subtype selectivity can cause confounding in interpreting results. In the present study, we sought to design and characterize a library of 24 antagonist ligands for the mu opioid receptor. Ligands were evaluated for the binding affinity, intrinsic activity, and predicted blood-brain barrier permeability. Several ligands demonstrated single-digit nM binding affinity for the mu opioid receptor while also demonstrating selectivity over the delta and kappa opioid receptors. The antagonist behavior of <b>1A</b> and <b>3A</b> at the mu opioid receptor indicate that these ligands would likely not induce opioid-dependent respiratory depression. Therefore, these ligands can enable a safer means to interrogate the endogenous opioid system. Based on binding affinity, selectivity, and potential off-target binding, [¹¹C]<b>1A</b> was prepared via metallophotoredox of the aryl-bromide functional group to [¹¹C]methyl iodide. The nascent radioligand demonstrated brain uptake in a rhesus macaque model and accumulation in the caudate and putamen. Naloxone was able to reduce [¹¹C]<b>1A</b> binding, though the interactions were not as pronounced as naloxone's ability to displace [¹¹C]carfentanil. These results suggest that GSK1521498 and related congeners are amenable to radioligand design and can offer a safer way to query opioid neurobiology.