Brain and Whole-Body Imaging of Nociceptin/Orphanin FQ Peptide Receptor in Humans Using the PET Ligand 11C-NOP-1A

The nociceptin/orphanin FQ peptide (NOP) receptor was cloned as an orphan receptor with no known endogenous transmitter (1). Subsequently, NOP itself was discovered as a 17-amino-acid peptide with sequence similarities to endogenous opioid peptide dynorphin A (2). The NOP receptor is coupled to the G-protein Gi/Go, inhibits the production of cyclic adenosine monophosphate, activates potassium channels, and inhibits calcium channels. Although the NOP receptor shares some amino acid sequence similarities with the classic opiate receptor, the mechanism of action of the NOP transmitter could not be blocked by the opioid antagonist naloxone; thus, the NOP receptor is considered a nonopiate member of the opioid receptor family (3). NOP receptors are widely distributed in brain, spinal cord, heart, lungs, kidneys, intestine, and immune cells of different mammalian species, where they mediate the actions of endogenous peptides in a complex manner. For example, animal studies suggest that NOP receptor activation in the periphery reduces pain perception, but similar activation in the brain increases pain perception (3). In addition, NOP receptors may mediate both the consumption of alcohol and anxiety-related behaviors. Elevated NOP receptor messenger RNA levels, as well as increased 3H-nociceptin binding in central amygdala, were both noted in Marchigian Sardinian alcohol-preferring rats (4). NOP receptor agonists were also shown to have an anxiolytic effect across multiple species (5). As a result, investigators have focused on developing NOP receptor ligands for therapeutic trials in humans. PET radioligands would be useful for exploring the roles that NOP receptors may play in human health and disease where relevant animal models showed changes. In addition, an NOP receptor radioligand could help determine the therapeutic mechanisms of some opiates; buprenorphine, for example, is used to treat both pain and heroin dependence and may act on NOP and other opiate receptors (6). Finally, a PET radioligand for the NOP receptor would aid in the early evaluation of potential therapeutic NOP receptor agonists and antagonists. Such early studies could determine receptor occupancy and clarify required dose and dosing intervals, which are often critically important for the development of drugs that may have restricted access to brain because of the blood–brain barrier and efflux transporters. Our laboratory developed 11C-NOP-1A, which is to our knowledge the first successful radioligand to image NOP receptors in rat and monkey brain (7). 11C-NOP-1A is a selective antagonist at the NOP receptor and has high affinity and appropriate lipophilicity for blood–brain barrier permeability. 11C-NOP-1A imaging in rhesus monkeys showed high brain uptake and a large receptor-specific signal and could be quantified with the gold standard method of compartmental modeling (8). The present study sought to determine whether 11C-NOP-1A could image and quantify NOP receptor distribution in the living human brain at a dose safe for human subjects. To evaluate how well uptake could be quantified relative to the amount of radioligand delivered to the brain, we imaged the brain and measured serial arterial blood samples after injecting 11C-NOP-1A. We further imaged the whole body to measure radioactivity in identifiable organs and to estimate radiation exposure to the whole body.