Opioids such as morphine are analgesics that are commonly used in clinical practice. Three opioid receptors (mu, µ; delta, δ; and kappa, κ) that mediate opioid effects have been identified by molecular cloning: δ (enkephalin-preferring), κ (dynorphin-preferring), and µ (morphine- and ß-endorphin–preferring) (1). Each type of opioid receptors consists of subtypes of receptors as suggested by pharmacological studies (2, 3). These receptors exhibit apparent specificity to both the central and peripheral nervous systems, and their presence is ubiquitous in these systems. The opioid receptors (G-protein–coupled, resulting in decrease in adenylyl cyclase activity) play an important role in the regulation of analgesia, shock, appetite, thermoregulation, and cardiovascular, mental, and endocrine function (2-5). Although µ opioid receptors are the major receptors to mediate the analgesic effects of opioids, δ and κ receptors are also important in antinociception. Opioids have been found to protect cells from ischemic injury in the heart and brain via the δ receptors. On the other hand, κ antagonists prevent neurodegeneration.
The µ opioid receptors are localized predominately in the hypothalamus and thalamus, and the δ opioid receptors are localized predominately in the striatum, limbic system, and cerebral cortex (6, 7). The κ opioid receptors (κ1 and κ2) are the most abundant brain opioid receptors and are widely distributed in deeper layers of the neocortex (particularly temporal, parietal, and frontal cortices), striatum, amygdala, and thalamus, with lower levels in the hippocampus, occipital cortex, and cerebellum (8-10). The κ opioid receptors have been implicated in several clinical brain disorders, including drug abuse (11), epilepsy (12), Tourette’s syndrome (13), and Alzheimer’s disease (14).
Diprenorphine is a highly potent and nonselective opioid receptor antagonist with subnanomolar affinity (7). Diprenorphine has been labeled as [6-O-methyl-11C]diprenorphine ([11C]DPN) (15, 16). [11C]DPN is being developed as a positron emission tomography (PET) agent for the non-invasive study of opioid receptors in the brain. However, pharmacological studies in humans (17) and rats (18) demonstrated minimal competition between the high-efficacy agonists and the non-subtype–selective antagonist radioligand [11C]DPN, which limits the use of [11C]DPN PET to monitor in vivo occupancy. (20R)-4,5-α-Epoxy-17-methyl-3-hydroxy-6-methoxy-α,17-dimethyl-α-(2-phenylethyl)-6,14-ethenomorphinan-7-methanol (PEO) was found to be a highly potent opioid receptor agonist (19). [6-O-methyl-11C]PEO ([11C]PEO) has been evaluated for PET imaging of opioid receptors in rats.