Opioids such as morphine are commonly used analgesics in clinical practice. Three opioid receptors that mediate opioid effects have been identified with molecular cloning: delta, δ (enkephalin-preferring); kappa, κ (dynorphin-preferring); and mu, µ (ß-endorphin–preferring) (1). Each type of opioid receptor consists of subtypes of receptors as suggested by pharmacological studies (2, 3). These receptors have high specificity in both the central and peripheral nervous systems, and their presence is ubiquitous. The opioid receptors (G-protein–coupled; decrease adenylyl cyclase activity) play an important role in the regulation of analgesia, shock, appetite, thermoregulation, cardiovascular, and mental and endocrine function (2-5). Although µ opioid receptors are the major receptor to mediate the analgesic effects of opioids, κ opioid receptors (KOR) and δ opioid receptors are also important in antinociception. Opioids have been found to protect cells from ischemia injury in the heart and brain via the δ receptors. On the other hand, the κ antagonist prevents neurodegeneration.

In humans, the κ₁ and κ₂ KORs are the most abundant brain opioid receptors and are widely distributed in deeper layers of the neocortex (particularly temporal, parietal, and frontal cortices), striatum, and thalamus, with lower levels in the amygdala, hippocampus, occipital cortex, and cerebellum (6, 7). The KORs have been implicated in several clinical brain disorders, including substance abuse (8), epilepsy (9), Tourette’s syndrome (10), and Alzheimer’s disease (11).

(±)-4-Methoxycarbonyl-2-[1-pyrrolidinylmethyl]-1-[(3,4-dichlorophenyl)acetyl]-piperidine (GR89696) is a novel, highly potent, and selective KOR agonist (12). The (–)-isomer, (–)-4-methoxycarbonyl-2-[1-pyrrolidinylmethyl]-1-[(3,4-dichlorophenyl)acetyl]-piperidine, also known as GR103545, is the more potent optical isomer of GR89696 (IC₅₀, 0.018 nM versus 6.0 nM, respectively). GR89696 is centrally penetrating, with a log P value of 3.14, and it has potent antinociceptive, sedative, and diuretic effects. The K_i values for GR89696 κ₁- and κ₂-receptor binding are in the low nanomolar or subnanomolar range. GR89696 is an agonist for the κ₂ opioid receptor and an antagonist for the κ₁ receptor in the guinea pig hippocampus (13). [¹¹C]GR103545 was studied as a positron emission tomography (PET) agent for use with the noninvasive study of κ opioid receptors in the brain. However, there is a need for KOR antagonist radioligands because they tend to bind to both high- and low-affinity receptors (14). Hence, antagonists bind to a higher number of receptors than the agonists (15). (S)-3-Chloro-4-(4-((2-(pyridine-3-yl)pyrrolidin-1-yl)methyl)phenoxy)benzamide (LY2795050) was determined to be a selective KOR antagonist. Zheng et al. (16) prepared and evaluated [carbonyl-¹¹C]LY2795050 ([¹¹C]LY2795050) for use with in vivo PET imaging of KOR distribution in monkey brain tissue.