LY-2459989 is a silent antagonist of the ú-opioid receptor (KOR) that has been developed by Eli Lilly as a radiotracer of that receptor, labeled either with carbon-11 or fluorine-18.
LY-2459989 exhibits greatly improved central nervous system permeation relative to LY-2795050, with brain levels approximately six times higher than those of its predecessor. The compound has a short duration of action, with only 25% of the compound remaining in serum 30 minutes post-injection in rhesus monkeys, making it an ideal agent for application in biomedical imaging, such as positron emission tomography (PET).
LY-2459989 possesses high affinity for the KOR (K<sub>i</sub> = 0.18 nM) and is highly selective for it over the ü-opioid receptor (K<sub>i</sub> = 7.68 nM) and the ô-opioid receptor (K<sub>i</sub> = 91.3 nM), showing over 43-fold selectivity for the KOR relative to the other opioid receptors. LY-2459989 is a fluorine-containing analogue and follow-up compound of LY-2795050, the first KOR-selective antagonist radiotracer. Relative to LY-2795050, LY-2459989 displays 4-fold higher affinity for the KOR and similar selectivity.
Earlier analogues of LY-2459989 besides LY-2795050 with similar actions and potential uses have also been described. Short-acting ú antagonists of this type have been shown to produce antidepressant-like effects in animal studies.