LY-2459989 is a silent antagonist of the κ-opioid receptor (KOR) that has been developed by Eli Lilly as a radiotracer of that receptor, labeled either with carbon-11[1] or fluorine-18.[2] It possesses high affinity for the KOR (Ki = 0.18 nM) and is highly selective for it over the μ-opioid receptor (Ki = 7.68 nM) and the δ-opioid receptor (Ki = 91.3 nM) (over 43-fold selectivity for the KOR over the other opioid receptors).[1] LY-2459989 is a fluorine-containing analogue and follow-up compound of LY-2795050, the first KOR-selective antagonist radiotracer.[1] Relative to LY-2795050, LY-2459989 displays 4-fold higher affinity for the KOR and similar selectivity and also possesses greatly improved central nervous system permeation (brain levels were found to be 6-fold higher than those of LY-2795050).[1] The drug appears to possess a short duration of action, with only 25% remaining in serum at 30 minutes post-injection in rhesus monkeys, making it an ideal agent for application in biomedical imaging, for instance in positron emission tomography (PET).[1]
Earlier analogues of LY-2459989 besides LY-2795050 with similar actions and potential uses have also been described.[3]
^Cai Z, Li S, Pracitto R, Navarro A, Shirali A, Ropchan J, Huang Y (2017). "Fluorine-18-Labeled Antagonist for PET Imaging of Kappa Opioid Receptors". ACS Chem Neurosci. 8 (1): 12–16. doi:10.1021/acschemneuro.6b00268. PMID27741398.
^Mitch CH, Quimby SJ, Diaz N, Pedregal C, de la Torre MG, Jimenez A, Shi Q, Canada EJ, Kahl SD, Statnick MA, McKinzie DL, Benesh DR, Rash KS, Barth VN (2011). "Discovery of aminobenzyloxyarylamides as κ opioid receptor selective antagonists: application to preclinical development of a κ opioid receptor antagonist receptor occupancy tracer". J. Med. Chem. 54 (23): 8000–12. doi:10.1021/jm200789r. PMID21958337.
