Pharmacokinetics and brain penetration of LF-3-88, (2-[5-[5-(2(S)-azetidinylmethoxyl)-3-pyridyl]-3-isoxazolyl]ethanol), a selective α4β2-nAChR partial agonist and promising antidepressant

LF-3-88 (2-[5-[5-(2(S)-azetidinylmethoxyl)-3-pyridyl]-3-isoxazolyl]ethanol) was identified as a highly selective α4β2-nAChRs partial agonist, with a Ki value of 0.4 nM and EC50 value of 110 nM. A sensitive and selective ultra high pressure liquid chromatography–tandem mass spectrometry (UHPLC–MS–MS) method was developed and validated to study the pharmacokinetics profile of this compound in mice. Protein precipitation with acetonitrile was used to prepare the plasma and brain samples, and the recovery was greater than 90%. The inter-day and intra-day accuracy and precision of the quantitative method ranged from 95% to 106% for plasma and from 93% to 105% for brain homogenates. The precision of the assay was <10%. The limit of detection and limit of quantitation were 0.5 ng/mL (1.8 nM) and 1 ng/mL (3.6 nM), respectively. LF-3-88 was stable (>93%) for 24 h on the bench top at room temperature, and for at least 3 weeks at 4 °C and −80 °C. The UHPLC–MS–MS assay was applied to the measurement of plasma and brain levels of LF-3-88 following oral administration to male Balb/c mice. Plasma concentrations of LF-3-88 and brain levels were dose-dependent with half-lives of approximately 60 min and 180 min, respectively, indicating good oral bioavailability and penetration of the blood–brain barrier.

► LF-3-88, a novel agonist of α4β2*-nAChRs, is being developed as an antidepressant. ► A quantitative method based on UHPLC–MS–MS was developed and validated for LF-3-88. ► LF-3-88 was measured in mouse plasma and brain tissue after oral administration. ► Pharmacokinetics of LF-3-88 indicated good bioavailability and brain penetration.