Bioanalytical method development and pharmacokinetics of MCI-92, a sigma-1 receptor ligand

Sigma-1 receptors are found throughout the nervous system and play a role in regulating nociception. They are highly expressed in nerve injury, making them a potential target for the treatment of neuropathic pain. Although sigma-1 receptor antagonists have been shown to have anti-nociceptive and anti-allodynic effects, improved selectivity of these ligands is needed to further investigate their potential to treat neuropathic pain. MCI-92 is a novel, selective sigma-1 receptor ligand developed to address this need. A sensitive and rapid ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the quantification of MCI-92 in mouse plasma and brain homogenate. A structural analog of the analyte, MCI-147, was used as the internal standard (IS). The chromatographic separation was achieved on an Acquity UPLC BEH C₁₈ column using a mobile phase consisting of water acidified with 0.1 % v/v formic acid and acetonitrile with gradient elution over 3.2 min. The method was linear over a concentration range of 1-200 ng/mL. Multiple reaction monitoring in the positive ionization mode was used for the mass spectrometric quantitation using m/z transitions 369.2 > 126.0 for MCI-92 and 448.9 > 350.1 for the IS. The method was successfully applied to the analysis of plasma and brain samples obtained in the course of oral and intravenous pharmacokinetic studies in CD-1 mice. MCI-92 showed a high volume of distribution (11.3 ± 0.6 L/kg) and rapid clearance (6.1 ± 0.8 L/h/kg) from systemic circulation. The concentration of the MCI-92 was higher in the brain than in plasma throughout all terminal time points, indicating high blood-to-brain partitioning and slow brain clearance.