UPLC-MS/MS method for the quantification of MCI-77, a novel sigma-1 receptor ligand, and its application to pharmacokinetic studies

• Published in: Journal of chromatography. B, Analytical technologies in the biomedical and life sciences Analytical technologies in the biomedical and life sciences, 2022-04, Vol.1196, p.123187-123187, Article 123187
• Main Authors: Popa, Raluca, Kamble, Shyam H., Kanumuri, Raju S., King, Tamara I., Berthold, Erin C., Intagliata, Sebastiano, Sharma, Abhisheak, McCurdy, Christopher R.
• Format: Article
• Language: English
• Subjects: Animals; Chromatography, High Pressure Liquid - methods; Chromatography, Liquid - methods; Ligands; Method validation; Mice; Pharmacokinetics; Receptors, sigma; Reproducibility of Results; Sigma-1 Receptor; Tandem Mass Spectrometry - methods; UPLC-MS/MS
• ISSN: 1570-0232; 1873-376X
• DOI: 10.1016/j.jchromb.2022.123187

•An UPLC-MS/MS method was developed to quantify the novel compound MCI-77.•The method was validated in accordance with FDA guidelines.•The method was used to analyze samples from pharmacokinetics studies in mice. Sigma-1 receptors are involved in pain modulation, particularly in cases of nerve injury and neuropathic pain. High-affinity ligands with improved pharmacokinetic profiles are needed to further investigate the properties of these receptors and their potential as a therapeutic target. The novel compound MCI-77 is one such selective sigma-1 receptor ligand, and the purpose of this study was to characterize its preclinical pharmacokinetic parameters. An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to quantify MCI-77 in mouse plasma and brain homogenate. The method was validated for sensitivity, selectivity, linearity, accuracy, precision, stability, and dilution integrity. The method has a linearity range of 2–200 ng/mL, a short run-time of 3.2 min, and requires a low sample volume of 25 µL. A simple protein precipitation procedure was used for compound extraction. Samples were run on an Acquity UPLC BEH C18 column (1.7 μm, 2.1 × 50 mm) following a gradient elution method using a mobile phase consisting of water containing 0.1% (v/v) formic acid and acetonitrile. The method was applied to the analysis of plasma and brain homogenate samples from preclinical pharmacokinetic studies in CD-1 mice. MCI-77 exhibited high systemic clearance (8.5 ± 0.3 L/h/kg) and extensive tissue distribution indicated by a high volume of distribution (20.1 ± 0.3 L/kg). The concentration levels were consistently higher in brain samples than in plasma (brain/plasma AUC ratio 2.9), indicating its ability to cross the blood–brain barrier.