The downfall of TBA-354 – a possible explanation for its neurotoxicity <i>via</i> mass spectrometric imaging

<p>1. TBA-354 was a promising antitubercular compound with activity against both replicating and static <i>Mycobacterium tuberculosis</i> (<i>M.tb</i>), making it the focal point of many clinical trials conducted by the TB Alliance. However, findings from these trials have shown that TBA-354 results in mild signs of reversible neurotoxicity; this left the TB Alliance with no other choice but to stop the research.</p> <p>2. In this study, mass spectrometric methods were used to evaluate the pharmacokinetics and spatial distribution of TBA-354 in the brain using a validated liquid chromatography tandem-mass spectrometry (LCMS/MS) and mass spectrometric imaging (MSI), respectively. Healthy female Sprague-Dawley rats received intraperitoneal (i.p.) doses of TBA-354 (20 mg/kg bw).</p> <p>3. The concentrationtime profiles showed a gradual absorption and tissue penetration of TBA-354 reaching the <i>C</i>_max at 6 h post dose, followed by a rapid elimination. MSI analysis showed a time-dependent drug distribution, with highest drug concentration mainly in the neocortical regions of the brain.</p> <p>4. The distribution of TBA-354 provides a possible explanation for the motor dysfunction observed in clinical trials. These results prove the importance of MSI as a potential tool in preclinical evaluations of suspected neurotoxic compounds.</p