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Background <p>The enzyme lysine-specific histone demethylase 1 (LSD1) epigenetically regulates gene expression and is a pharmacological target of interest in neurology. The aims of this study were to characterize the novel LSD1 brain PET tracer [<sup>18</sup>F]MNI-1054 in humans for the first time, including whole body radiation dosimetry and test-retest repeatability, and then utilize it to determine the enzyme occupancy of the brain-penetrant LSD1 inhibitor TAK-418. PET scans were acquired ~6&#xa0;h and ~ 26&#xa0;h following single oral doses (1.5&#xa0;mg, 10&#xa0;mg or 30&#xa0;mg) of TAK-418. Due to the irreversible binding of both compounds to the same LSD1 binding site and the presence of residual circulating TAK-418 at the later scan time, a binding model was developed and applied to account for ongoing irreversible binding and enzyme turnover, and to simultaneously estimate the Day 1 and Day 2 enzyme occupancies and the apparent LSD1 enzyme turnover rate using data from all three dose cohorts.</p> Results <p>Kinetic brain PET data were most accurately modeled by an irreversible two-tissue compartment model. The highest and most reproducible signal was observed in the cerebellum, for which an acquisition time of 120&#xa0;min was sufficient to maintain accurate and reliable estimates of <i>K</i><sub>i</sub>. Within the limits of the three TAK-418 dose levels assessed, the binding model estimated a maximum occupancy of 85–86% and an LSD1 enzyme turnover half-life of approximately 30&#xa0;h. The estimated whole body effective dose was 0.049 mSv/MBq, with the liver being the limiting organ (0.073 mSv/MBq).</p> Conclusions <p>[<sup>18</sup>F]MNI-1054 was evaluated in humans for the first time and demonstrated acceptable radiation dosimetry, brain tissue kinetics and test-retest reliability. It was successfully applied to assess enzyme occupancy of TAK-418, a novel LSD1 small molecule inhibitor, and the LSD1 enzyme turnover rate in humans.</p> Trial registration <p><a href="https://clinicaltrials.gov/study/NCT04202497">https://clinicaltrials.gov/study/NCT04202497</a>, registered 12 December 2019.</p>

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[18F]MNI-1054, a novel PET ligand for lysine-specific histone demethylase 1 A (LSD1): first-in human validation and enzyme occupancy of the LSD1 inhibitor TAK-418

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  • 发表日期：

    2026年7月3日

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  • Adam J Schwarz,
  • Christine M Sandiego,
  • Cristian Constantinescu,
  • Akihiro Takano,
  • Paul McQuade,
  • Johannes Tauscher,
  • Nichole Daegele,
  • Ken Marek,
  • Roger N Gunn,
  • Jennifer Madonia,
  • David S Russell

摘要

Background

The enzyme lysine-specific histone demethylase 1 (LSD1) epigenetically regulates gene expression and is a pharmacological target of interest in neurology. The aims of this study were to characterize the novel LSD1 brain PET tracer [18F]MNI-1054 in humans for the first time, including whole body radiation dosimetry and test-retest repeatability, and then utilize it to determine the enzyme occupancy of the brain-penetrant LSD1 inhibitor TAK-418. PET scans were acquired ~6 h and ~ 26 h following single oral doses (1.5 mg, 10 mg or 30 mg) of TAK-418. Due to the irreversible binding of both compounds to the same LSD1 binding site and the presence of residual circulating TAK-418 at the later scan time, a binding model was developed and applied to account for ongoing irreversible binding and enzyme turnover, and to simultaneously estimate the Day 1 and Day 2 enzyme occupancies and the apparent LSD1 enzyme turnover rate using data from all three dose cohorts.

Results

Kinetic brain PET data were most accurately modeled by an irreversible two-tissue compartment model. The highest and most reproducible signal was observed in the cerebellum, for which an acquisition time of 120 min was sufficient to maintain accurate and reliable estimates of Ki. Within the limits of the three TAK-418 dose levels assessed, the binding model estimated a maximum occupancy of 85–86% and an LSD1 enzyme turnover half-life of approximately 30 h. The estimated whole body effective dose was 0.049 mSv/MBq, with the liver being the limiting organ (0.073 mSv/MBq).

Conclusions

[18F]MNI-1054 was evaluated in humans for the first time and demonstrated acceptable radiation dosimetry, brain tissue kinetics and test-retest reliability. It was successfully applied to assess enzyme occupancy of TAK-418, a novel LSD1 small molecule inhibitor, and the LSD1 enzyme turnover rate in humans.

Trial registration

https://clinicaltrials.gov/study/NCT04202497, registered 12 December 2019.