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Histone deacetylase inhibitor, MS-275, exhibits poor brain penetration: PK studies of [C]MS-275 using Positron
Jacob M Hooker1, Sung Won Kim, David Alexoff
1Medical Department, Brookhaven National Laboratory, Upton, NY 11973.
Abstract:
MS-275 (Entinostat) is a histone deacetylase (HDAC) inhibitor currently in clinical trials for the treatment of several types of cancer. Recent reports have noted that MS-275 can cross the blood brain barrier (BBB) and cause region specific changes in rodent brain histone acetylation. To characterize the pharmacokinetics and distribution of MS-275 in the brain using positron emission tomography (PET), we labeled the carbamate carbon of MS-275 with carbon-11. Using PET, we determined that [(11)C]MS-275 has low uptake in brain tissue when administered intravenously to non-human primates. In rodent studies, we observed that pharmacokinetics and brain accumulation of [(11)C]MS-275 were not changed by the co-administration of large doses of unlabeled MS-275. These results, which both highlight the poor brain penetration of MS-275, clearly suggest its limitation as a therapeutic agent for the central nervous system (CNS). Moreover, our study demonstrates the effectiveness of PET at providing brain pharmacokinetic data for HDAC inhibitors. These data are important not only for the development of new compounds for peripheral cancer treatment (where CNS exclusion is often advantageous), but also for the treatment of neurological disorders (where CNS penetration is critical).
Insights
MS-275 (Entinostat), a cancer drug, shows poor brain penetration in primate and rodent studies. Positron emission tomography (PET) confirmed limited uptake, suggesting it is not ideal for central nervous system disorders.
Area of Science:
- Pharmacology
- Neuroscience
- Oncology
Background:
- MS-275 (Entinostat) is a histone deacetylase (HDAC) inhibitor investigated for cancer treatment.
- Previous studies suggested MS-275 crosses the blood-brain barrier (BBB) affecting brain histone acetylation.
Purpose of the Study:
- To characterize the brain pharmacokinetics and distribution of MS-275 using positron emission tomography (PET).
- To evaluate the efficacy of PET in assessing HDAC inhibitor brain penetration.
Main Methods:
- Carbon-11 labeled MS-275 ([ (11)C]MS-275) was synthesized.
- PET imaging was used to quantify brain uptake in non-human primates and rodents.
- Pharmacokinetics were assessed with and without co-administration of unlabeled MS-275.
Main Results:
- [(11)C]MS-275 demonstrated low uptake in non-human primate brain tissue after intravenous administration.
- Rodent studies showed no significant change in [(11)C]MS-275 brain accumulation with co-administered unlabeled MS-275.
- These findings indicate poor brain penetration of MS-275.
Conclusions:
- MS-275 has limitations as a therapeutic agent for central nervous system (CNS) disorders due to poor brain penetration.
- PET imaging is effective for obtaining brain pharmacokinetic data for HDAC inhibitors.
- Understanding CNS penetration is crucial for developing drugs for both peripheral cancers and neurological disorders.
