Open AccessHistone Deacetylase Inhibitor MS-275 Exhibits Poor Brain Penetration: Pharmacokinetic Studies of [11C]MS-275 using Positron Emission Tomography
Author(s) -
Jacob M. Hooker,
Sung Won Kim,
David Alexoff,
Youwen Xu,
Colleen Shea,
Alicia E. Reid,
Nora D. Volkow,
Joanna S. Fowler
Publication year - 2009
Publication title -
acs chemical neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.158
H-Index - 69
ISSN - 1948-7193
DOI - 10.1021/cn9000268
Subject(s) - pharmacokinetics , positron emission tomography , histone deacetylase inhibitor , histone deacetylase , pharmacology , blood–brain barrier , medicine , human brain , central nervous system , chemistry , histone , nuclear medicine , biochemistry , psychiatry , gene
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).