期刊
ACS CHEMICAL NEUROSCIENCE
卷 1, 期 1, 页码 65-73出版社
AMER CHEMICAL SOC
DOI: 10.1021/cn9000268
关键词
MS-275; entinostat; carbon-11; PET; HDAC; histone deacetylase; epigenetics; brain
资金
- U.S. Department of Energy, Office of Biological and Environmental Research [DE-ACO2-98CH10886]
- NIH [1F32EB008320-01]
- Goldhaber Distinguished Fellowship program at BNL
- NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERING [F32EB008320] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM [ZIAAA000550] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [R01DA030321] Funding Source: NIH RePORTER
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 [C-11]MS-275 has low uptake in brain tissue when administered intravenously to nonhuman primates. In rodent studies, we observed that pharmacokinetics and brain accumulation of [C-11]MS-275 were not changed by the coadministration 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).
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