Histone deacetylase inhibitor, MS-275, exhibits poor brain penetration: PK studies of [C]MS-275 using Positron Emission Tomography.
Histone deacetylase inhibitor, MS-275, exhibits poor brain penetration: PK studies of [C]MS-275 using Positron Emission Tomography.
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DOI：
10.1021/cn9000268
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发表时间：
2010
影响因子：
5
通讯作者：
Fowler, Joanna S.
中科院分区：
文献类型：
--
作者：
Hooker, Jacob M.;Kim, Sung Won;Alexoff, David;Xu, Youwen;Shea, Colleen;Reid, Alicia;Volkow, Nora;Fowler, Joanna S.
MS-275(Eninostat)是一种组蛋白脱乙酰酶(HDAC)抑制剂，目前正在进行临床试验，用于治疗几种类型的癌症。最近的报道指出，MS-275可以穿过血脑屏障(BBB)，引起啮齿动物脑组蛋白乙酰化的区域特异性变化。为了用正电子发射断层扫描(PET)研究MS-275的药代动力学和在脑内的分布，我们用碳-11标记了MS-275的氨基甲酸酯碳。使用正电子发射计算机断层扫描，我们确定当静脉给药给非人类灵长类动物时，[11C]MS-275在脑组织中的摄取率很低。在啮齿动物研究中，我们观察到，大剂量未标记MS-275的联合给药不会改变[11C]MS-275的药代动力学和脑积聚。这些结果都突显了MS-275的糟糕的大脑渗透能力，清楚地表明了它作为中枢神经系统(CNS)治疗剂的局限性。此外，我们的研究证明了正电子发射计算机断层扫描在为HDAC抑制剂提供脑药代动力学数据方面的有效性。这些数据不仅对开发治疗外周癌症的新化合物(排除中枢神经系统通常是有利的)很重要，而且对治疗神经系统疾病(中枢神经系统渗透至关重要)也很重要。
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 [11C]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 [11C]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).
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影响因子：
2.2
作者：
Hauschild, Axel;Trefzer, Uwe;Schadendorf, Dirk
通讯作者：
Schadendorf, Dirk
影响因子：
5.7
作者：
Eyüpoglu, LY;Hahnen, E;Blümcke, I
通讯作者：
Blümcke, I
影响因子：
3.1
作者：
ALEXOFF, DL;SHEA, C;WOLF, AP
通讯作者：
WOLF, AP
影响因子：
12.7
作者：
Hoelsken, Annett;Eyuepoglu, Ilker Y.;Siebzehnruebl, Florian A.
通讯作者：
Siebzehnruebl, Florian A.
影响因子：
4.7
作者：
Hahnen, E;Eyüpoglu, IY;Blümcke, I
通讯作者：
Blümcke, I