In vivo PET imaging of histone deacetylases by 18F-suberoylanilide hydroxamic acid (18F-SAHA).
In vivo PET imaging of histone deacetylases by 18F-suberoylanilide hydroxamic acid (18F-SAHA).
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DOI：
10.1021/jm200620f
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发表时间：
2011-08-11
影响因子：
7.3
通讯作者：
Mazitschek, Ralph
中科院分区：
文献类型：
--
作者：
Hendricks, J. Adam;Keliher, Edmund J.;Marinelli, Brett;Reiner, Thomas;Weissleder, Ralph;Mazitschek, Ralph
组蛋白去乙酰化酶（hdac）是一类通过组蛋白和非组蛋白的去乙酰化来调节基因表达和细胞状态的酶。多种HDAC抑制剂（HDACi）已经在癌症中进行了临床试验。hdac的实时体内成像及其抑制作用将是非常宝贵的；然而，开发合适的显像剂仍然是一个重大挑战。在这里，我们描述了18f -亚羟苯胺羟肟酸（18F-SAHA 1a）的发展和评估，这是临床最相关的HDACi亚羟苯胺羟肟酸（SAHA）的类似物。我们证明了1a具有与SAHA几乎相同的生化活性谱，并报告了药代动力学研究的结果。使用小鼠卵巢癌模型，我们同样表明HDACi靶结合效果可以在给药24小时内量化。因此，1a代表了第一种18f正电子发射断层扫描（PET） HDAC显像剂，它也表现出低纳摩尔的效力，在药理学上类似于临床相关的HDAC。
Histone deacetylases (HDACs) are a group of enzymes that modulate gene expression and cell state by deacetylation of both histone and non-histone proteins. A variety of HDAC inhibitors (HDACi) have already undergone clinical testing in cancer. Real-time in vivo imaging of HDACs and their inhibition would be invaluable; however, the development of appropriate imaging agents has remained a major challenge. Here, we describe the development and evaluation of 18F-suberoylanilide hydroxamic acid (18F-SAHA 1a), a close analog of the most clinically relevant HDACi, suberoylanilide hydroxamic acid (SAHA). We demonstrate that 1a has near identical biochemical activity profiles to SAHA, and report findings from pharmacokinetic studies. Using a murine ovarian cancer model, we likewise show that HDACi target binding efficacy can be quantitated within 24 hours of administration. 1a thus represents the first 18F-positron emission tomography (PET) HDAC imaging agent, which also exhibits low nanomolar potency and is pharmacologically analogous to a clinically relevant HDACi.
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影响因子：
56.9
作者：
Choudhary, Chunaram;Kumar, Chanchal;Mann, Matthias
通讯作者：
Mann, Matthias
影响因子：
5
作者：
Hooker, Jacob M.;Kim, Sung Won;Alexoff, David;Xu, Youwen;Shea, Colleen;Reid, Alicia;Volkow, Nora;Fowler, Joanna S.
通讯作者：
Fowler, Joanna S.
影响因子：
14.8
作者：
Bradner, James E.;West, Nathan;Grachan, Melissa L.;Greenberg, Edward F.;Haggarty, Stephen J.;Warnow, Tandy;Mazitschek, Ralph
通讯作者：
Mazitschek, Ralph
DOI：
10.1126/science.1198125
发表时间：
2011-03-11
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Feng D;Liu T;Sun Z;Bugge A;Mullican SE;Alenghat T;Liu XS;Lazar MA
通讯作者：
Lazar MA
影响因子：
5.6
作者：
Gregoretti, IV;Lee, YM;Goodson, HV
通讯作者：
Goodson, HV