Epigenetic Radiotracers for PET Imaging: Isoform-SelectiveHDAC Probes

项目摘要 异构体选择性组蛋白脱乙酰酶(HDAC)放射性示踪剂的开发将填补关键的知识空白 存在于我们对人脑中HDAC功能的理解中。HDAC6是多种亚型中最主要的 到目前为止，HDAC已经显示出很强的治疗潜力。令人信服的临床前证据支持 用于治疗抑郁症和神经退行性疾病的HDAC6抑制剂和翻译工具 作为一种正电子发射断层扫描靶向HDAC6的放射性示踪剂，我们将能够评估 人类大脑中的临床前发现。HDAC6的作用不是像它的名字那样从组蛋白中去掉乙酰基 可能暗示，但通过调节几个非组蛋白蛋白的乙酰化状态，包括α- 微管蛋白、皮质蛋白、tau蛋白、热休克蛋白90和β-连环蛋白。选择性地与HDAC6结合的抑制剂 HDAC的异构体已经由我们的团队和该领域的其他人开发出来，并为 PET放射性示踪剂的开发。使用已知的HDAC6抑制剂支架，我们将设计和合成一个库 可以很容易地用发射正电子的同位素(碳-11或氟-18)标记的HDAC6抑制剂。这个 图书馆将经过严格的理化和生化分析，包括评估HDAC- 在培养的人类神经元中的异构体选择性和有效性，并预测血脑屏障的穿透。 通过这些分析确定优先顺序的化合物将被放射性标记，并在啮齿类动物身上进行大脑摄取评估， 药代动力学和特定(饱和)结合。有希望的活体成像结果将得到验证 HDAC6基因敲除的小鼠成像。最后，为转换到人类HDAC6成像(我们的 团队已经完成了I类HDAC成像)，我们将评估优先化合物在非人类中的应用 灵长类动物使用完全代谢物校正的动脉血输入功能确定区域脑结合 修正和动力学建模。在赠款项目期间结束时，我们的团队将准备好衡量 HDAC6在自然异质性(如年龄和性别)过程中在人脑中的密度分布 差异)和HDAC6相关脑部疾病的患者。

Project Summary The development of isoform-selective histone deacetylase (HDAC) radiotracers will fill critical knowledge gaps that exist in our understanding of HDAC function in the human brain. HDAC6 is primary among the isoforms of HDAC that, to date, have exhibited strong therapeutic potential. Compelling preclinical evidence supports HDAC6 inhibition for the treatment of depression and neurodegenerative diseases and translational tools such as a positron emission tomography radiotracer targeting HDAC6 will allow us to assess the relevance of preclinical findings in the human brain. HDAC6 acts not by removing acetyl groups from histones as its name might suggest, but instead by regulating the acetylation state of several non-histone proteins including α- tubulin, cortactin, tau, HSP90 and β-catenin. Inhibitors that selectively engage HDAC6 over the other ten isoforms of HDAC have been developed by our team and by others in the field and provide the foundation for PET radiotracer development. Using known HDAC6 inhibitor scaffolds, we will design and synthesize a library of HDAC6 inhibitors that can be readily labeled with a positron-emitting isotope (carbon-11 or fluorine-18). The library will undergo rigorous physiochemical and biochemical profiling including assays that evaluate HDAC- isoform selectivity and efficacy in cultured human neurons and that predict blood-brain barrier penetration. Compounds prioritized through these assays will be radiolabeled and evaluated in rodents for brain uptake, pharmacokinetics and specific (saturable) binding. Promising in vivo imaging results will be validated using HDAC6 knock-out mouse imaging. Finally to set the stage for translation to human HDAC6 imaging (which our team has accomplished for class-I HDAC imaging), we will evaluate priority compounds in non-human primates to determine regional brain binding using full metabolite-corrected arterial blood input function correction and kinetic modeling. By the end of the grant project period, our team will be poised to measure the density-distribution of HDAC6 in the human brain over the course of natural heterogeneity (e.g. age and sex differences) and in patients with HDAC6-implicated brain disorders.