A blood-brain-barrier permeable imaging biomarker for microtubules in the brain: A first-in-human clinical trial

申请编号：1 R21 AG 072570 -01联系PD/PI：Mintz，Akiva 阿尔茨海默病中微管的血脑屏障渗透性成像生物标志物：首次人体评估。 研究微管功能障碍的工具可能对神经退行性疾病产生变革性影响，包括阿尔茨海默病（AD），这是美国第六大死亡原因，2017年有550万美国人受到影响。AD的特征在于由Aβ片段组成的细胞外淀粉样蛋白斑块和由过度磷酸化tau（一种通常作为微管相关蛋白（MAP）发挥作用的蛋白质）形成的细胞内神经元缠结。据报道，在AD中，微管动力学在疾病过程的早期受到影响，包括通过隔离MAP和Aβ斑块诱导的微管解聚而干扰微管组装。微管骨架是神经元健康的关键，它为轴突运输提供主要通道，有助于结构完整性，并在神经元可塑性和细胞分裂中发挥重要作用。因此，微管动力学的异常被认为在AD中观察到的神经变性中起主要作用。该R21的目标是开发一种BBB渗透PET放射性示踪剂，可以实时成像和量化微管，利用我们在正电子发射断层扫描（PET）方面的初步数据和专业知识。这种新型放射性示踪剂可以阐明微管在AD中的作用，并有助于开发和评估新型微管靶向治疗策略。中心假设是，[11 C]MPC-6827，我们的新型微管蛋白PET示踪剂，可以穿过BBB和非侵入性成像和量化微管动力学，以可视化AD的早期改变和AD患者随时间的变化。我们的假设是基于我们的初步数据，显示MPC- 6827在体外结合β-微管蛋白，可以被放射性标记，在非人灵长类动物中穿过BBB，并且在AD的小鼠模型中表现出较低的结合。FDA已批准我们的探索性首次人体IND使用[11 C]MPC-6827成像的“安全进行”信函。我们将追求两个具体的目标，使我们能够在AD患者中测试我们的新型示踪剂。在特定目标1中，我们将按照FDA的要求，通过对5名受试者进行连续首次人体全身PET/CT成像，表征初始[11 C]MPC-6827剂量测定。在目标2中，我们将在测试-再测试设计中表征[11 C]MPC-6827脑摄取和结合，并开发脑中PET [11 C]MPC-6827动力学的定量方法。我们成功的标准是，在拟议的研究结束时，我们将验证[11 C]MPC-6827对人体BBB的渗透，开发出强大的定量方法来分析[11 C]MPC- 6827 PET，并建立了我们的新型微管成像剂的人体剂量测定，有可能对AD中的微管动力学进行成像。这将使我们能够纵向成像AD患者的微管动力学，并首次阐明微管在疾病过程中发挥的作用，为靶向微管的新型疗法打开大门。由于我们在进行首次人体临床试验和从实验室到床边开发[11 C]MPC-6827方面的直接经验，我们有能力开展本文提出的研究。

Application Number: 1 R21 AG072570-01 Contact PD/PI: Mintz, Akiva A blood-brain-barrier permeable imaging biomarker for microtubules in Alzheimer’s Disease: A first-in-human evaluation. Tools to study microtubule dysfunction could have a transformative impact on neurodegenerative diseases including Alzheimer's disease (AD), the sixth-leading cause of death in the United States, which afflicted 5.5 million Americans in 2017. AD is characterized by extracellular amyloid plaques composed of Aβ fragments and intracellular neurofibrillary tangles formed by hyperphosphorylated tau, a protein that normally functions as a microtubule‐associated protein (MAP). In AD, it has been reported that microtubule dynamics are affected early in the disease process, including disturbed microtubule assembly by sequestration of MAPs and microtubule depolymerization induced by Aβ plaques. The microtubule skeleton is critical for neuronal health by providing the main tracks for axonal transport, contributing to structural integrity, and playing a significant role in neuronal plasticity and cell division. Thus, abnormalities in microtubule dynamics are thought to play a major role in the neurodegeneration seen in AD. The goal of this R21 is to develop a BBB-penetrant PET radiotracer that can image and quantify microtubules in real-time, leveraging our preliminary data and expertise in positron emission tomography (PET). This novel radiotracer can elucidate the role of microtubules in AD and aid in the development and evaluation of novel microtubule-targeted therapeutic strategies. The central hypothesis is that [11C]MPC-6827, our novel tubulin PET tracer, can cross the BBB and non-invasively image and quantify microtubule dynamics to visualize early alterations in AD and changes over time in patients afflicted with AD. Our hypothesis is based on our preliminary data showing that MPC- 6827 binds β-tubulin in vitro, can be radiolabeled, crosses the BBB in non-human primates, and demonstrates lower binding in mouse models of AD. The FDA has granted us a “safe to proceed” letter for our exploratory first-in-human IND to image with [11C]MPC-6827. We will pursue two specific aims that will enable us to test our novel tracer in AD patients. In Specific Aim 1, we will characterize the initial [11C]MPC-6827 dosimetry, as required by the FDA, by performing sequential first-in-human whole body PET/CT imaging on 5 subjects. In Aim 2, we will characterize [11C]MPC-6827 brain uptake and binding in a test-retest design, and develop quantification methods for PET [11C]MPC-6827 kinetics in the brain. Our criteria for success are that, at the conclusion of the proposed research, we will have validated [11C]MPC-6827 penetration of the BBB in humans, developed robust quantitative methods to analyze [11C]MPC- 6827 PET, and established the human dosimetry of our novel microtubule imaging agent with potential to image microtubule dynamics in AD. This will enable us to image microtubule dynamics in AD patients longitudinally and for the first time elucidate the role that microtubules play in the disease process, opening the door for novel therapeutics that target microtubules. We are well positioned to pursue the studies proposed here because of our direct experience performing first- in-human clinical trials and developing [11C]MPC-6827 from bench-to-bedside.