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

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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.