Increased Brain Exposure of an Alpha-Synuclein Fibrillization Modulator by Utilization of an Activated Ester Prodrug Strategy

Andrew G. Cairns, Ana Vazquez-Romero, Mohammad Mahdi Moein, Jörgen Ådén, Charles S. Elmore, Akihiro Takano, Ryosuke Arakawa, Andrea Varrone, Fredrik Almqvist (Lead / Corresponding author), Magnus Schou (Lead / Corresponding author)

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Abstract

Previous work in our laboratories has identified a series of peptidomimetic 2-pyridone molecules as modulators of alpha-synuclein (α-syn) fibrillization in vitro. As a first step toward developing molecules from this scaffold as positron emission tomography imaging agents, we were interested in evaluating their blood-brain barrier permeability in nonhuman primates (NHP) in vivo. For this purpose, 2-pyridone 12 was prepared and found to accelerate α-syn fibrillization in vitro. Acid 12, and its acetoxymethyl ester analogue 14, were then radiolabeled with 11C (t1/2 = 20.4 min) at high radiochemical purity (>99%) and high specific radioactivity (>37 GBq/μmol). Following intravenous injection of each compound in NHP, a 4-fold higher radioactivity in brain was observed for [11C]14 compared to [11C]12 (0.8 vs 0.2 SUV, respectively). [11C]14 was rapidly eliminated from plasma, with [11C]12 as the major metabolic product observed by radio-HPLC. The presented prodrug approach paves the way for future development of 2-pyridones as imaging biomarkers for in vivo imaging of α-synuclein deposits in brain.

Original languageEnglish
Pages (from-to)2542-2547
Number of pages6
JournalACS Chemical Neuroscience
Volume9
Issue number11
Early online date14 Jun 2018
DOIs
Publication statusPublished - 21 Nov 2018

Keywords

  • Alpha-synuclein
  • carbon-11
  • PET

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    Cairns, A. G., Vazquez-Romero, A., Moein, M. M., Ådén, J., Elmore, C. S., Takano, A., Arakawa, R., Varrone, A., Almqvist, F., & Schou, M. (2018). Increased Brain Exposure of an Alpha-Synuclein Fibrillization Modulator by Utilization of an Activated Ester Prodrug Strategy. ACS Chemical Neuroscience, 9(11), 2542-2547. https://doi.org/10.1021/acschemneuro.8b00236