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Increased Brain Exposure of an Alpha-Synuclein Fibrillization Modulator by Utilization of an Activated Ester Prodrug Strategy
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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2018 (English)In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 9, no 11, p. 2542-2547Article in journal, Letter (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018. Vol. 9, no 11, p. 2542-2547
Keywords [en]
Alpha-synuclein, carbon-11, PET
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-151139DOI: 10.1021/acschemneuro.8b00236ISI: 000451496200005PubMedID: 29901990OAI: oai:DiVA.org:umu-151139DiVA, id: diva2:1242508
Available from: 2018-08-28 Created: 2018-08-28 Last updated: 2018-12-19Bibliographically approved

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Cairns, Andrew G.Ådén, JörgenAlmqvist, Fredrik

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