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Increased Brain Exposure of an Alpha-Synuclein Fibrillization Modulator by Utilization of an Activated Ester Prodrug Strategy
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
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2018 (Engelska)Ingår i: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 9, nr 11, s. 2542-2547Artikel i tidskrift, Letter (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
American Chemical Society (ACS), 2018. Vol. 9, nr 11, s. 2542-2547
Nyckelord [en]
Alpha-synuclein, carbon-11, PET
Nationell ämneskategori
Organisk kemi
Identifikatorer
URN: urn:nbn:se:umu:diva-151139DOI: 10.1021/acschemneuro.8b00236ISI: 000451496200005PubMedID: 29901990OAI: oai:DiVA.org:umu-151139DiVA, id: diva2:1242508
Tillgänglig från: 2018-08-28 Skapad: 2018-08-28 Senast uppdaterad: 2018-12-19Bibliografiskt granskad

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Cairns, Andrew G.Ådén, JörgenAlmqvist, Fredrik

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