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Increased Brain Exp...
Increased Brain Exposure of an Alpha-Synuclein Fibrillization Modulator by Utilization of an Activated Ester Prodrug Strategy
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- Cairns, Andrew G. (author)
- Umeå universitet,Kemiska institutionen
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Vazquez-Romero, Ana (author)
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- Mahdi-Moein, Mohammad (author)
- Karolinska Institutet
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- Ådén, Jörgen, 1980- (author)
- Umeå universitet,Kemiska institutionen
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Elmore, Charles S. (author)
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Takano, Akihiro (author)
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- Arakawa, Ryosuke (author)
- Karolinska Institutet
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- Varrone, Andrea (author)
- Karolinska Institutet
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- Almqvist, Fredrik (author)
- Umeå universitet,Kemiska institutionen
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- Schou, Magnus (author)
- Karolinska Institutet
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(creator_code:org_t)
- 2018-06-14
- 2018
- English.
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In: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 9:11, s. 2542-2547
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Subject headings
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- 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.
Subject headings
- NATURVETENSKAP -- Kemi -- Organisk kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences -- Organic Chemistry (hsv//eng)
Keyword
- Alpha-synuclein
- carbon-11
- PET
Publication and Content Type
- ref (subject category)
- art (subject category)
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Cairns, Andrew G ...
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Vazquez-Romero, ...
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Mahdi-Moein, Moh ...
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Ådén, Jörgen, 19 ...
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Elmore, Charles ...
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Takano, Akihiro
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show more...
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Arakawa, Ryosuke
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Varrone, Andrea
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Almqvist, Fredri ...
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Schou, Magnus
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show less...
- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Chemical Science ...
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and Organic Chemistr ...
- Articles in the publication
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ACS Chemical Neu ...
- By the university
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Umeå University
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Karolinska Institutet