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Detection of Microglial Activation in an Acute Model of Neuroinflammation Using PET and Radiotracers 11C-(R)-PK11195 and 18F-GE-180.

Dickens, Alex M; Vainio, Susanne; Marjamäki, Päivi; Johansson, Jarkko; Lehtiniemi, Paula; Rokka, Johanna; Rinne, Juha; Solin, Olof; Haaparanta-Solin, Merja; Jones, Paul A; Trigg, William; Anthony, Daniel C; Airas, Laura


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    <subfield code="c">466-72</subfield>
    <subfield code="n">3</subfield>
    <subfield code="p">J Nucl Med.</subfield>
    <subfield code="v">55</subfield>
    <subfield code="y">2014</subfield>
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    <subfield code="a">&lt;p&gt;It remains unclear how different translocator protein (TSPO) ligands reflect the spatial extent of astrocyte or microglial activation in various neuroinflammatory conditions. Here, we use a reproducible lipopolysaccharide (LPS)-induced model of acute central nervous system inflammation to compare the binding performance of a new TSPO ligand (18)F-GE-180 with (11)C-(R)-PK11195. Using immunohistochemistry, we also explore the ability of the TSPO ligands to detect activated microglial cells and astrocytes.&lt;/p&gt;

&lt;p&gt;METHODS: Lewis rats (n = 30) were microinjected with LPS (1 or 10 &amp;mu;g) or saline (1 &amp;mu;L) into the left striatum. The animals were imaged in vivo at 16 h after the injection using PET radiotracers (18)F-GE-180 or (11)C-(R)-PK11195 (n = 3 in each group) and were killed afterward for autoradiography of the brain. Immunohistochemical assessment of OX-42 and glial fibrillary acidic protein (GFAP) was performed to identify activated microglial cells and reactive astrocytes.&lt;/p&gt;

&lt;p&gt;RESULTS: In vivo PET imaging revealed an increase in the ipsilateral TSPO binding, compared with binding in the contralateral hemisphere, after the microinjection of 10 &amp;mu;g of LPS. No increase was observed with vehicle. By autoradiography, the TSPO radiotracer binding potential in the injected hemisphere was increased after striatal injection of 1 or 10 &amp;mu;g of LPS. However, the significant increase was observed only when using (18)F-GE-180. The area of CD11b-expressing microglial cells extended beyond that of enhanced GFAP staining and mapped more closely to the extent of (18)F-GE-180 binding than to (11)C-(R)-PK11195 binding. The signal from either PET ligand was significantly increased in regions of increased GFAP immunoreactivity and OX-42 colocalization, meaning that the presence of both activated microglia and astrocytes in a given area leads to increased binding of the TSPO radiotracers.&lt;/p&gt;

&lt;p&gt;CONCLUSION: (18)F-GE-180 is able to reveal sites of activated microglia in both gray and white matter. However, the signal is increased by the presence of activated astrocytes. Therefore, (18)F-GE-180 is a promising new fluorinated longer-half-life tracer that reveals the presence of activated microglia in a manner that is superior to (11)C-(R)-PK11195 due to the higher binding potential observed for this ligand.&lt;/p&gt;</subfield>
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    <subfield code="u">MediCity/PET Preclinical Laboratory, University of Turku, Turku, Finland</subfield>
    <subfield code="a">Vainio, Susanne</subfield>
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  <datafield tag="700" ind1=" " ind2=" ">
    <subfield code="u">MediCity/PET Preclinical Laboratory, University of Turku, Turku, Finland</subfield>
    <subfield code="a">Marjamäki, Päivi</subfield>
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  <datafield tag="700" ind1=" " ind2=" ">
    <subfield code="u">Turku PET Centre, University of Turku, Turku, Finland</subfield>
    <subfield code="a">Johansson, Jarkko</subfield>
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  <datafield tag="700" ind1=" " ind2=" ">
    <subfield code="u">Radiopharmaceutical Chemistry Laboratory, University of Turku, Turku PET Centre, Turku, Finland</subfield>
    <subfield code="a">Lehtiniemi, Paula</subfield>
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  <datafield tag="700" ind1=" " ind2=" ">
    <subfield code="u">Radiopharmaceutical Chemistry Laboratory, University of Turku, Turku PET Centre, Turku, Finland</subfield>
    <subfield code="a">Rokka, Johanna</subfield>
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    <subfield code="u">Turku PET Centre, University of Turku, Turku, Finland</subfield>
    <subfield code="a">Rinne, Juha</subfield>
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  <datafield tag="700" ind1=" " ind2=" ">
    <subfield code="u">Radiopharmaceutical Chemistry Laboratory, University of Turku, Turku PET Centre, Turku, Finland</subfield>
    <subfield code="a">Solin, Olof</subfield>
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    <subfield code="u">MediCity/PET Preclinical Laboratory, University of Turku, Turku, Finland</subfield>
    <subfield code="a">Haaparanta-Solin, Merja</subfield>
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  <datafield tag="700" ind1=" " ind2=" ">
    <subfield code="u">GE Healthcare Ltd., Amersham, United Kingdom</subfield>
    <subfield code="a">Jones, Paul A</subfield>
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  <datafield tag="700" ind1=" " ind2=" ">
    <subfield code="u">GE Healthcare Ltd., Amersham, United Kingdom</subfield>
    <subfield code="a">Trigg, William</subfield>
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  <datafield tag="700" ind1=" " ind2=" ">
    <subfield code="u">Department of Pharmacology, University of Oxford, Oxford, United Kingdom</subfield>
    <subfield code="a">Anthony, Daniel C</subfield>
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  <datafield tag="700" ind1=" " ind2=" ">
    <subfield code="u">Department of Neurology, Turku University Hospital, Turku, Finland</subfield>
    <subfield code="a">Airas, Laura</subfield>
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    <subfield code="u">Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland and MediCity/PET Preclinical Laboratory, University of Turku, Turku, Finland</subfield>
    <subfield code="a">Dickens, Alex M</subfield>
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    <subfield code="a">neuroinflammation</subfield>
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    <subfield code="a">positron emission tomography</subfield>
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    <subfield code="a">second-generation TSPO ligand</subfield>
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    <subfield code="a">brain</subfield>
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  <datafield tag="024" ind1=" " ind2=" ">
    <subfield code="a">10.2967/jnumed.113.125625</subfield>
    <subfield code="2">doi</subfield>
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  <datafield tag="245" ind1=" " ind2=" ">
    <subfield code="a">Detection of Microglial Activation in an Acute Model of Neuroinflammation Using PET and Radiotracers 11C-(R)-PK11195 and 18F-GE-180.</subfield>
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  <datafield tag="536" ind1=" " ind2=" ">
    <subfield code="c">278850</subfield>
    <subfield code="a">Imaging of Neuroinflammation in Neurodegenerative Diseases</subfield>
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