Journal article Open Access

Determination and reduction of translocator protein (TSPO) ligand rs6971 discrimination

Sokias, Renee; Werry, Eryn L; Chua, Sook W; Reekie, Tristan A; Munoz, Lenka; Wong, Erik CN; Ittner, Lars M; Kassiou, Michael


MARC21 XML Export

<?xml version='1.0' encoding='UTF-8'?>
<record xmlns="http://www.loc.gov/MARC21/slim">
  <leader>00000nam##2200000uu#4500</leader>
  <datafield tag="942" ind1=" " ind2=" ">
    <subfield code="a">2017-11-15</subfield>
  </datafield>
  <controlfield tag="005">20190410040630.0</controlfield>
  <controlfield tag="001">291817</controlfield>
  <datafield tag="700" ind1=" " ind2=" ">
    <subfield code="u">Faculty of Health Sciences, The University of Sydney, NSW 2006, Australia and School of Medical Sciences (Pharmacology), Bosch Institute, The University of Sydney, NSW 2006, Australia</subfield>
    <subfield code="a">Werry, Eryn L</subfield>
  </datafield>
  <datafield tag="700" ind1=" " ind2=" ">
    <subfield code="u">Dementia Research Unit, School of Medical Sciences, University of New South Wales, NSW 2052, Australia</subfield>
    <subfield code="a">Chua, Sook W</subfield>
  </datafield>
  <datafield tag="700" ind1=" " ind2=" ">
    <subfield code="u">School of Chemistry, The University of Sydney, Australia</subfield>
    <subfield code="a">Reekie, Tristan A</subfield>
  </datafield>
  <datafield tag="700" ind1=" " ind2=" ">
    <subfield code="u">School of Medical Sciences (Pathology) and Charles Perkins Centre, The University of Sydney, NSW 2006, Australia</subfield>
    <subfield code="a">Munoz, Lenka</subfield>
  </datafield>
  <datafield tag="700" ind1=" " ind2=" ">
    <subfield code="u">School of Medical Sciences (Pharmacology), Bosch Institute, The University of Sydney, NSW 2006, Australia</subfield>
    <subfield code="a">Wong, Erik CN</subfield>
  </datafield>
  <datafield tag="700" ind1=" " ind2=" ">
    <subfield code="u">Dementia Research Unit, School of Medical Sciences, University of New South Wales, NSW 2052, Australia</subfield>
    <subfield code="a">Ittner, Lars M</subfield>
  </datafield>
  <datafield tag="700" ind1=" " ind2=" ">
    <subfield code="u">School of Chemistry, The University of Sydney, Australia</subfield>
    <subfield code="a">Kassiou, Michael</subfield>
  </datafield>
  <datafield tag="856" ind1="4" ind2=" ">
    <subfield code="s">1459497</subfield>
    <subfield code="z">md5:ff81525bfa4ccad3bc12c073593cb2d8</subfield>
    <subfield code="u">https://zenodo.org/record/291817/files/Sokias_MedChemComm_2016-P19-AAM.pdf</subfield>
  </datafield>
  <datafield tag="542" ind1=" " ind2=" ">
    <subfield code="l">open</subfield>
  </datafield>
  <datafield tag="260" ind1=" " ind2=" ">
    <subfield code="c">2016-11-15</subfield>
  </datafield>
  <datafield tag="909" ind1="C" ind2="O">
    <subfield code="p">openaire</subfield>
    <subfield code="p">user-ecfunded</subfield>
    <subfield code="p">user-inmind</subfield>
    <subfield code="o">oai:zenodo.org:291817</subfield>
  </datafield>
  <datafield tag="909" ind1="C" ind2="4">
    <subfield code="c">202-210</subfield>
    <subfield code="v">8</subfield>
    <subfield code="p">Med. Chem. Commun.</subfield>
  </datafield>
  <datafield tag="100" ind1=" " ind2=" ">
    <subfield code="u">School of Chemistry, The University of Sydney, Australia</subfield>
    <subfield code="a">Sokias, Renee</subfield>
  </datafield>
  <datafield tag="245" ind1=" " ind2=" ">
    <subfield code="a">Determination and reduction of translocator protein (TSPO) ligand rs6971 discrimination</subfield>
  </datafield>
  <datafield tag="980" ind1=" " ind2=" ">
    <subfield code="a">user-ecfunded</subfield>
  </datafield>
  <datafield tag="980" ind1=" " ind2=" ">
    <subfield code="a">user-inmind</subfield>
  </datafield>
  <datafield tag="536" ind1=" " ind2=" ">
    <subfield code="c">278850</subfield>
    <subfield code="a">Imaging of Neuroinflammation in Neurodegenerative Diseases</subfield>
  </datafield>
  <datafield tag="540" ind1=" " ind2=" ">
    <subfield code="u">http://creativecommons.org/licenses/by/4.0/legalcode</subfield>
    <subfield code="a">Creative Commons Attribution 4.0 International</subfield>
  </datafield>
  <datafield tag="650" ind1="1" ind2="7">
    <subfield code="a">cc-by</subfield>
    <subfield code="2">opendefinition.org</subfield>
  </datafield>
  <datafield tag="520" ind1=" " ind2=" ">
    <subfield code="a">&lt;p&gt;The 18 kDa translocator protein (TSPO) is a target for development of diagnostic imaging agents for glioblastoma and neuroinflammation. Clinical translation of TSPO imaging agents has been hindered by the presence of a polymorphism, rs6971, which causes a non-conservative substitution of alanine for threonine at amino acid residue 147 (TSPO A147T). Disclosed brain-permeant second-generation TSPO ligands bind TSPO A147T with reduced affinity compared to the wild type protein (TSPO WT). Efforts to develop a TSPO ligand that binds TSPO WT and TSPO A147T with similarly high affinity have been hampered by a lack of knowledge about how ligand structure differentially influences interaction with the two forms of TSPO. To gain insight, we have established human embryonic kidney cell lines stably over-expressing human TSPO WT and TSPO A147T, and tested how modifications of a novel &lt;em&gt;N&lt;/em&gt;-alkylated carbazole scaffold influence affinity to both TSPO isoforms. Most of the new analogues developed in this study showed high affinity to TSPO WT and a 5–6-fold lower affinity to TSPO A147T. Addition of electron-withdrawing substituents yielded analogues with highest affinity for TSPO A147T without decreasing affinity for TSPO WT. This knowledge can be used to inform further development of non-discriminating TSPO ligands for use as diagnostic markers for glioblastoma and neuroinflammation irrespective of rs6971.&lt;/p&gt;</subfield>
  </datafield>
  <datafield tag="024" ind1=" " ind2=" ">
    <subfield code="a">10.1039/C6MD00523C</subfield>
    <subfield code="2">doi</subfield>
  </datafield>
  <datafield tag="980" ind1=" " ind2=" ">
    <subfield code="a">publication</subfield>
    <subfield code="b">article</subfield>
  </datafield>
</record>
18
13
views
downloads
Views 18
Downloads 13
Data volume 19.0 MB
Unique views 18
Unique downloads 13

Share

Cite as