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


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  <identifier identifierType="URL">https://zenodo.org/record/291817</identifier>
  <creators>
    <creator>
      <creatorName>Sokias, Renee</creatorName>
      <givenName>Renee</givenName>
      <familyName>Sokias</familyName>
      <affiliation>School of Chemistry, The University of Sydney, Australia</affiliation>
    </creator>
    <creator>
      <creatorName>Werry, Eryn L</creatorName>
      <givenName>Eryn L</givenName>
      <familyName>Werry</familyName>
      <affiliation>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</affiliation>
    </creator>
    <creator>
      <creatorName>Chua, Sook W</creatorName>
      <givenName>Sook W</givenName>
      <familyName>Chua</familyName>
      <affiliation>Dementia Research Unit, School of Medical Sciences, University of New South Wales, NSW 2052, Australia</affiliation>
    </creator>
    <creator>
      <creatorName>Reekie, Tristan A</creatorName>
      <givenName>Tristan A</givenName>
      <familyName>Reekie</familyName>
      <affiliation>School of Chemistry, The University of Sydney, Australia</affiliation>
    </creator>
    <creator>
      <creatorName>Munoz, Lenka</creatorName>
      <givenName>Lenka</givenName>
      <familyName>Munoz</familyName>
      <affiliation>School of Medical Sciences (Pathology) and Charles Perkins Centre, The University of Sydney, NSW 2006, Australia</affiliation>
    </creator>
    <creator>
      <creatorName>Wong, Erik CN</creatorName>
      <givenName>Erik CN</givenName>
      <familyName>Wong</familyName>
      <affiliation>School of Medical Sciences (Pharmacology), Bosch Institute, The University of Sydney, NSW 2006, Australia</affiliation>
    </creator>
    <creator>
      <creatorName>Ittner, Lars M</creatorName>
      <givenName>Lars M</givenName>
      <familyName>Ittner</familyName>
      <affiliation>Dementia Research Unit, School of Medical Sciences, University of New South Wales, NSW 2052, Australia</affiliation>
    </creator>
    <creator>
      <creatorName>Kassiou, Michael</creatorName>
      <givenName>Michael</givenName>
      <familyName>Kassiou</familyName>
      <affiliation>School of Chemistry, The University of Sydney, Australia</affiliation>
    </creator>
  </creators>
  <titles>
    <title>Determination and reduction of translocator protein (TSPO) ligand rs6971 discrimination</title>
  </titles>
  <publisher>Zenodo</publisher>
  <publicationYear>2016</publicationYear>
  <dates>
    <date dateType="Issued">2016-11-15</date>
  </dates>
  <resourceType resourceTypeGeneral="Text">Journal article</resourceType>
  <alternateIdentifiers>
    <alternateIdentifier alternateIdentifierType="url">https://zenodo.org/record/291817</alternateIdentifier>
  </alternateIdentifiers>
  <relatedIdentifiers>
    <relatedIdentifier relatedIdentifierType="DOI" relationType="IsIdenticalTo">10.1039/C6MD00523C</relatedIdentifier>
    <relatedIdentifier relatedIdentifierType="URL" relationType="IsPartOf">https://zenodo.org/communities/ecfunded</relatedIdentifier>
    <relatedIdentifier relatedIdentifierType="URL" relationType="IsPartOf">https://zenodo.org/communities/inmind</relatedIdentifier>
  </relatedIdentifiers>
  <rightsList>
    <rights rightsURI="http://creativecommons.org/licenses/by/4.0/legalcode">Creative Commons Attribution 4.0 International</rights>
    <rights rightsURI="info:eu-repo/semantics/openAccess">Open Access</rights>
  </rightsList>
  <descriptions>
    <description descriptionType="Abstract">&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;</description>
  </descriptions>
  <fundingReferences>
    <fundingReference>
      <funderName>European Commission</funderName>
      <funderIdentifier funderIdentifierType="Crossref Funder ID">10.13039/501100000780</funderIdentifier>
      <awardNumber awardURI="info:eu-repo/grantAgreement/EC/FP7/278850/">278850</awardNumber>
      <awardTitle>Imaging of Neuroinflammation in Neurodegenerative Diseases</awardTitle>
    </fundingReference>
  </fundingReferences>
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