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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  <dc:creator>Sokias, Renee</dc:creator>
  <dc:creator>Werry, Eryn L</dc:creator>
  <dc:creator>Chua, Sook W</dc:creator>
  <dc:creator>Reekie, Tristan A</dc:creator>
  <dc:creator>Munoz, Lenka</dc:creator>
  <dc:creator>Wong, Erik CN</dc:creator>
  <dc:creator>Ittner, Lars M</dc:creator>
  <dc:creator>Kassiou, Michael</dc:creator>
  <dc:date>2016-11-15</dc:date>
  <dc:description>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 N-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.</dc:description>
  <dc:identifier>https://zenodo.org/record/291817</dc:identifier>
  <dc:identifier>10.1039/C6MD00523C</dc:identifier>
  <dc:identifier>oai:zenodo.org:291817</dc:identifier>
  <dc:relation>info:eu-repo/grantAgreement/EC/FP7/278850/</dc:relation>
  <dc:relation>url:https://zenodo.org/communities/ecfunded</dc:relation>
  <dc:relation>url:https://zenodo.org/communities/inmind</dc:relation>
  <dc:rights>info:eu-repo/semantics/openAccess</dc:rights>
  <dc:rights>http://creativecommons.org/licenses/by/4.0/legalcode</dc:rights>
  <dc:source>Med. Chem. Commun. 8 202-210</dc:source>
  <dc:title>Determination and reduction of translocator protein (TSPO) ligand rs6971 discrimination</dc:title>
  <dc:type>info:eu-repo/semantics/article</dc:type>
  <dc:type>publication-article</dc:type>
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