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

Dublin Core Export

<?xml version='1.0' encoding='utf-8'?>
<oai_dc:dc xmlns:dc="" xmlns:oai_dc="" xmlns:xsi="" xsi:schemaLocation="">
  <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: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:source>Med. Chem. Commun. 8 202-210</dc:source>
  <dc:title>Determination and reduction of translocator protein (TSPO) ligand rs6971 discrimination</dc:title>
Views 32
Downloads 27
Data volume 39.4 MB
Unique views 32
Unique downloads 27


Cite as