Vo Sophie V, Banister Samuel D, Freelander Isaac, Werry Eryn L, Reekie Tristan A, Ittner Lars M, Kassiou Michael
Faculty of Medicine and Health , The University of Sydney , Sydney , New South Wales 2006 , Australia.
The Lambert Initiative for Cannabinoid Therapeutics , Brain and Mind Centre , The University of Sydney , Camperdown , NSW 2050 , Australia.
RSC Med Chem. 2020 Mar 12;11(4):511-517. doi: 10.1039/c9md00580c. eCollection 2020 Apr 1.
The translocator protein (TSPO) is a target for the development of neuroinflammation imaging agents. Clinical translation of TSPO PET ligands, such as [C]DPA-713, has been hampered by the presence of a common polymorphism (A147T TSPO), at which all second-generation TSPO ligands lose affinity. Little is known about what drives binding at A147T compared to WT TSPO. This study aimed to identify moieties in DPA-713, and related derivatives, that influence binding at A147T compared to WT TSPO. We found changes to the nitrogen position and number in the heterocyclic core influences affinity to WT and A147T to a similar degree. Hydrogen bonding groups in molecules with an indole core improve binding at A147T compared to WT, a strategy that generated compounds that possess up to ten-times greater affinity for A147T. These results should inform the future design of compounds that bind both A147T and WT TSPO for use in neuroinflammation imaging.
转位蛋白（TSPO）是神经炎症成像剂开发的一个靶点。TSPO正电子发射断层扫描（PET）配体，如[C]DPA - 713的临床转化受到一种常见多态性（A147T TSPO）的阻碍，在这种多态性下，所有第二代TSPO配体都会失去亲和力。与野生型（WT）TSPO相比，关于驱动A147T结合的因素知之甚少。本研究旨在确定DPA - 713及相关衍生物中与WT TSPO相比影响A147T结合的部分。我们发现杂环核心中氮的位置和数量的变化对WT和A147T亲和力的影响程度相似。与WT相比，具有吲哚核心的分子中的氢键基团可改善在A147T处的结合，这一策略产生了对A147T亲和力高达十倍的化合物。这些结果应为未来设计同时结合A147T和WT TSPO用于神经炎症成像的化合物提供参考。
