Reversing binding sensitivity to A147T translocator protein

Sophie V. Vo; Samuel D. Banister; Isaac Freelander; Eryn L. Werry; Tristan A. Reekie; Lars M. Ittner; Michael Kassiou

doi:10.1039/c9md00580c

Reversing binding sensitivity to A147T translocator protein

Sophie V. Vo, Samuel D. Banister, Isaac Freelander, Eryn L. Werry, Tristan A. Reekie, Lars M. Ittner, Michael Kassiou^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

5 Citations (Scopus)

Abstract

The translocator protein (TSPO) is a target for the development of neuroinflammation imaging agents. Clinical translation of TSPO PET ligands, such as [¹¹C]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.

Original language	English
Pages (from-to)	511-517
Number of pages	7
Journal	RSC Medicinal Chemistry
Volume	11
Issue number	4
DOIs	https://doi.org/10.1039/c9md00580c
Publication status	Published - Apr 2020

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title = "Reversing binding sensitivity to A147T translocator protein",

abstract = "The translocator protein (TSPO) is a target for the development of neuroinflammation imaging agents. Clinical translation of TSPO PET ligands, such as [11C]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.",

author = "Vo, {Sophie V.} and Banister, {Samuel D.} and Isaac Freelander and Werry, {Eryn L.} and Reekie, {Tristan A.} and Ittner, {Lars M.} and Michael Kassiou",

note = "Publisher Copyright: This journal is {\textcopyright} The Royal Society of Chemistry.",

year = "2020",

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doi = "10.1039/c9md00580c",

language = "English",

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AU - Vo, Sophie V.

AU - Banister, Samuel D.

AU - Freelander, Isaac

AU - Werry, Eryn L.

AU - Reekie, Tristan A.

AU - Ittner, Lars M.

AU - Kassiou, Michael

PY - 2020/4

Y1 - 2020/4

N2 - The translocator protein (TSPO) is a target for the development of neuroinflammation imaging agents. Clinical translation of TSPO PET ligands, such as [11C]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.

AB - The translocator protein (TSPO) is a target for the development of neuroinflammation imaging agents. Clinical translation of TSPO PET ligands, such as [11C]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.

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JO - RSC Medicinal Chemistry

JF - RSC Medicinal Chemistry

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Reversing binding sensitivity to A147T translocator protein

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