Synthesis and evaluation of novel potent TSPO PET ligands with 2-phenylpyrazolo[1,5-a]pyrimidin-3-yl acetamide

Van Hieu Tran; Hyunjun Park; Jaekyung Park; Young Do Kwon; Shinwoo Kang; Jae Ho Jung; Keun A. Chang; Byung Chul Lee; Sang Yoon Lee; Soosung Kang; Hee Kwon Kim

doi:10.1016/j.bmc.2019.07.036

Synthesis and evaluation of novel potent TSPO PET ligands with 2-phenylpyrazolo[1,5-a]pyrimidin-3-yl acetamide

Van Hieu Tran, Hyunjun Park, Jaekyung Park, Young Do Kwon, Shinwoo Kang, Jae Ho Jung, Keun A. Chang, Byung Chul Lee, Sang Yoon Lee, Soosung Kang, Hee Kwon Kim

Department of Pharmaceutical Sciences

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

13 Scopus citations

Abstract

Translocator protein (TSPO) expression is closely related with neuroinflammation and neuronal damage which might cause several central nervous system diseases. Herein, a series of TSPO ligands (11a–c and 13a–d) with a 2-phenylpyrazolo[1,5-a]pyrimidin-3-yl acetamide structure were prepared and evaluated via an in vitro binding assay. Most of the novel ligands exhibited a nano-molar affinity for TSPO, which was better than that of DPA-714. Particularly, 11a exhibited a subnano-molar TSPO binding affinity with suitable lipophilicity for in vivo brain studies. After radiolabeling with fluorine-18, [¹⁸F]11a was used for a dynamic positron emission tomography (PET) study in a rat LPS-induced neuroinflammation model; the inflammatory lesion was clearly visualized with a superior target-to-background ratio compared to [¹⁸F]DPA-714. An immunohistochemical examination of the dissected brains confirmed that the uptake location of [¹⁸F]11a in the PET study was consistent with a positively activated microglia region. This study proved that [¹⁸F]11a could be employed as a potential PET tracer for detecting neuroinflammation and could give possibility for diagnosis of other diseases, such as cancers related with TSPO expression.

Original language	English
Pages (from-to)	4069-4080
Number of pages	12
Journal	Bioorganic and Medicinal Chemistry
Volume	27
Issue number	18
DOIs	https://doi.org/10.1016/j.bmc.2019.07.036
State	Published - 15 Sep 2019

Bibliographical note

Funding Information:
This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education , Republic of Korea ( 2018R1D1A1B07047572 ). This work was supported by Fund of Biomedical Research Institute, Chonbuk National University Hospital , Republic of Korea. This work was supported by a grant from the Korea Health Technology R & D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry for Health and Welfare , Republic of Korea ( HI14C1135 ).

Publisher Copyright:
© 2019 Elsevier Ltd

Keywords

Neuroinflammation
Positron emission tomography probe
Structure activity relationships
Translocator protein

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10.1016/j.bmc.2019.07.036

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@article{478ddc69a5ec4f0685c430eae0cbbfc4,

title = "Synthesis and evaluation of novel potent TSPO PET ligands with 2-phenylpyrazolo[1,5-a]pyrimidin-3-yl acetamide",

abstract = "Translocator protein (TSPO) expression is closely related with neuroinflammation and neuronal damage which might cause several central nervous system diseases. Herein, a series of TSPO ligands (11a–c and 13a–d) with a 2-phenylpyrazolo[1,5-a]pyrimidin-3-yl acetamide structure were prepared and evaluated via an in vitro binding assay. Most of the novel ligands exhibited a nano-molar affinity for TSPO, which was better than that of DPA-714. Particularly, 11a exhibited a subnano-molar TSPO binding affinity with suitable lipophilicity for in vivo brain studies. After radiolabeling with fluorine-18, [18F]11a was used for a dynamic positron emission tomography (PET) study in a rat LPS-induced neuroinflammation model; the inflammatory lesion was clearly visualized with a superior target-to-background ratio compared to [18F]DPA-714. An immunohistochemical examination of the dissected brains confirmed that the uptake location of [18F]11a in the PET study was consistent with a positively activated microglia region. This study proved that [18F]11a could be employed as a potential PET tracer for detecting neuroinflammation and could give possibility for diagnosis of other diseases, such as cancers related with TSPO expression.",

keywords = "Neuroinflammation, Positron emission tomography probe, Structure activity relationships, Translocator protein",

author = "{Hieu Tran}, Van and Hyunjun Park and Jaekyung Park and Kwon, {Young Do} and Shinwoo Kang and {Ho Jung}, Jae and Chang, {Keun A.} and {Chul Lee}, Byung and Lee, {Sang Yoon} and Soosung Kang and Kim, {Hee Kwon}",

note = "Funding Information: This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education , Republic of Korea ( 2018R1D1A1B07047572 ). This work was supported by Fund of Biomedical Research Institute, Chonbuk National University Hospital , Republic of Korea. This work was supported by a grant from the Korea Health Technology R & D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry for Health and Welfare , Republic of Korea ( HI14C1135 ). Publisher Copyright: {\textcopyright} 2019 Elsevier Ltd",

year = "2019",

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doi = "10.1016/j.bmc.2019.07.036",

language = "English",

volume = "27",

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T1 - Synthesis and evaluation of novel potent TSPO PET ligands with 2-phenylpyrazolo[1,5-a]pyrimidin-3-yl acetamide

AU - Hieu Tran, Van

AU - Park, Hyunjun

AU - Park, Jaekyung

AU - Kwon, Young Do

AU - Kang, Shinwoo

AU - Ho Jung, Jae

AU - Chang, Keun A.

AU - Chul Lee, Byung

AU - Lee, Sang Yoon

AU - Kang, Soosung

AU - Kim, Hee Kwon

N1 - Funding Information: This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education , Republic of Korea ( 2018R1D1A1B07047572 ). This work was supported by Fund of Biomedical Research Institute, Chonbuk National University Hospital , Republic of Korea. This work was supported by a grant from the Korea Health Technology R & D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry for Health and Welfare , Republic of Korea ( HI14C1135 ). Publisher Copyright: © 2019 Elsevier Ltd

PY - 2019/9/15

Y1 - 2019/9/15

N2 - Translocator protein (TSPO) expression is closely related with neuroinflammation and neuronal damage which might cause several central nervous system diseases. Herein, a series of TSPO ligands (11a–c and 13a–d) with a 2-phenylpyrazolo[1,5-a]pyrimidin-3-yl acetamide structure were prepared and evaluated via an in vitro binding assay. Most of the novel ligands exhibited a nano-molar affinity for TSPO, which was better than that of DPA-714. Particularly, 11a exhibited a subnano-molar TSPO binding affinity with suitable lipophilicity for in vivo brain studies. After radiolabeling with fluorine-18, [18F]11a was used for a dynamic positron emission tomography (PET) study in a rat LPS-induced neuroinflammation model; the inflammatory lesion was clearly visualized with a superior target-to-background ratio compared to [18F]DPA-714. An immunohistochemical examination of the dissected brains confirmed that the uptake location of [18F]11a in the PET study was consistent with a positively activated microglia region. This study proved that [18F]11a could be employed as a potential PET tracer for detecting neuroinflammation and could give possibility for diagnosis of other diseases, such as cancers related with TSPO expression.

AB - Translocator protein (TSPO) expression is closely related with neuroinflammation and neuronal damage which might cause several central nervous system diseases. Herein, a series of TSPO ligands (11a–c and 13a–d) with a 2-phenylpyrazolo[1,5-a]pyrimidin-3-yl acetamide structure were prepared and evaluated via an in vitro binding assay. Most of the novel ligands exhibited a nano-molar affinity for TSPO, which was better than that of DPA-714. Particularly, 11a exhibited a subnano-molar TSPO binding affinity with suitable lipophilicity for in vivo brain studies. After radiolabeling with fluorine-18, [18F]11a was used for a dynamic positron emission tomography (PET) study in a rat LPS-induced neuroinflammation model; the inflammatory lesion was clearly visualized with a superior target-to-background ratio compared to [18F]DPA-714. An immunohistochemical examination of the dissected brains confirmed that the uptake location of [18F]11a in the PET study was consistent with a positively activated microglia region. This study proved that [18F]11a could be employed as a potential PET tracer for detecting neuroinflammation and could give possibility for diagnosis of other diseases, such as cancers related with TSPO expression.

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KW - Positron emission tomography probe

KW - Structure activity relationships

KW - Translocator protein

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SN - 0968-0896

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JO - Bioorganic and Medicinal Chemistry

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IS - 18

ER -

Synthesis and evaluation of novel potent TSPO PET ligands with 2-phenylpyrazolo[1,5-a]pyrimidin-3-yl acetamide

Abstract

Bibliographical note

Keywords

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