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Eur J Med Chem. 2018 Nov 5;159:292-306. doi: 10.1016/j.ejmech.2018.09.069. Epub 2018 Sep 29.

Novel potential pyrazolopyrimidine based translocator protein ligands for the evaluation of neuroinflammation with PET.

Author information

1
Department of Nuclear Medicine, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea; Department of Nuclear Medicine, Molecular Imaging & Therapeutic Medicine Research Center, Chonbuk National University Medical School and Hospital, Jeonju, 54907, Republic of Korea.
2
Department of Pharmacology, College of Medicine, Gachon University, Incheon, 21936, Republic of Korea; Neuroscience Research Institute, Gachon University, Incheon, 21565, Republic of Korea.
3
Department of Pharmacology, College of Medicine, Gachon University, Incheon, 21936, Republic of Korea; Neuroscience Research Institute, Gachon University, Incheon, 21565, Republic of Korea; Gachon Advanced Institute for Health Science and Technology, Graduate School, Gachon University, Incheon, 21936, Republic of Korea.
4
Neuroscience Research Institute, Gachon University, Incheon, 21565, Republic of Korea; Gachon Advanced Institute for Health Science and Technology, Graduate School, Gachon University, Incheon, 21936, Republic of Korea.
5
Department of Pharmacology, College of Medicine, Gachon University, Incheon, 21936, Republic of Korea; Neuroscience Research Institute, Gachon University, Incheon, 21565, Republic of Korea; Gachon Advanced Institute for Health Science and Technology, Graduate School, Gachon University, Incheon, 21936, Republic of Korea. Electronic address: kachang74@gmail.com.
6
Neuroscience Research Institute, Gachon University, Incheon, 21565, Republic of Korea; Gachon Advanced Institute for Health Science and Technology, Graduate School, Gachon University, Incheon, 21936, Republic of Korea; Department of Neuroscience, College of Medicine, Gachon University, Incheon, 21936, Republic of Korea.
7
Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, 13620, Republic of Korea.
8
Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, 13620, Republic of Korea; Center for Nanomolecular Imaging and Innovative Drug Development, Advanced Institutes of Convergence Technology, Suwon, 16229, Republic of Korea.
9
Department of Nuclear Medicine, Molecular Imaging & Therapeutic Medicine Research Center, Chonbuk National University Medical School and Hospital, Jeonju, 54907, Republic of Korea; Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju, 54907, Republic of Korea.
10
Department of Nuclear Medicine, Molecular Imaging & Therapeutic Medicine Research Center, Chonbuk National University Medical School and Hospital, Jeonju, 54907, Republic of Korea; Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju, 54907, Republic of Korea. Electronic address: hkkim717@jbnu.ac.kr.

Abstract

Translocator protein (TSPO) is an interesting biological target because TSPO overexpression is associated with microglial activation caused by neuronal damage or neuroinflammation, and these activated microglia are involved in several central nervous system diseases. Herein, novel fluorinated ligands (14a-c and 16a-c) based on a 2-phenylpyrazolo[1,5-a]pyrimidin-3-yl acetamide scaffold were synthesized, and in vitro characterization of each of the novel ligands was performed to elucidate structure activity relationships. All of the newly synthesized ligands displayed nano-molar affinity for TSPO. Particularly, an in vitro affinity study suggests that 2-(5,7-diethyl-2-(4-(3-fluoro-2-methylpropoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide (14a), which exhibited high nano-molar affinity for TSPO and proper lipophilicity, was suitable for in vivo brain studies. Thus, radiosynthesis from tosylate precursor 13a using fluorine-18 was performed, and [18F]14a was obtained in a 31% radiochemical yield (decay-corrected). Dynamic positron emission tomography (PET) imaging studies were performed in a lipopolysaccharide (LPS)-induced neuroinflammation rat model using [18F]14a to identify the location of inflammation in the brain with a high target-to-background signal ratio. In addition, we validated that the locations of inflammatory lesions found by PET imaging were consistent with the locations observed by histological examination of dissected brains using antibodies. These results suggest that [18F]14a is a novel promising PET imaging agent for diagnosing neuroinflammation, and it may also prove to be applicable for diagnosing other diseases, including cancers associated with altered TSPO expression, using PET techniques.

KEYWORDS:

Imaging probe; Neuroinflammation; Positron emission tomography; Translocator protein

PMID:
30296688
DOI:
10.1016/j.ejmech.2018.09.069
[Indexed for MEDLINE]

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