Automated Synthesis and Initial Evaluation of (4′-Amino-5′,8′-difluoro-1′H-spiro[piperidine-4,2′-quinazolin]-1-yl)(4-[18F]fluorophenyl)methanone for PET/MR Imaging of Inducible Nitric Oxide Synthase
Background. Inducible nitric oxide synthase (iNOS) plays a crucial role in neuroinflammation, especially microglial activity, and may potentially represent a useful biomarker of neuroinflammation. In this study, we carefully defined a strategic plan to develop iNOS-targeted molecular PET imaging usi...
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| Format: | Article |
| Language: | English |
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SAGE Publishing
2021-01-01
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| Series: | Molecular Imaging |
| Online Access: | http://dx.doi.org/10.1155/2021/9996125 |
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| author | Skye Hsin-Hsien Yeh Wen-Sheng Huang Chuang-Hsin Chiu Chuan-Lin Chen Hui-Ting Chen Dae Yoon Chi Zhengxing Ge Tsung-Hsun Yu Pao-Yeh Wang Yu-Yeh Kuo Chun-Tse Hung Geng-Ying Li Chi-Wei Chang |
| author_facet | Skye Hsin-Hsien Yeh Wen-Sheng Huang Chuang-Hsin Chiu Chuan-Lin Chen Hui-Ting Chen Dae Yoon Chi Zhengxing Ge Tsung-Hsun Yu Pao-Yeh Wang Yu-Yeh Kuo Chun-Tse Hung Geng-Ying Li Chi-Wei Chang |
| author_sort | Skye Hsin-Hsien Yeh |
| collection | DOAJ |
| description | Background. Inducible nitric oxide synthase (iNOS) plays a crucial role in neuroinflammation, especially microglial activity, and may potentially represent a useful biomarker of neuroinflammation. In this study, we carefully defined a strategic plan to develop iNOS-targeted molecular PET imaging using (4′-amino-5′,8′-difluoro-1′H-spiro[piperidine-4,2′-quinazolin]-1-yl)(4-fluorophenyl)methanone ([18F]FBAT) as a tracer in a mouse model of lipopolysaccharide- (LPS-) induced brain inflammation. Methods. An in vitro model, murine microglial BV2 cell line, was used to assess the uptake of [18F]FBAT in response to iNOS induction at the cellular level. In vivo whole-body dynamic PET/MR imaging was acquired in LPS-treated (5 mg/kg) and control mice. Standard uptake value (SUV), total volume of distribution (Vt), and area under the curve (AUC) based on the [18F]FBAT PET signals were determined. The expression of iNOS was confirmed by immunohistochemistry (IHC) of brain tissues. Results. At the end of synthesis, the yield of [18F]FBAT was 2.2–3.1% (EOS), radiochemical purity was >99%, and molar radioactivity was 125–137 GBq/μmol. In vitro, [18F]FBAT rapidly and progressively accumulated in murine microglial BV2 cells exposed to LPS; however, [18F]FBAT accumulation was inhibited by aminoguanidine, a selective iNOS inhibitor. In vivo biodistribution studies of [18F]FBAT showed a significant increase in the liver and kidney on LPS-treated mice. At 3 h postinjection of LPS, in vivo, the [18F]FBAT accumulation ratios at 30 min post intravenous (i.v.) radiotracer injection for the whole brain, cortex, cerebellum, and brainstem were 2.16±0.18, 1.53±0.25, 1.41±0.21, and 1.90±0.12, respectively, compared to those of mice not injected with LPS. The mean area under the curve (AUC0-30min), total volume of distribution (Vt, mL/cm3), and Ki (influx rate) of [18F]FBAT were 1.9±0.21- and 1.4±0.22-fold higher in the 3 h LPS group, respectively, than in the control group. In the pharmacokinetic two-compartment model, the whole brain Ki of [18F]FBAT was significantly higher in mice injected with LPS compared to the control group. Aminoguanidine, selective iNOS inhibitor, pretreatment significantly reduced the AUC0-30min and Vt values in LPS-induced mice. Quantitative analysis of immunohistochemically stained brain sections confirmed iNOS was preferentially upregulated in the cerebellum and cortex of mice injected with LPS. Conclusion. An automated robotic method was established for radiosynthesis of [18F]FBAT, and the preliminary in vitro and in vivo results demonstrated the feasibility of detecting iNOS activity/expression in LPS-treated neuroinflammation by noninvasive imaging with [18F]FBAT PET/MRI. |
| format | Article |
| id | doaj-art-7117741d026b42b79b6cd7df2cab4598 |
| institution | Kabale University |
| issn | 1536-0121 |
| language | English |
| publishDate | 2021-01-01 |
| publisher | SAGE Publishing |
| record_format | Article |
| series | Molecular Imaging |
| spelling | doaj-art-7117741d026b42b79b6cd7df2cab45982025-02-03T10:07:24ZengSAGE PublishingMolecular Imaging1536-01212021-01-01202110.1155/2021/99961259996125Automated Synthesis and Initial Evaluation of (4′-Amino-5′,8′-difluoro-1′H-spiro[piperidine-4,2′-quinazolin]-1-yl)(4-[18F]fluorophenyl)methanone for PET/MR Imaging of Inducible Nitric Oxide SynthaseSkye Hsin-Hsien Yeh0Wen-Sheng Huang1Chuang-Hsin Chiu2Chuan-Lin Chen3Hui-Ting Chen4Dae Yoon Chi5Zhengxing Ge6Tsung-Hsun Yu7Pao-Yeh Wang8Yu-Yeh Kuo9Chun-Tse Hung10Geng-Ying Li11Chi-Wei Chang12Brain Research Center, National Yang Ming Chiao Tung University, Taipei, TaiwanDepartment of Nuclear Medicine, Taipei Medical University Hospital, Taipei, TaiwanDepartment of Nuclear Medicine, Tri-Service General Hospital, Taipei, TaiwanDepartment of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, TaiwanDepartment of Pharmacy, National Yang Ming Chiao Tung University, Taipei, TaiwanFutureChem Co. Ltd., Seoul, Republic of KoreaJiangsu Huayi Technology Co. Ltd., Jiangsu, ChinaBrain Research Center, National Yang Ming Chiao Tung University, Taipei, TaiwanBrain Research Center, National Yang Ming Chiao Tung University, Taipei, TaiwanDepartment of Nuclear Medicine, Taipei Medical University Hospital, Taipei, TaiwanDepartment of Nuclear Medicine, Taipei Veterans General Hospital, Taipei, TaiwanDepartment of Nuclear Medicine, Taipei Veterans General Hospital, Taipei, TaiwanDepartment of Nuclear Medicine, Taipei Veterans General Hospital, Taipei, TaiwanBackground. Inducible nitric oxide synthase (iNOS) plays a crucial role in neuroinflammation, especially microglial activity, and may potentially represent a useful biomarker of neuroinflammation. In this study, we carefully defined a strategic plan to develop iNOS-targeted molecular PET imaging using (4′-amino-5′,8′-difluoro-1′H-spiro[piperidine-4,2′-quinazolin]-1-yl)(4-fluorophenyl)methanone ([18F]FBAT) as a tracer in a mouse model of lipopolysaccharide- (LPS-) induced brain inflammation. Methods. An in vitro model, murine microglial BV2 cell line, was used to assess the uptake of [18F]FBAT in response to iNOS induction at the cellular level. In vivo whole-body dynamic PET/MR imaging was acquired in LPS-treated (5 mg/kg) and control mice. Standard uptake value (SUV), total volume of distribution (Vt), and area under the curve (AUC) based on the [18F]FBAT PET signals were determined. The expression of iNOS was confirmed by immunohistochemistry (IHC) of brain tissues. Results. At the end of synthesis, the yield of [18F]FBAT was 2.2–3.1% (EOS), radiochemical purity was >99%, and molar radioactivity was 125–137 GBq/μmol. In vitro, [18F]FBAT rapidly and progressively accumulated in murine microglial BV2 cells exposed to LPS; however, [18F]FBAT accumulation was inhibited by aminoguanidine, a selective iNOS inhibitor. In vivo biodistribution studies of [18F]FBAT showed a significant increase in the liver and kidney on LPS-treated mice. At 3 h postinjection of LPS, in vivo, the [18F]FBAT accumulation ratios at 30 min post intravenous (i.v.) radiotracer injection for the whole brain, cortex, cerebellum, and brainstem were 2.16±0.18, 1.53±0.25, 1.41±0.21, and 1.90±0.12, respectively, compared to those of mice not injected with LPS. The mean area under the curve (AUC0-30min), total volume of distribution (Vt, mL/cm3), and Ki (influx rate) of [18F]FBAT were 1.9±0.21- and 1.4±0.22-fold higher in the 3 h LPS group, respectively, than in the control group. In the pharmacokinetic two-compartment model, the whole brain Ki of [18F]FBAT was significantly higher in mice injected with LPS compared to the control group. Aminoguanidine, selective iNOS inhibitor, pretreatment significantly reduced the AUC0-30min and Vt values in LPS-induced mice. Quantitative analysis of immunohistochemically stained brain sections confirmed iNOS was preferentially upregulated in the cerebellum and cortex of mice injected with LPS. Conclusion. An automated robotic method was established for radiosynthesis of [18F]FBAT, and the preliminary in vitro and in vivo results demonstrated the feasibility of detecting iNOS activity/expression in LPS-treated neuroinflammation by noninvasive imaging with [18F]FBAT PET/MRI.http://dx.doi.org/10.1155/2021/9996125 |
| spellingShingle | Skye Hsin-Hsien Yeh Wen-Sheng Huang Chuang-Hsin Chiu Chuan-Lin Chen Hui-Ting Chen Dae Yoon Chi Zhengxing Ge Tsung-Hsun Yu Pao-Yeh Wang Yu-Yeh Kuo Chun-Tse Hung Geng-Ying Li Chi-Wei Chang Automated Synthesis and Initial Evaluation of (4′-Amino-5′,8′-difluoro-1′H-spiro[piperidine-4,2′-quinazolin]-1-yl)(4-[18F]fluorophenyl)methanone for PET/MR Imaging of Inducible Nitric Oxide Synthase Molecular Imaging |
| title | Automated Synthesis and Initial Evaluation of (4′-Amino-5′,8′-difluoro-1′H-spiro[piperidine-4,2′-quinazolin]-1-yl)(4-[18F]fluorophenyl)methanone for PET/MR Imaging of Inducible Nitric Oxide Synthase |
| title_full | Automated Synthesis and Initial Evaluation of (4′-Amino-5′,8′-difluoro-1′H-spiro[piperidine-4,2′-quinazolin]-1-yl)(4-[18F]fluorophenyl)methanone for PET/MR Imaging of Inducible Nitric Oxide Synthase |
| title_fullStr | Automated Synthesis and Initial Evaluation of (4′-Amino-5′,8′-difluoro-1′H-spiro[piperidine-4,2′-quinazolin]-1-yl)(4-[18F]fluorophenyl)methanone for PET/MR Imaging of Inducible Nitric Oxide Synthase |
| title_full_unstemmed | Automated Synthesis and Initial Evaluation of (4′-Amino-5′,8′-difluoro-1′H-spiro[piperidine-4,2′-quinazolin]-1-yl)(4-[18F]fluorophenyl)methanone for PET/MR Imaging of Inducible Nitric Oxide Synthase |
| title_short | Automated Synthesis and Initial Evaluation of (4′-Amino-5′,8′-difluoro-1′H-spiro[piperidine-4,2′-quinazolin]-1-yl)(4-[18F]fluorophenyl)methanone for PET/MR Imaging of Inducible Nitric Oxide Synthase |
| title_sort | automated synthesis and initial evaluation of 4 amino 5 8 difluoro 1 h spiro piperidine 4 2 quinazolin 1 yl 4 18f fluorophenyl methanone for pet mr imaging of inducible nitric oxide synthase |
| url | http://dx.doi.org/10.1155/2021/9996125 |
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