Synthesis and evaluation of 99mTc-labeled 1-(2-Pyridyl)piperazine derivatives as radioligands for 5HT7 receptors
Copyright © 2023 Elsevier Inc. All rights reserved..
Glioblastoma multiform (GBM) is one of the most aggressive tumors of the central nervous system in humans. GBM overexpresses serotonin-7 receptors (5-HT7Rs); hence, this study aims to develop 5-HT7R targeted radiotracers. Aryl piperazine derivatives can act as ligands for 5-HT7R. Therefore, compounds 6 and 7 as 1-(3-nitropyridin-2-yl)piperazine derivatives were synthesized and radiolabeled with 99mTcN2+ core. Radiolabeled 6 and 7 (99mTcN-[6] and 99mTcN-[7]) were prepared with high radiochemical purity (RCP > 96%). They displayed high affinity toward U-87 MG cell line 5-HT7R. The calculated Ki for 99mTcN-[7] was lower than that of 99mTcN-[6] (14.85 ± 0.32 vs 22.57 ± 0.73 nM) which indicates the higher affinity of 99mTcN-[7] toward 5-HT7R. A molecular docking study also confirmed the binding of these radiotracers to 5-HT7R. The biodistribution study in normal mice revealed that 99mTcN-[7] has the highest brain accumulation at 30 min post-injection (0.54 ± 0.12 %ID/g) while the uptake of 99mTcN-[6] is much lower (0.14 ± 0.02 %ID/g). The biodistribution study in the xenograft model confirms that the radiotracers recognize the tumor site. 99mTcN-[6], and 99mTcN-[7] showed the highest tumor uptake at 1-hour post-injection (5.44 ± 0.58 vs 4.94 ± 1.65 %ID/g) and tumor-to-muscle ratios were (4.61 vs. 5.61). The injection of pimozide blocks the receptors and significantly reduces the tumor-to-muscle ratios at 1-hour post-injection to 0.81 and 0.31, respectively. In correlation with in vitro study, 99mTcN-[6] and 99mTcN-[7] visualize the tumor site in U-87 MG glioma xenografted nude mice and display the tumor-to-muscle ratios of 7.05 and 6.03.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:135 |
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| Enthalten in: |
Bioorganic chemistry - 135(2023) vom: 26. Juni, Seite 106486 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Karimi, Maryam [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 01.05.2023 Date Revised 02.05.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bioorg.2023.106486 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM354703668 |
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| 520 | |a Glioblastoma multiform (GBM) is one of the most aggressive tumors of the central nervous system in humans. GBM overexpresses serotonin-7 receptors (5-HT7Rs); hence, this study aims to develop 5-HT7R targeted radiotracers. Aryl piperazine derivatives can act as ligands for 5-HT7R. Therefore, compounds 6 and 7 as 1-(3-nitropyridin-2-yl)piperazine derivatives were synthesized and radiolabeled with 99mTcN2+ core. Radiolabeled 6 and 7 (99mTcN-[6] and 99mTcN-[7]) were prepared with high radiochemical purity (RCP > 96%). They displayed high affinity toward U-87 MG cell line 5-HT7R. The calculated Ki for 99mTcN-[7] was lower than that of 99mTcN-[6] (14.85 ± 0.32 vs 22.57 ± 0.73 nM) which indicates the higher affinity of 99mTcN-[7] toward 5-HT7R. A molecular docking study also confirmed the binding of these radiotracers to 5-HT7R. The biodistribution study in normal mice revealed that 99mTcN-[7] has the highest brain accumulation at 30 min post-injection (0.54 ± 0.12 %ID/g) while the uptake of 99mTcN-[6] is much lower (0.14 ± 0.02 %ID/g). The biodistribution study in the xenograft model confirms that the radiotracers recognize the tumor site. 99mTcN-[6], and 99mTcN-[7] showed the highest tumor uptake at 1-hour post-injection (5.44 ± 0.58 vs 4.94 ± 1.65 %ID/g) and tumor-to-muscle ratios were (4.61 vs. 5.61). The injection of pimozide blocks the receptors and significantly reduces the tumor-to-muscle ratios at 1-hour post-injection to 0.81 and 0.31, respectively. In correlation with in vitro study, 99mTcN-[6] and 99mTcN-[7] visualize the tumor site in U-87 MG glioma xenografted nude mice and display the tumor-to-muscle ratios of 7.05 and 6.03 | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a 5-HT(7) receptor | |
| 650 | 4 | |a Glioblastoma multiform | |
| 650 | 4 | |a Molecular imaging, tumor imaging | |
| 650 | 4 | |a SPECT | |
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| 700 | 1 | |a Irannejad, Hamid |e verfasserin |4 aut | |
| 700 | 1 | |a Mohammad Abedi, Seyed |e verfasserin |4 aut | |
| 700 | 1 | |a Molavipordanjani, Sajjad |e verfasserin |4 aut | |
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