Synthesis and Evaluation of [11C]7-Halogen-2-Phenyl Isoindolone Derivatives: Potential PET Radioligands for in vivo Imaging of 5-HT2C Receptors
The serotonin 5-HT2C receptor (5-HT2CR) is abundantly expressed throughout the central nervous system, and involved in a variety of neuroendocrine and neurobehavioral processes. The development of a selective radioligand that will enable in vivo imaging and quantification of 5-HT2CR densities repres...
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2021
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oai:doaj.org-article:069f82e0d7c44debaea12f523363efe62021-12-01T06:12:05ZSynthesis and Evaluation of [11C]7-Halogen-2-Phenyl Isoindolone Derivatives: Potential PET Radioligands for in vivo Imaging of 5-HT2C Receptors1662-453X10.3389/fnins.2021.766320https://doaj.org/article/069f82e0d7c44debaea12f523363efe62021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fnins.2021.766320/fullhttps://doaj.org/toc/1662-453XThe serotonin 5-HT2C receptor (5-HT2CR) is abundantly expressed throughout the central nervous system, and involved in a variety of neuroendocrine and neurobehavioral processes. The development of a selective radioligand that will enable in vivo imaging and quantification of 5-HT2CR densities represents a significant technological advancement in understanding both the normal function and pathophysiology of the 5-HT2CR. Four 7-halogen-2-phenyl isoindolones (7-F, Cl, Br, I) were synthesized and displayed high affinities for 5-HT2CR and high selectivity over 5-HT2A and 5-HT2B. [11C]7-Chloro-2-[4-methoxy-3-[2-(4-methylpiperidin-1-yl)ethoxy]phenyl]isoindolin-1-one (6) and [11C]7-iodo-2-[4-methoxy-3-[2-(4-methylpiperidin-1-yl)ethoxy]phenyl]isoindolin-1-one (9) were synthesized in high radiochemical yield of 37–44% [n = 10, decay corrected from end of (11C)CH3I synthesis] with high radiochemical purity via O-methylation with [11C]CH3I, respectively. MicroPET imaging studies in male rats with or without 5-HT2C antagonist SB-242084 showed that [11C]6 and [11C]9 display specific bindings to 5-HT2CR in the choroid plexus and hippocampus. In vivo microPET brain imaging studies in rhesus monkeys demonstrated that [11C]6 and [11C]9 exhibit excellent blood-brain barrier penetration. The contrast of bindings to the choroid plexus and hippocampus compared to the cerebellum peaked at 2.7 and 1.6, respectively, for [11C]6, and 3.7 and 2.7, respectively, for [11C]9, which were reduced by administration of a dose of SB-242084. Our results support the candidacy of [11C]6 and [11C]9 for further study as radioligands for in vivo quantitation of 5-HT2C sites by PET.Fanxing ZengJonathon A. NyeJonathon A. NyeRonald J. VollRonald J. VollJiyoung MunMark M. GoodmanMark M. GoodmanFrontiers Media S.A.articlePET radioligand5-HT2C receptorin vivobrain imagingcarbon-11Neurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENFrontiers in Neuroscience, Vol 15 (2021) |
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PET radioligand 5-HT2C receptor in vivo brain imaging carbon-11 Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 |
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PET radioligand 5-HT2C receptor in vivo brain imaging carbon-11 Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Fanxing Zeng Jonathon A. Nye Jonathon A. Nye Ronald J. Voll Ronald J. Voll Jiyoung Mun Mark M. Goodman Mark M. Goodman Synthesis and Evaluation of [11C]7-Halogen-2-Phenyl Isoindolone Derivatives: Potential PET Radioligands for in vivo Imaging of 5-HT2C Receptors |
| description |
The serotonin 5-HT2C receptor (5-HT2CR) is abundantly expressed throughout the central nervous system, and involved in a variety of neuroendocrine and neurobehavioral processes. The development of a selective radioligand that will enable in vivo imaging and quantification of 5-HT2CR densities represents a significant technological advancement in understanding both the normal function and pathophysiology of the 5-HT2CR. Four 7-halogen-2-phenyl isoindolones (7-F, Cl, Br, I) were synthesized and displayed high affinities for 5-HT2CR and high selectivity over 5-HT2A and 5-HT2B. [11C]7-Chloro-2-[4-methoxy-3-[2-(4-methylpiperidin-1-yl)ethoxy]phenyl]isoindolin-1-one (6) and [11C]7-iodo-2-[4-methoxy-3-[2-(4-methylpiperidin-1-yl)ethoxy]phenyl]isoindolin-1-one (9) were synthesized in high radiochemical yield of 37–44% [n = 10, decay corrected from end of (11C)CH3I synthesis] with high radiochemical purity via O-methylation with [11C]CH3I, respectively. MicroPET imaging studies in male rats with or without 5-HT2C antagonist SB-242084 showed that [11C]6 and [11C]9 display specific bindings to 5-HT2CR in the choroid plexus and hippocampus. In vivo microPET brain imaging studies in rhesus monkeys demonstrated that [11C]6 and [11C]9 exhibit excellent blood-brain barrier penetration. The contrast of bindings to the choroid plexus and hippocampus compared to the cerebellum peaked at 2.7 and 1.6, respectively, for [11C]6, and 3.7 and 2.7, respectively, for [11C]9, which were reduced by administration of a dose of SB-242084. Our results support the candidacy of [11C]6 and [11C]9 for further study as radioligands for in vivo quantitation of 5-HT2C sites by PET. |
| format |
article |
| author |
Fanxing Zeng Jonathon A. Nye Jonathon A. Nye Ronald J. Voll Ronald J. Voll Jiyoung Mun Mark M. Goodman Mark M. Goodman |
| author_facet |
Fanxing Zeng Jonathon A. Nye Jonathon A. Nye Ronald J. Voll Ronald J. Voll Jiyoung Mun Mark M. Goodman Mark M. Goodman |
| author_sort |
Fanxing Zeng |
| title |
Synthesis and Evaluation of [11C]7-Halogen-2-Phenyl Isoindolone Derivatives: Potential PET Radioligands for in vivo Imaging of 5-HT2C Receptors |
| title_short |
Synthesis and Evaluation of [11C]7-Halogen-2-Phenyl Isoindolone Derivatives: Potential PET Radioligands for in vivo Imaging of 5-HT2C Receptors |
| title_full |
Synthesis and Evaluation of [11C]7-Halogen-2-Phenyl Isoindolone Derivatives: Potential PET Radioligands for in vivo Imaging of 5-HT2C Receptors |
| title_fullStr |
Synthesis and Evaluation of [11C]7-Halogen-2-Phenyl Isoindolone Derivatives: Potential PET Radioligands for in vivo Imaging of 5-HT2C Receptors |
| title_full_unstemmed |
Synthesis and Evaluation of [11C]7-Halogen-2-Phenyl Isoindolone Derivatives: Potential PET Radioligands for in vivo Imaging of 5-HT2C Receptors |
| title_sort |
synthesis and evaluation of [11c]7-halogen-2-phenyl isoindolone derivatives: potential pet radioligands for in vivo imaging of 5-ht2c receptors |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/069f82e0d7c44debaea12f523363efe6 |
| work_keys_str_mv |
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| _version_ |
1718405455828484096 |