Structure–activity relationship of pyrazol-4-yl-pyridine derivatives and identification of a radiofluorinated probe for imaging the muscarinic acetylcholine receptor M4
There is an accumulating body of evidence implicating the muscarinic acetylcholine receptor 4 (M4) in schizophrenia and dementia with Lewy bodies, however, a clinically validated M4 positron emission tomography (PET) radioligand is currently lacking. As such, the aim of this study was to develop a s...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | Acta Pharmaceutica Sinica B |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383522003203 |
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| author | Ahmed Haider Xiaoyun Deng Olivia Mastromihalis Stefanie K. Pfister Troels E. Jeppesen Zhiwei Xiao Vi Pham Shaofa Sun Jian Rong Chunyu Zhao Jiahui Chen Yinlong Li Theresa R. Connors April T. Davenport James B. Daunais Vahid Hosseini Wenqing Ran Arthur Christopoulos Lu Wang Celine Valant Steven H. Liang |
| author_facet | Ahmed Haider Xiaoyun Deng Olivia Mastromihalis Stefanie K. Pfister Troels E. Jeppesen Zhiwei Xiao Vi Pham Shaofa Sun Jian Rong Chunyu Zhao Jiahui Chen Yinlong Li Theresa R. Connors April T. Davenport James B. Daunais Vahid Hosseini Wenqing Ran Arthur Christopoulos Lu Wang Celine Valant Steven H. Liang |
| author_sort | Ahmed Haider |
| collection | DOAJ |
| description | There is an accumulating body of evidence implicating the muscarinic acetylcholine receptor 4 (M4) in schizophrenia and dementia with Lewy bodies, however, a clinically validated M4 positron emission tomography (PET) radioligand is currently lacking. As such, the aim of this study was to develop a suitable M4 PET ligand that allows the non-invasive visualization of M4 in the brain. Structure–activity relationship studies of pyrazol-4-yl-pyridine derivates led to the discovery of target compound 12 ― a subtype-selective positive allosteric modulator (PAM). The radiofluorinated analogue, [18F]12, was synthesized in 28 ± 10% radiochemical yield, >37 GBq/μmol and an excellent radiochemical purity >99%. Initial in vitro autoradiograms on rodent brain sections were performed in the absence of carbachol and showed moderate specificity as well as a low selectivity of [18F]12 for the M4-rich striatum. However, in the presence of carbachol, a significant increase in tracer binding was observed in the rat striatum, which was reduced by >60% under blocking conditions, thus indicating that orthosteric ligand interaction is required for efficient binding of [18F]12 to the allosteric site. Remarkably, however, the presence of carbachol was not required for high specific binding in the non-human primate (NHP) and human striatum, and did not further improve the specificity and selectivity of [18F]12 in higher species. These results pointed towards significant species-differences and paved the way for a preliminary PET study in NHP, where peak brain uptake of [18F]12 was found in the putamen and temporal cortex. In conclusion, we report on the identification and preclinical development of the first radiofluorinated M4 PET radioligand with promising attributes. The availability of a clinically validated M4 PET radioligand harbors potential to facilitate drug development and provide a useful diagnostic tool for non-invasive imaging. |
| first_indexed | 2024-04-10T17:23:27Z |
| format | Article |
| id | doaj.art-23c849f24d484180a951dacc1844f3f8 |
| institution | Directory Open Access Journal |
| issn | 2211-3835 |
| language | English |
| last_indexed | 2024-04-10T17:23:27Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
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| series | Acta Pharmaceutica Sinica B |
| spelling | doaj.art-23c849f24d484180a951dacc1844f3f82023-02-05T04:15:59ZengElsevierActa Pharmaceutica Sinica B2211-38352023-01-01131213226Structure–activity relationship of pyrazol-4-yl-pyridine derivatives and identification of a radiofluorinated probe for imaging the muscarinic acetylcholine receptor M4Ahmed Haider0Xiaoyun Deng1Olivia Mastromihalis2Stefanie K. Pfister3Troels E. Jeppesen4Zhiwei Xiao5Vi Pham6Shaofa Sun7Jian Rong8Chunyu Zhao9Jiahui Chen10Yinlong Li11Theresa R. Connors12April T. Davenport13James B. Daunais14Vahid Hosseini15Wenqing Ran16Arthur Christopoulos17Lu Wang18Celine Valant19Steven H. Liang20Department of Radiology, Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USADepartment of Radiology, Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, ChinaDrug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, AustraliaDepartment of Radiology, Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USADepartment of Radiology, Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USADepartment of Radiology, Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USADrug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; Neuromedicines Discovery Centre, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, AustraliaHubei Collaborative Innovation Centre for Non-power Nuclear Technology, College of Nuclear Technology & Chemistry and Biology, Hubei University of Science and Technology, Xianning 437100, ChinaDepartment of Radiology, Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USADepartment of Radiology, Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USADepartment of Radiology, Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USADepartment of Radiology, Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USADepartment of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USADepartment of Physiology and Pharmacology, Wake Forest School of Medicine, Winston Salem, NC 27157, USADepartment of Physiology and Pharmacology, Wake Forest School of Medicine, Winston Salem, NC 27157, USATerasaki Institute for Biomedical Innovation (TIBI), Los Angeles, CA 90024, USACenter of Cyclotron and PET Radiopharmaceuticals, Department of Nuclear Medicine and PET/CT-MRI Center, the First Affiliated Hospital of Jinan University, Guangzhou 510630, ChinaDrug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; Neuromedicines Discovery Centre, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, AustraliaCenter of Cyclotron and PET Radiopharmaceuticals, Department of Nuclear Medicine and PET/CT-MRI Center, the First Affiliated Hospital of Jinan University, Guangzhou 510630, ChinaDrug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; Neuromedicines Discovery Centre, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; Corresponding authors. Tel./fax.: +1 617 230 5491.Department of Radiology, Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Corresponding authors. Tel./fax.: +1 617 230 5491.There is an accumulating body of evidence implicating the muscarinic acetylcholine receptor 4 (M4) in schizophrenia and dementia with Lewy bodies, however, a clinically validated M4 positron emission tomography (PET) radioligand is currently lacking. As such, the aim of this study was to develop a suitable M4 PET ligand that allows the non-invasive visualization of M4 in the brain. Structure–activity relationship studies of pyrazol-4-yl-pyridine derivates led to the discovery of target compound 12 ― a subtype-selective positive allosteric modulator (PAM). The radiofluorinated analogue, [18F]12, was synthesized in 28 ± 10% radiochemical yield, >37 GBq/μmol and an excellent radiochemical purity >99%. Initial in vitro autoradiograms on rodent brain sections were performed in the absence of carbachol and showed moderate specificity as well as a low selectivity of [18F]12 for the M4-rich striatum. However, in the presence of carbachol, a significant increase in tracer binding was observed in the rat striatum, which was reduced by >60% under blocking conditions, thus indicating that orthosteric ligand interaction is required for efficient binding of [18F]12 to the allosteric site. Remarkably, however, the presence of carbachol was not required for high specific binding in the non-human primate (NHP) and human striatum, and did not further improve the specificity and selectivity of [18F]12 in higher species. These results pointed towards significant species-differences and paved the way for a preliminary PET study in NHP, where peak brain uptake of [18F]12 was found in the putamen and temporal cortex. In conclusion, we report on the identification and preclinical development of the first radiofluorinated M4 PET radioligand with promising attributes. The availability of a clinically validated M4 PET radioligand harbors potential to facilitate drug development and provide a useful diagnostic tool for non-invasive imaging.http://www.sciencedirect.com/science/article/pii/S2211383522003203Muscarinic acetylcholine receptorPositron emission tomographyNeuroimagingNeuropharmacologyNeurological disorders |
| spellingShingle | Ahmed Haider Xiaoyun Deng Olivia Mastromihalis Stefanie K. Pfister Troels E. Jeppesen Zhiwei Xiao Vi Pham Shaofa Sun Jian Rong Chunyu Zhao Jiahui Chen Yinlong Li Theresa R. Connors April T. Davenport James B. Daunais Vahid Hosseini Wenqing Ran Arthur Christopoulos Lu Wang Celine Valant Steven H. Liang Structure–activity relationship of pyrazol-4-yl-pyridine derivatives and identification of a radiofluorinated probe for imaging the muscarinic acetylcholine receptor M4 Acta Pharmaceutica Sinica B Muscarinic acetylcholine receptor Positron emission tomography Neuroimaging Neuropharmacology Neurological disorders |
| title | Structure–activity relationship of pyrazol-4-yl-pyridine derivatives and identification of a radiofluorinated probe for imaging the muscarinic acetylcholine receptor M4 |
| title_full | Structure–activity relationship of pyrazol-4-yl-pyridine derivatives and identification of a radiofluorinated probe for imaging the muscarinic acetylcholine receptor M4 |
| title_fullStr | Structure–activity relationship of pyrazol-4-yl-pyridine derivatives and identification of a radiofluorinated probe for imaging the muscarinic acetylcholine receptor M4 |
| title_full_unstemmed | Structure–activity relationship of pyrazol-4-yl-pyridine derivatives and identification of a radiofluorinated probe for imaging the muscarinic acetylcholine receptor M4 |
| title_short | Structure–activity relationship of pyrazol-4-yl-pyridine derivatives and identification of a radiofluorinated probe for imaging the muscarinic acetylcholine receptor M4 |
| title_sort | structure activity relationship of pyrazol 4 yl pyridine derivatives and identification of a radiofluorinated probe for imaging the muscarinic acetylcholine receptor m4 |
| topic | Muscarinic acetylcholine receptor Positron emission tomography Neuroimaging Neuropharmacology Neurological disorders |
| url | http://www.sciencedirect.com/science/article/pii/S2211383522003203 |
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