Synthesis and biological evaluation of 18F-labelled deuterated tropane derivatives as dopamine transporter probes
Purpose: Dopamine transporter (DAT) is a promising target for positron emission tomography (PET) imaging of many neuropsychiatric diseases. 18F-labelled N-alkyl tropane analogues were reported to be useful PET radioligands for DAT. However, the drawback of 18F-labelled tropane analogues is that N-al...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-11-01
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| Series: | Arabian Journal of Chemistry |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1878535223007402 |
| _version_ | 1797657881588269056 |
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| author | Qianyue Hu Qingming Li Jie Tang Jie Liu Yi Fang Chunyi Liu Meihui Qi Zhengping Chen |
| author_facet | Qianyue Hu Qingming Li Jie Tang Jie Liu Yi Fang Chunyi Liu Meihui Qi Zhengping Chen |
| author_sort | Qianyue Hu |
| collection | DOAJ |
| description | Purpose: Dopamine transporter (DAT) is a promising target for positron emission tomography (PET) imaging of many neuropsychiatric diseases. 18F-labelled N-alkyl tropane analogues were reported to be useful PET radioligands for DAT. However, the drawback of 18F-labelled tropane analogues is that N-alkyl on tropane is easily metabolized in vivo, which interferes with brain imaging. To develop a more in vivo stable DAT-targeted PET radioligand with high DAT affinity and specificity, in this study, we synthesized and compared a series of 18F-labelled novel deuterated N-fluoropropyl tropane derivatives [18F]4a-e for DAT tracing. Procedures: Five deuterated N-fluoropropyl-d6 tropane derivatives (4a-e) and corresponding non-deuterated compounds (6a-e) were synthesized, and their semi-inhibitory concentrations (IC50) were measured by competitive binding assay. The radioligands [18F]4a-e and [18F]6a-e were obtained by two-step one-pot radio-labelling reactions. The selectivity and specificity of these radioligands were evaluated by cellular uptake and microPET in normal rats. [18F]4e was selected for further investigation with microPET of the PD model, autoradiography and biodistribution experiments and compared with its non-deuterated [18F]6e. Finally, in vivo metabolic stability was analyzed by radio-HPLC. Results: Ten tropane compounds had high DAT affinity (IC50 = 2–21 nM), in which FP-CIT-d6 (4e) had the lowest IC50 value of 2.7 nM. Radiolabelled [18F]4a-e and [18F]6a-e were obtained with radiochemical yields ranging from 10.6 ± 2.8% to 35.1 ± 5.4% with molar activities >20 GBq/μmol and the radiochemical purities >99%. [18F]4e showed the highest cell uptake (12%) and CFT inhibition efficacy (∼72%) among [18F]4a-e. MicroPET results showed [18F]4e has the highest target to non-target ratio (striatum/cerebellum). Therefore, [18F]4e was then selected for further biological evaluation. Ex vivo autoradiography experiment confirmed high specific binding of [18F]4e towards DAT. Biodistribution results indicated that [18F]4e has a higher striatum/cerebellum value than [18F]FP-CIT ([18F]6e) at 30–120 min. Furthermore, in vivo metabolism studies in rats revealed improved stability of [18F]4e as compared with that of [18F]6e. Conclusions: The new probe [18F]4e is a promising candidate with good DAT affinity, specificity and metabolic stability for PET imaging, and might provide reliable diagnosis, treatment and prognostic detection of DAT-related neuropsychiatric diseases. |
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| institution | Directory Open Access Journal |
| issn | 1878-5352 |
| language | English |
| last_indexed | 2024-03-11T17:50:54Z |
| publishDate | 2023-11-01 |
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| series | Arabian Journal of Chemistry |
| spelling | doaj.art-5374c6f1568540c986776b66ba2197952023-10-18T04:30:48ZengElsevierArabian Journal of Chemistry1878-53522023-11-011611105278Synthesis and biological evaluation of 18F-labelled deuterated tropane derivatives as dopamine transporter probesQianyue Hu0Qingming Li1Jie Tang2Jie Liu3Yi Fang4Chunyi Liu5Meihui Qi6Zhengping Chen7Department of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing 211166, ChinaNHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063, China; Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical University, Xuzhou 221004, ChinaNHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063, ChinaDepartment of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China; NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063, ChinaNHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063, ChinaNHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063, ChinaNHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063, China; School of Pharmaceutical Science, Inner Mongolia Medical University, Hohhot 010110, ChinaDepartment of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China; NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063, China; Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical University, Xuzhou 221004, China; Corresponding author at: 20 Qianrong Road, Wuxi 214063, China.Purpose: Dopamine transporter (DAT) is a promising target for positron emission tomography (PET) imaging of many neuropsychiatric diseases. 18F-labelled N-alkyl tropane analogues were reported to be useful PET radioligands for DAT. However, the drawback of 18F-labelled tropane analogues is that N-alkyl on tropane is easily metabolized in vivo, which interferes with brain imaging. To develop a more in vivo stable DAT-targeted PET radioligand with high DAT affinity and specificity, in this study, we synthesized and compared a series of 18F-labelled novel deuterated N-fluoropropyl tropane derivatives [18F]4a-e for DAT tracing. Procedures: Five deuterated N-fluoropropyl-d6 tropane derivatives (4a-e) and corresponding non-deuterated compounds (6a-e) were synthesized, and their semi-inhibitory concentrations (IC50) were measured by competitive binding assay. The radioligands [18F]4a-e and [18F]6a-e were obtained by two-step one-pot radio-labelling reactions. The selectivity and specificity of these radioligands were evaluated by cellular uptake and microPET in normal rats. [18F]4e was selected for further investigation with microPET of the PD model, autoradiography and biodistribution experiments and compared with its non-deuterated [18F]6e. Finally, in vivo metabolic stability was analyzed by radio-HPLC. Results: Ten tropane compounds had high DAT affinity (IC50 = 2–21 nM), in which FP-CIT-d6 (4e) had the lowest IC50 value of 2.7 nM. Radiolabelled [18F]4a-e and [18F]6a-e were obtained with radiochemical yields ranging from 10.6 ± 2.8% to 35.1 ± 5.4% with molar activities >20 GBq/μmol and the radiochemical purities >99%. [18F]4e showed the highest cell uptake (12%) and CFT inhibition efficacy (∼72%) among [18F]4a-e. MicroPET results showed [18F]4e has the highest target to non-target ratio (striatum/cerebellum). Therefore, [18F]4e was then selected for further biological evaluation. Ex vivo autoradiography experiment confirmed high specific binding of [18F]4e towards DAT. Biodistribution results indicated that [18F]4e has a higher striatum/cerebellum value than [18F]FP-CIT ([18F]6e) at 30–120 min. Furthermore, in vivo metabolism studies in rats revealed improved stability of [18F]4e as compared with that of [18F]6e. Conclusions: The new probe [18F]4e is a promising candidate with good DAT affinity, specificity and metabolic stability for PET imaging, and might provide reliable diagnosis, treatment and prognostic detection of DAT-related neuropsychiatric diseases.http://www.sciencedirect.com/science/article/pii/S1878535223007402Dopamine transporterPETDeuterium18F-labellingTropaneIn vivo metabolism |
| spellingShingle | Qianyue Hu Qingming Li Jie Tang Jie Liu Yi Fang Chunyi Liu Meihui Qi Zhengping Chen Synthesis and biological evaluation of 18F-labelled deuterated tropane derivatives as dopamine transporter probes Arabian Journal of Chemistry Dopamine transporter PET Deuterium 18F-labelling Tropane In vivo metabolism |
| title | Synthesis and biological evaluation of 18F-labelled deuterated tropane derivatives as dopamine transporter probes |
| title_full | Synthesis and biological evaluation of 18F-labelled deuterated tropane derivatives as dopamine transporter probes |
| title_fullStr | Synthesis and biological evaluation of 18F-labelled deuterated tropane derivatives as dopamine transporter probes |
| title_full_unstemmed | Synthesis and biological evaluation of 18F-labelled deuterated tropane derivatives as dopamine transporter probes |
| title_short | Synthesis and biological evaluation of 18F-labelled deuterated tropane derivatives as dopamine transporter probes |
| title_sort | synthesis and biological evaluation of 18f labelled deuterated tropane derivatives as dopamine transporter probes |
| topic | Dopamine transporter PET Deuterium 18F-labelling Tropane In vivo metabolism |
| url | http://www.sciencedirect.com/science/article/pii/S1878535223007402 |
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