Nuclear medicine and biology · 2023
Deuterated [18F]fluoroethyl tropane analogs as dopamine transporter probes: Synthesis and biological evaluation.
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Li Qingming, Hu Qianyue, Tang Jie, Fang Yi, Liu Chunyi, Liu Jie, Qi Meihui, Chen Zhengping, Zhang Ling
Аннотация
INTRODUCTION: The dopamine transporter (DAT) is vitally correlated with Parkinson's disease (PD) and other neurodegenerative diseases. Non-invasive imaging of DAT contributes to early diagnosis and monitoring of related diseases. Recently, we reported a deuterated [18F]fluoroethyl tropane analogue [18F]FECNT-d4 as a potential DAT PET imaging agent. The objective of this work was to extend the investigation by comparing four deuterated [18F]fluoroethyl tropane derivatives ([18F]2a-d) to develop metabolically stable DAT radioligands.
METHODS: Four fluoroethyl substituted phenyl-tropane compounds 1a-d and deuterated compounds 2a-d were synthesized and their IC50 values to DAT were evaluated. The [18F]fluoroethyl ligands [18F]1a-d and [18F]2a-d were obtained from corresponding labeling precursors by one-step radio-labeling reactions and investigated in terms of lipophilicity and in vitro binding affinity studies. [18F]1d and [18F]2d were then selected for further evaluations by in vivo metabolism study, biodistribution, ex vivo autoradiography, and microPET imaging studies.
RESULTS: [18F]1a-d and [18F]2a-d were obtained in radiochemical yield of 11-32 % with molar activities of 28-54 GBq/μmol. The 1d and 2d exhibited relatively high affinity to DAT (IC50: 1.9-2.1 nM). Ex vivo autoradiography and microPET studies showed that [18F]2d selectively localized on DAT-rich striatal regions and the specific signal could be blocked by DAT inhibitor. Biodistribution results showed that [18F]2d consistently exhibited a higher ratio of the target to non-target (striatum/cerebellum) than [18F]1d. Furthermore, metabolism study indicated that the in vivo metabolic stability of [18F]2d was superior to that of [18F]1d.
CONCLUSION: Our findings suggested that the deuterated compound [18F]2d might be a potential probe for DAT PET imaging in the brain.
METHODS: Four fluoroethyl substituted phenyl-tropane compounds 1a-d and deuterated compounds 2a-d were synthesized and their IC50 values to DAT were evaluated. The [18F]fluoroethyl ligands [18F]1a-d and [18F]2a-d were obtained from corresponding labeling precursors by one-step radio-labeling reactions and investigated in terms of lipophilicity and in vitro binding affinity studies. [18F]1d and [18F]2d were then selected for further evaluations by in vivo metabolism study, biodistribution, ex vivo autoradiography, and microPET imaging studies.
RESULTS: [18F]1a-d and [18F]2a-d were obtained in radiochemical yield of 11-32 % with molar activities of 28-54 GBq/μmol. The 1d and 2d exhibited relatively high affinity to DAT (IC50: 1.9-2.1 nM). Ex vivo autoradiography and microPET studies showed that [18F]2d selectively localized on DAT-rich striatal regions and the specific signal could be blocked by DAT inhibitor. Biodistribution results showed that [18F]2d consistently exhibited a higher ratio of the target to non-target (striatum/cerebellum) than [18F]1d. Furthermore, metabolism study indicated that the in vivo metabolic stability of [18F]2d was superior to that of [18F]1d.
CONCLUSION: Our findings suggested that the deuterated compound [18F]2d might be a potential probe for DAT PET imaging in the brain.