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Synthesis and Biological Evaluation of [18F]FECNT-d4 as a Novel PET Agent for Dopamine Transporter Imaging

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Abstract

Purpose

The dopamine transporter (DAT) is a marker of the occurrence and development of Parkinson’s disease (PD) and other diseases with nigrostriatal degeneration. 2β-Carbomethoxy-3β-(4-chlorophenyl)-8-(2-[18F]-fluoroethyl)nortropane ([18F]FECNT), an 18F-labelled tropane derivative, was reported to be a useful positron-emitting probe for DAT. However, the rapid formation of brain-penetrating radioactive metabolites is an impediment to the proper quantitation of DAT in PET studies with [18F]FECNT. Deuterium-substituted analogues have presented better in vivo stability to reduce metabolites. This study aimed to synthesize a deuterium-substituted DAT radiotracer, [18F]FECNT-d4, and to make a preliminary investigation of its properties as a DAT tracer in vivo.

Procedures

The ligand [18F]FECNT-d4 was obtained by one-step radiolabelling reaction. The lipophilicity was measured by the shake-flask method. Binding properties of [18F]FECNT-d4 were estimated by in vitro binding assay, biodistribution, and microPET imaging in rats. In vivo stability of [18F]FECNT-d4 was estimated by radio-HPLC.

Results

[18F]FECNT-d4 was synthesized at an average activity yield of 46 ± 17 % (n = 15) and the molar activity was 67 ± 12 GBq/μmol. The deuterated tracer showed suitable lipophilicity and the ability to penetrate the blood-brain barrier (brain uptake of 1.72 % ID at 5 min). [18F]FECNT-d4 displayed a high binding affinity for DAT comparable to that of [18F]FECNT in rat striatum homogenates. Biodistribution results in normal rats showed that [18F]FECNT-d4 exhibited a higher ratio of the target to non-target (striatum/cerebellum) at 15 min post administration (5.00 ± 0.44 vs 3.84 ± 0.24 for [18F]FECNT-d4 vs [18F]FECNT). MicroPET imaging studies of [18F]FECNT-d4 in normal rats showed that the ligand selectively localized to DAT-rich striatal regions and the accumulation could be blocked with DAT inhibitor. Furthermore, in the unilateral PD model rat, a significant reduction of the signal was found in the lesioned side relative to the unlesioned side. Striatal standardized uptake value of [18F]FECNT-d4 remained ~4.02 in the striatum between 5 and 20 min, whereas that of [18F]FECNT fell rapidly from 4.11 to 2.95. Radio-HPLC analysis of the plasma demonstrated better in vivo stability of [18F]FECNT-d4 than [18F]FECNT.

Conclusion

The deuterated compound [18F]FECNT-d4 may serve as a promising PET imaging agent to assess DAT-related disorders.

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Funding

This work was supported by the National Natural Science Foundation of China (81671723, 81801742), the Natural Science Foundation of Jiangsu Province (BK20201133), Wuxi Municipal Science and Technology Development Fund (WX18IIAN048, N20192015), Program from Jiangsu Commission of Health (H2018086), and Wuxi Municipal Health Commission (Q201946).

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Authors and Affiliations

  1. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China

    Shanshan Cao, Linyang Ji & Zhengping Chen

  2. NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, China

    Jie Tang, Chunyi Liu, Yi Fang, Yingjiao Xu & Zhengping Chen

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  1. Shanshan Cao
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Correspondence to Zhengping Chen.

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Cao, S., Tang, J., Liu, C. et al. Synthesis and Biological Evaluation of [18F]FECNT-d4 as a Novel PET Agent for Dopamine Transporter Imaging. Mol Imaging Biol 23, 733–744 (2021). https://doi.org/10.1007/s11307-021-01603-2

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