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An Efficient Automated Radiosynthesis and Bioactivity Confirmation of VMAT2 Tracer [18F]FP-(+)-DTBZ

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Abstract

Purpose

The aim of this study was to optimize the radiolabeling method of [18F]fluoropropyl-(+)-dihydrotetrabenazine ([18F]FP-(+)-DTBZ) to fulfill the demand of preclinical and clinical application.

Procedures

Optimized labeling conditions were performed by altering the molar ratio of precursor to base (P/B), base species, solvents, reaction temperature, reaction time, and precursor concentration through manual radiosynthesis of [18F]FP-(+)-DTBZ. The conditions with the highest radiochemical yield (RCY) were applied to automated radiosynthesis, and the crude product was purified with a Sep-Pak Plus C18 cartridge. Quality control and stability of [18F]FP-(+)-DTBZ were carried out by HPLC. In vitro cellular uptake and blocking assays were conducted in human neuroblastoma cell line SH-SY5Y. In vivo imaging with small animal positron emission tomography (microPET) was performed with Sprague–Dawley rats.

Results

Under the optimized conditions (P/K2CO3 = 1:8, heating at 120 °C for 3 min in dimethyl sulfoxide), an RCY of 88.7 % was obtained with 1.0 mg precursor. The optimized reaction conditions were successfully applied to an automated module and gave a high activity yield (AY) of 30–55 % in about 40 min with a > 99.0 % radiochemical purity (RCP) and a > 44.4 GBq/μmol molar activity (Am). Stability test displayed that the RCP retained > 98.0 % in 8 h in saline and in phosphate buffer saline (PBS, pH 7.4). In vitro cellular uptake assay showed accumulation of [18F]FP-(+)-DTBZ in SH-SY5Y cells, which could be significantly inhibited by vesicular monoamine transporter 2 (VMAT2) inhibitor DTBZ. MicroPET images of rat brain displayed that the striatum showed the highest uptake with a standardized uptake value (SUV) of 3.91 ± 0.30 at ~ 70 min. Co-injection with DTBZ (1.0 mg/kg) resulted in a 75 % decrease of the striatal SUV, confirming the specificity of [18F]FP-(+)-DTBZ to VMAT2.

Conclusions

We obtained an optimized radiolabeling method of [18F]FP-(+)-DTBZ and successfully applied it to a commercial available module. The automated synthesis gave a high AY and RCP of [18F]FP-(+)-DTBZ with high and specific binding to VMAT2, facilitating its routine application for VMAT2 tracing.

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Funding

This work was supported by the National Key R&D Program of China (NO. 2016YFC1306600), the National Natural Science Foundation of China (NO. 81671723, 81801742), the Jiangsu Provincial Natural Science Foundation (NO. BK20161138), the Program for Jiangsu Provincial High-Level Talents in Six Major Industries (NO. 2016-WSN-037), the Jiangsu Provincial Key Medical Discipline (NO. ZDXKA2016017), and the Wuxi Municipal Science and Technology Development Fund (NO. WX18IIAN048).

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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

    Chao Zhao & Zhengping Chen

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

    Chunyi Liu, Jie Tang, Yingjiao Xu, Minhao Xie & Zhengping Chen

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  1. Chao Zhao
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  2. Chunyi Liu
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  3. Jie Tang
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  4. Yingjiao Xu
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  5. Minhao Xie
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  6. Zhengping Chen
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Correspondence to Zhengping Chen.

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All animal experiments were approved by the Animal Care and Ethics Committee of Jiangsu Institute of Nuclear Medicine.

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Zhao, C., Liu, C., Tang, J. et al. An Efficient Automated Radiosynthesis and Bioactivity Confirmation of VMAT2 Tracer [18F]FP-(+)-DTBZ. Mol Imaging Biol 22, 265–273 (2020). https://doi.org/10.1007/s11307-019-01379-6

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