Initial Evaluation of AF78: a Rationally Designed Fluorine-18-Labelled PET Radiotracer Targeting Norepinephrine Transporter
Initial Evaluation of AF78: a Rationally Designed Fluorine-18-Labelled PET Radiotracer Targeting Norepinephrine Transporter
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DOI：
10.1007/s11307-019-01407-5
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发表时间：
2020-06-01
影响因子：
3.1
通讯作者：
Higuchi, Takahiro
中科院分区：
文献类型：
--
作者：
Chen, Xinyu;Fritz, Alexander;Higuchi, Takahiro
目的充分利用正电子发射断层扫描（PET）技术，针对去甲肾上腺素转运蛋白（NET）的氟18标记放射性示踪剂在心脏交感神经状况的诊断和评估以及神经内分泌肿瘤的描绘中具有潜在的应用。然而，迄今为止，尚未应用于临床。目前报道的放射性示踪剂的缺点包括动力学欠佳和放射性标记程序具有挑战性。我们开发了一种针对 NET AF78 的新型氟 18 标记放射性示踪剂，具有基于苯乙基胍结构的高效一步放射性标记。对 AF78 进行放射合成，然后在细胞摄取研究、放射自显影和大鼠体内成像中进行验证。结果 [F-18]AF78 成功合成，放射化学收率为 27.9 +/- 3.1 %，放射化学纯度 > 97 %，摩尔活性 > 53.8 GBq/mmol。细胞摄取研究表明，NET 的亲和力与去甲肾上腺素和间碘苄基高尼啶基本相同。大鼠离体放射自显影和体内成像均显示出均匀且特异性的心脏摄取。结论 新型 PET 放射性示踪剂 [F-18]AF78 对 NET 具有高亲和力，并且在大鼠体内具有良好的生物分布。揭示了放射性示踪剂结构与 NET 亲和力之间的构效关系，这可以作为进一步设计具有良好特性的 NET 靶向放射性示踪剂的基础。
Purpose Taking full advantage of positron emission tomography (PET) technology, fluorine-18-labelled radiotracers targeting norepinephrine transporter (NET) have potential applications in the diagnosis and assessment of cardiac sympathetic nerve conditions as well as the delineation of neuroendocrine tumours. However, to date, none have been used clinically. Drawbacks of currently reported radiotracers include suboptimal kinetics and challenging radiolabelling procedures. Procedures We developed a novel fluorine-18-labelled radiotracer targeting NET, AF78, with efficient one-step radiolabelling based on the phenethylguanidine structure. Radiosynthesis of AF78 was undertaken, followed by validation in cell uptake studies, autoradiography, and in vivo imaging in rats. Results [F-18]AF78 was successfully synthesized with 27.9 +/- 3.1 % radiochemical yield, > 97 % radiochemical purity and > 53.8 GBq/mmol molar activity. Cell uptake studies demonstrated essentially identical affinity for NET as norepinephrine and meta-iodobenzylgaunidine. Both ex vivo autoradiography and in vivo imaging in rats showed homogeneous and specific cardiac uptake. Conclusions The new PET radiotracer [F-18]AF78 demonstrated high affinity for NET and favourable biodistribution in rats. A structure-activity relationship between radiotracer structures and affinity for NET was revealed, which may serve as the basis for the further design of NET targeting radiotracers with favourable features.