Direct Cu-mediated aromatic (18)F-labeling of highly reactive tetrazines for pretargeted bioorthogonal PET imaging.
Direct Cu-mediated aromatic (18)F-labeling of highly reactive tetrazines for pretargeted bioorthogonal PET imaging.
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DOI：
10.1039/d1sc02789a
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发表时间：
2021-09-15
期刊：
影响因子：
8.4
通讯作者：
Herth MM
中科院分区：
文献类型：
--
作者：
García-Vázquez R;Battisti UM;Jørgensen JT;Shalgunov V;Hvass L;Stares DL;Petersen IN;Crestey F;Löffler A;Svatunek D;Kristensen JL;Mikula H;Kjaer A;Herth MM
预靶向成像可用于可视化和量化具有短寿命放射性核素（例如氟-18-最流行的临床应用的正电子发射断层扫描（PET）放射性核素）的缓慢积累的靶向载体。与使用长寿命放射性核素的常规成像方法相比，预靶向导致更高的靶与背景比。目前，四嗪连接是用于预靶向成像的最流行的生物正交反应，但迄今为止尚未报道用于高反应性四嗪的直接18F标记策略，其如果不是临床翻译所必需的，则将是非常有益的。在这项工作中，一个简单的，可扩展的和可靠的直接18F标记程序已经开发出来。我们初步研究了不同离去基团和标记方法的适用性，以开发此程序。利用锡烷前体的铜介导的18 F标记显示出最有希望的结果。然后，这种方法被成功地应用于一组四嗪，包括高反应性的H-四嗪，适合于预靶向PET成像。标记成功的放射化学产率（RCY）高达约。百分之二十五然后应用新程序开发基于四嗪的预靶向成像剂。该示踪剂的合成具有良好的反应条件，反应时间约为10 min。10%，摩尔活性为134 ± 22 GBq μmol−1，放射化学纯度> 99%。进一步的评价表明，示踪剂显示出有利的特性（目标-背景比和清除率），可能使其有资格用于未来的临床转化。一个简单的，可扩展的和可靠的直接18 F-标记程序已被开发和应用，以获得具有良好的体内特性的预靶向四嗪为基础的显像剂。
Pretargeted imaging can be used to visualize and quantify slow-accumulating targeting vectors with short-lived radionuclides such as fluorine-18 – the most popular clinically applied Positron Emission Tomography (PET) radionuclide. Pretargeting results in higher target-to-background ratios compared to conventional imaging approaches using long-lived radionuclides. Currently, the tetrazine ligation is the most popular bioorthogonal reaction for pretargeted imaging, but a direct 18F-labeling strategy for highly reactive tetrazines, which would be highly beneficial if not essential for clinical translation, has thus far not been reported. In this work, a simple, scalable and reliable direct 18F-labeling procedure has been developed. We initially studied the applicability of different leaving groups and labeling methods to develop this procedure. The copper-mediated 18F-labeling exploiting stannane precursors showed the most promising results. This approach was then successfully applied to a set of tetrazines, including highly reactive H-tetrazines, suitable for pretargeted PET imaging. The labeling succeeded in radiochemical yields (RCYs) of up to approx. 25%. The new procedure was then applied to develop a pretargeting tetrazine-based imaging agent. The tracer was synthesized in a satisfactory RCY of ca. 10%, with a molar activity of 134 ± 22 GBq μmol−1 and a radiochemical purity of >99%. Further evaluation showed that the tracer displayed favorable characteristics (target-to-background ratios and clearance) that may qualify it for future clinical translation. A simple, scalable and reliable direct 18F-labeling procedure has been developed and applied to obtain a pretargeting tetrazine-based imaging agent with favorable in vivo characteristics.
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