The inverse electron demand Diels-Alder click reaction in radiochemistry.

The inverse electron-demand Diels-Alder (IEDDA) cycloaddition between 1,2,4,5-tetrazines and strained alkene dienophiles is an emergent variety of catalyst-free ‘click’ chemistry that has the potential to have a transformational impact on the synthesis and development of radiopharmaceuticals. The ligation is selective, rapid, high-yielding, clean, and bioorthogonal and, since its advent in 2008, has been employed in a wide variety of chemical settings. In radiochemistry, the reaction has proven particularly useful with 18F and has already been utilized to create a number of 18F-labeled agents, including the PARP1-targeting small molecule 18F-AZD2281, the αvβ3 integrin-targeting peptide 18F-RGD, and the GLP-1-targeting peptide 18F-exendin. The inherent flexibility of the ligation has also been applied to the construction of radiometal-based probes, specifically the development of a modular strategy for the synthesis of radioimmunoconjugates that effectively eliminates variability in the construction of these agents. Further, the exceptional speed and biorthogonality of the reaction have made it especially promising in the realm of in vivo pretargeted imaging and therapy, and pretargeted imaging strategies based on the isotopes 111In, 18F, and 64Cu have already proven capable of producing images with high tumor contrast and low levels of uptake in background, nontarget organs. Ultimately, the characteristics of inverse electron-demand Diels–Alder click chemistry make it almost uniquely well-suited for radiochemistry, and although the field is young, this ligation has the potential to make a tremendous impact on the synthesis, development, and study of novel radiopharmaceuticals.

1,2,4,5 - 四嗪与张力烯烃亲二烯体之间的反电子需求的狄尔斯 - 阿尔德（IEDDA）环加成反应是一种新兴的无催化剂“点击”化学类型，它有可能对放射性药物的合成和开发产生变革性的影响。这种连接具有选择性、快速、高产率、清洁以及生物正交的特点，自2008年出现以来，已在多种化学环境中得到应用。在放射化学中，该反应已被证明对\(^{18}F\)特别有用，并且已经被用于制备多种\(^{18}F\)标记的试剂，包括靶向PARP1的小分子\(^{18}F - AZD2281\)、靶向\(\alpha_{v}\beta_{3}\)整合素的肽\(^{18}F - RGD\)以及靶向GLP - 1的肽\(^{18}F - 艾塞那肽。这种连接固有的灵活性也已应用于放射性金属探针的构建，特别是开发了一种用于合成放射免疫偶联物的模块化策略，该策略有效消除了这些试剂构建过程中的变异性。此外，该反应出色的速度和生物正交性使其在体内预靶向成像和治疗领域极具前景，并且基于\(^{111}In\)、\(^{18}F\)和\(^{64}Cu\)同位素的预靶向成像策略已被证明能够产生肿瘤对比度高且在背景非靶器官中摄取水平低的图像。最终，反电子需求的狄尔斯 - 阿尔德点击化学的特性使其几乎独一无二地非常适合放射化学，尽管该领域还很年轻，但这种连接有可能对新型放射性药物的合成、开发和研究产生巨大影响。