{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T02:54:25Z","timestamp":1792205665683,"version":"4.4.0"},"reference-count":120,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2021,7,30]],"date-time":"2021-07-30T00:00:00Z","timestamp":1627603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004622","name":"KWF Kankerbestrijding","doi-asserted-by":"publisher","award":["12259"],"award-info":[{"award-number":["12259"]}],"id":[{"id":"10.13039\/501100004622","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The pretargeting strategy has recently emerged in order to overcome the limitations of direct targeting, mainly in the field of radioimmunotherapy (RIT). This strategy is directly dependent on chemical reactions, namely bioorthogonal reactions, which have been developed for their ability to occur under physiological conditions. The Staudinger ligation, the copper catalyzed azide-alkyne cycloaddition (CuAAC) and the strain-promoted [3 + 2] azide\u2013alkyne cycloaddition (SPAAC) were the first bioorthogonal reactions introduced in the literature. However, due to their incomplete biocompatibility and slow kinetics, the inverse-electron demand Diels-Alder (IEDDA) reaction was advanced in 2008 by Blackman et al. as an optimal bioorthogonal reaction. The IEDDA is the fastest bioorthogonal reaction known so far. Its biocompatibility and ideal kinetics are very appealing for pretargeting applications. The use of a trans-cyclooctene (TCO) and a tetrazine (Tz) in the reaction encouraged researchers to study them deeply. It was found that both reagents are sensitive to acidic or basic conditions. Furthermore, TCO is photosensitive and can be isomerized to its cis-conformation via a radical catalyzed reaction. Unfortunately, the cis-conformer is significantly less reactive toward tetrazine than the trans-conformation. Therefore, extensive research has been carried out to optimize both click reagents and to employ the IEDDA bioorthogonal reaction in biomedical applications.<\/jats:p>","DOI":"10.3390\/molecules26154640","type":"journal-article","created":{"date-parts":[[2021,8,1]],"date-time":"2021-08-01T21:44:32Z","timestamp":1627854272000},"page":"4640","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":93,"title":["IEDDA: An Attractive Bioorthogonal Reaction for Biomedical Applications"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2927-5684","authenticated-orcid":false,"given":"Maryana","family":"Handula","sequence":"first","affiliation":[{"name":"Department of Radiology and Nuclear Medicine, Erasmus MC, University Medical Center Rotterdam, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2432-2074","authenticated-orcid":false,"given":"Kuo-Ting","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Chemistry, National Dong Hwa University, Shoufeng, Hualien 974301, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9736-5318","authenticated-orcid":false,"given":"Yann","family":"Seimbille","sequence":"additional","affiliation":[{"name":"Department of Radiology and Nuclear Medicine, Erasmus MC, University Medical Center Rotterdam, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands"},{"name":"Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, BC V6T 2A3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1080\/07357900500449553","article-title":"Advances in Radioimmunotherapy in the Age of Molecular Engineering and Pretargeting","volume":"24","author":"Sharkey","year":"2006","journal-title":"Cancer Investig."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1524\/ract.2012.1964","article-title":"Inorganic chemistry in nuclear imaging and radiotherapy: Current and future directions","volume":"100","author":"Carroll","year":"2012","journal-title":"Radiochim. 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