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Its multiple oxidation states allow for the design and production of radiopharmaceuticals with versatile properties, namely in terms of pharmacokinetic profile. <jats:sup>99m<\/jats:sup>Tc(V) is the most common oxidation state, but <jats:sup>99m<\/jats:sup>Tc(I) gained traction after the pioneering work of Alberto and colleagues, which resulted in the introduction of the organometallic core <jats:italic>fac<\/jats:italic>\u2010[<jats:sup>99m<\/jats:sup>Tc(CO)<jats:sub>3<\/jats:sub>(H<jats:sub>2<\/jats:sub>O)<jats:sub>3<\/jats:sub>]<jats:sup>+<\/jats:sup>. This core is readily available from [<jats:sup>99m<\/jats:sup>TcO<jats:sub>4<\/jats:sub>]<jats:sup>\u2212<\/jats:sup> and displays three labile water molecules that can be easily swapped for ligands with different denticity and\/or donor atoms in aqueous environment. This makes it possible to radiolabel small molecules as well as high molecular weight molecules, such as antibodies or other proteins, while assuring biological activity. Direct radiolabelling of those proteins with <jats:italic>fac<\/jats:italic>\u2010[<jats:sup>99m<\/jats:sup>Tc(CO)<jats:sub>3<\/jats:sub>]<jats:sup>+<\/jats:sup> under mild conditions is accomplished through incorporation of a polyhistidine tag (His\u2010tag), a commonly used tag for purification of recombinant proteins. This review aims to address the direct radiolabelling of His\u2010tagged macromolecules with <jats:italic>fac<\/jats:italic>\u2010[<jats:sup>99m<\/jats:sup>Tc(CO)<jats:sub>3<\/jats:sub>]<jats:sup>+<\/jats:sup> for development of molecular imaging agents and the impact of this technology in the discovery and development of imaging and\/or therapeutic agents towards clinical application.<\/jats:p>","DOI":"10.1002\/cbic.202400645","type":"journal-article","created":{"date-parts":[[2024,8,19]],"date-time":"2024-08-19T11:24:16Z","timestamp":1724066656000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<sup>99m<\/sup>Tc(I)\u2010Labeled His\u2010Tagged Proteins: Impact in the Development of Novel Imaging Probes and in Drug Discovery"],"prefix":"10.1002","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0575-2650","authenticated-orcid":false,"given":"Sofia A.","family":"Martins","sequence":"first","affiliation":[{"name":"Centro de Ci\u00eancias e Tecnologias Nucleares Instituto Superior T\u00e9cnico Universidade de Lisboa, CTN  Estrada Nacional 10 (km 139,7) 2695\u2013066 Bobadela LRS Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7847-4906","authenticated-orcid":false,"given":"Jo\u00e3o D. 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