{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T19:37:21Z","timestamp":1792265841627,"version":"4.4.0"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,10,11]],"date-time":"2024-10-11T00:00:00Z","timestamp":1728604800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013348","name":"Innosuisse","doi-asserted-by":"publisher","award":["37014"],"award-info":[{"award-number":["37014"]}],"id":[{"id":"10.13039\/501100013348","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Nucl. Med."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Gallium-68 positron emission tomography (<jats:sup>68<\/jats:sup>Ga-PET) with the two registered somatostatin analogs, [<jats:sup>68<\/jats:sup>Ga]Ga-DOTA-Tyr<jats:sup>3<\/jats:sup>-octreotide ([<jats:sup>68<\/jats:sup>Ga]Ga-DOTA-TOC) and [<jats:sup>68<\/jats:sup>Ga]Ga-DOTA-Tyr<jats:sup>3<\/jats:sup>-octreotate ([<jats:sup>68<\/jats:sup>Ga]Ga-DOTA-TATE), where DOTA\u2009=\u20091,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, is routinely used for imaging of somatostatin receptor (SST)-expressing tumors. We investigated copper-61 (<jats:sup>61<\/jats:sup>Cu) as an alternative radiometal for PET imaging of SST-expressing tumors. Compared to gallium-68, copper-61 (t<jats:sub>1\/2<\/jats:sub>\u2009=\u20093.33\u2005h, E<jats:italic><jats:sub>\u03b2<\/jats:sub><\/jats:italic><jats:sup>+<\/jats:sup><jats:sub>max<\/jats:sub>\u2009=\u20091.22\u2005MeV) can be produced on a large scale, enables late time point imaging, and has the therapeutic twin copper-67. Herein, DOTA-TOC and 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA)-TOC were labeled with copper-61 and compared with the clinically used [<jats:sup>68<\/jats:sup>Ga]Ga-DOTA-TOC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>[<jats:sup>61<\/jats:sup>Cu]CuCl<jats:sub>2<\/jats:sub> was produced from an irradiated natural nickel target. DOTA-TOC and NODAGA-TOC were labeled with [<jats:sup>61<\/jats:sup>Cu]CuCl<jats:sub>2<\/jats:sub> in ammonium acetate buffer so to achieve a reaction pH of 5\u20136 and a temperature of 95\u00b0C for DOTA-TOC or room temperature for NODAGA-TOC. The radioligands were evaluated head-to-head <jats:italic>in vitro<\/jats:italic> using human embryonic kidney (HEK)-SST<jats:sub>2<\/jats:sub> cells (affinity, binding sites, cellular uptake, and efflux) and <jats:italic>in vivo<\/jats:italic> using HEK-SST<jats:sub>2<\/jats:sub> xenografts [PET\/computed tomography (CT) imaging, biodistribution, and pharmacokinetics] and compared with [<jats:sup>68<\/jats:sup>Ga]Ga-DOTA-TOC, which was prepared using a standard procedure. Dosimetry estimates were made for [<jats:sup>61<\/jats:sup>Cu]Cu-NODAGA-TOC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>[<jats:sup>61<\/jats:sup>Cu]Cu-DOTA-TOC and [<jats:sup>61<\/jats:sup>Cu]Cu-NODAGA-TOC were prepared at an apparent molar activity of 25\u2005MBq\/nmol with radiochemical purities of \u226596% and \u226598%, respectively. <jats:italic>In vitro<\/jats:italic>, both presented a sub-nanomolar affinity for SST<jats:sub>2<\/jats:sub> (IC<jats:sub>50<\/jats:sub>\u2009=\u20090.23 and 0.34\u2005nM, respectively). They were almost entirely internalized upon binding to SST<jats:sub>2<\/jats:sub>-expressing cells and had similar efflux rates at 37\u00b0C. <jats:italic>In vivo<\/jats:italic>, [<jats:sup>61<\/jats:sup>Cu]Cu-DOTA-TOC and [<jats:sup>61<\/jats:sup>Cu]Cu-NODAGA-TOC showed the same accumulation in SST<jats:sub>2<\/jats:sub>-expressing tumors. However, PET\/CT images and biodistribution analyses clearly showed an unfavorable biodistribution for [<jats:sup>61<\/jats:sup>Cu]Cu-DOTA-TOC, characterized by accumulation in the liver and the abdomen. [<jats:sup>61<\/jats:sup>Cu]Cu-NODAGA-TOC displayed favorable biodistribution, comparable with [<jats:sup>68<\/jats:sup>Ga]Ga-DOTA-TOC at 1\u2005h post-injection (p.i.). Notwithstanding, [<jats:sup>61<\/jats:sup>Cu]Cu-NODAGA-TOC showed advantages at 4\u2005h p.i., due to the tumor retention and improved tumor-to-non-tumor ratios. The effective dose (2.41\u2009\u00d7\u200910<jats:sup>\u22123<\/jats:sup>\u2005mSv\/MBq) of [<jats:sup>61<\/jats:sup>Cu]Cu-NODAGA-TOC, but also the dose to the other organs and the kidneys (9.65\u2009\u00d7\u200910<jats:sup>\u22122<\/jats:sup>\u2005mGy\/MBq), suggested a favorable safety profile.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Somatostatin receptor <jats:sup>61<\/jats:sup>Cu-PET imaging not only matches the performance of <jats:sup>68<\/jats:sup>Ga-PET at 1\u2005h p.i. but has advantages in late-time imaging at 4\u2005h p.i., as it provides improved tumor-to-non-tumor ratios. [<jats:sup>61<\/jats:sup>Cu]Cu-NODAGA-TOC is superior to [<jats:sup>61<\/jats:sup>Cu]Cu-DOTA-TOC <jats:italic>in vivo<\/jats:italic>. The use of the chelator NODAGA allows quantitative labeling with copper-61 at room temperature and enables the straightforward use of a kit formulation for simple manufacturing in medical centers.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnume.2024.1481343","type":"journal-article","created":{"date-parts":[[2024,10,11]],"date-time":"2024-10-11T11:13:47Z","timestamp":1728645227000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Copper-61 is an advantageous alternative to gallium-68 for PET imaging of somatostatin receptor-expressing tumors: a head-to-head comparative preclinical study"],"prefix":"10.3389","volume":"4","author":[{"given":"Tais","family":"Basaco Bernabeu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosalba","family":"Mansi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Del 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