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This study aimed to investigate lisinopril-based radioconjugates for nuclear imaging of ACE.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Lisinopril conjugates were prepared using solid-phase peptide synthesis and labeled with gallium-67. The resulting radioconjugates were assessed for their in vitro stability in saline and in mouse and human blood plasma. ACE-mediated uptake was evaluated in HEK cells transfected with human ACE, and the findings were interpreted using molecular dynamic studies. Tissue distribution profiles of the radioconjugates were evaluated in mice bearing HEK-ACE xenografts by means of nuclear imaging and classic biodistribution studies. The feasibility to detect physiologic ACE was further assessed by ex vivo autoradiography of the lungs and the kidneys collected from mice injected with [\n                      <jats:sup>67<\/jats:sup>\n                      Ga]Ga-DOTA-LIS-02.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      DOTA-LIS-01, DOTA-LIS-02 and NODAGA-LIS-02 were prepared with &gt;\u200998% chemical purity. Radiolabeling of the conjugates with gallium-67 was achieved at 80 MBq\/nmol with &gt;\u200999% radiochemical purity. [\n                      <jats:sup>67<\/jats:sup>\n                      Ga]Ga-DOTA-LIS-02 and [\n                      <jats:sup>67<\/jats:sup>\n                      Ga]Ga-NODAGA-LIS-02 exhibited radiolytic stability for up to 3\u00a0h in saline and remained intact in mouse and human blood plasma for 1\u00a0h. The uptake of [\n                      <jats:sup>67<\/jats:sup>\n                      Ga]Ga-DOTA-LIS-02 and [\n                      <jats:sup>67<\/jats:sup>\n                      Ga]Ga-NODAGA-LIS-02 in HEK-ACE cells after 3\u00a0h incubation reached\u2009~\u200957% and ~\u200950%, respectively, while only\u2009~\u200921% cell uptake was reached with [\n                      <jats:sup>67<\/jats:sup>\n                      Ga]Ga-DOTA-LIS-01. This discrepancy was ascribed to the favorable binding mode of the LIS-02 radioconjugates with a longer linker between DOTA and lisinopril, as demonstrated by molecular dynamic studies. Nuclear images demonstrated uptake of all radioconjugates in HEK-ACE xenografts but not in HEK-ACE2 xenografts. At 1\u00a0h after injection of [\n                      <jats:sup>67<\/jats:sup>\n                      Ga]Ga-DOTA-LIS-02, the accumulation in HEK-ACE xenografts of mice reached 14\u2009\u00b1\u20093% IA\/g, whereas only 3.6\u2009\u00b1\u20090.3% IA\/g uptake was observed for [\n                      <jats:sup>67<\/jats:sup>\n                      Ga]Ga-NODAGA-LIS-02. The ex vivo autoradiograms of kidneys and lungs of mice injected with [\n                      <jats:sup>67<\/jats:sup>\n                      Ga]Ga-DOTA-LIS-02 only, or co-injected with excess lisinopril confirmed ACE-specific binding of this radioconjugate.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      [\n                      <jats:sup>67<\/jats:sup>\n                      Ga]Ga-DOTA-LIS-02 emerged as the most promising candidate to visualize ACE in mice. Further (pre)clinical studies will be necessary to validate the radioconjugate\u2019s potential for assessing ACE expression dynamics under pathophysiological conditions.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s00259-025-07386-w","type":"journal-article","created":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T21:50:00Z","timestamp":1749246600000},"page":"5030-5043","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Development of lisinopril radioconjugates for nuclear imaging of the angiotensin converting enzyme"],"prefix":"10.1007","volume":"52","author":[{"given":"Christian","family":"Vaccarin","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Darja","family":"Beyer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anzhelika","family":"Moiseeva","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiara","family":"Favaretto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas P.","family":"van der Meulen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin D.","family":"Hunkeler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Niels J.","family":"Rupp","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanni","family":"Marzaro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roger","family":"Schibli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9357-9688","authenticated-orcid":false,"given":"Cristina","family":"M\u00fcller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,6,7]]},"reference":[{"key":"7386_CR1","doi-asserted-by":"publisher","unstructured":"Ksiazek SH, Hu L, Ando S, Pirklbauer M, Saemann MD, Ruotolo C, et al. 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In vivo experiments were approved by the local veterinarian department and ethics committee and conducted in accordance with the Swiss law of animal protection.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"The authors declare no conflict of interest.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"All applicable international, national, and\/or institutional guidelines for the care and use of animals were followed. In particular, all animal experiments were carried out according to the guidelines of the Swiss Regulations for Animal Welfare. The preclinical studies have been ethically approved by the Cantonal Committee of Animal Experimentation and permitted by the responsible cantonal authorities (License N\u00b0 75743).","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Institutional review board statement"}},{"value":"Not applicable.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Clinical trial number"}}]}}