{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T21:31:07Z","timestamp":1790112667884,"version":"4.0.1"},"reference-count":31,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,5,27]],"date-time":"2021-05-27T00:00:00Z","timestamp":1622073600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["200021-157076"],"award-info":[{"award-number":["200021-157076"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>The cholecystokinin-2 receptor (CCK2R) is an attractive target in nuclear medicine due to its overexpression by different tumors. Several radiolabeled peptidic ligands targeting the CCK2R have been investigated in the past; however, their low stability against proteases can limit their uptake in tumors and metastases. Substitution of single or multiple amide bonds with metabolically stable 1,4-disubstituted 1,2,3-triazoles as amide bond bioisosteres proved a promising strategy for improving the tumor-targeting properties of a truncated analog of minigastrin. In this study, we applied the previously studied structural modifications to improve the pharmacokinetic and pharmacodynamic properties of PP-F11N, a minigastrin analog currently in clinical trials. Novel minigastrins (NMGs) as analogs of PP-F11N with one or two amide bonds substituted by 1,2,3-triazoles were synthesized, radiolabeled with 177Lu3+, and subjected to full evaluation in vitro (cell internalization, receptor affinity, stability in blood plasma) and in vivo (stability, biodistribution, SPECT\/CT imaging). NMGs with triazoles inserted between the amino acids DGlu10-Ala11 and\/or Tyr12-Gly13 showed a significantly increased cellular uptake and affinity toward the CCK2R in vitro. Resistance against the metabolic degradation of the NMGs was comparable to those of the clinical candidate PP-F11N. Imaging by SPECT\/CT and biodistribution studies demonstrated a higher uptake in CCK2R-positive tumors but also in the CCK2R-positive stomach. The peptidomimetic compounds showed a slow tumor washout and high tumor-to-kidney ratios. The structural modifications led to the identification of analogs with promising properties for progression to clinical applications in the diagnosis and therapy of CCK2R-positive neoplasms.<\/jats:p>","DOI":"10.3390\/cancers13112629","type":"journal-article","created":{"date-parts":[[2021,5,27]],"date-time":"2021-05-27T11:07:02Z","timestamp":1622113622000},"page":"2629","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Improved Tumor-Targeting with Peptidomimetic Analogs of Minigastrin 177Lu-PP-F11N"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1031-5105","authenticated-orcid":false,"given":"Nathalie M.","family":"Grob","sequence":"first","affiliation":[{"name":"Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, 8093 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1537-3833","authenticated-orcid":false,"given":"Roger","family":"Schibli","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, 8093 Zurich, Switzerland"},{"name":"Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1110-2665","authenticated-orcid":false,"given":"Martin","family":"B\u00e9h\u00e9","sequence":"additional","affiliation":[{"name":"Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas L.","family":"Mindt","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute Applied Diagnostics, Vienna General Hospital, 1090 Vienna, Austria"},{"name":"Department of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria"},{"name":"Department of Biomedical Imaging and Image Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1002\/(SICI)1097-0215(19960904)67:5<644::AID-IJC9>3.0.CO;2-U","article-title":"Unexpected High Incidence of Cholecystokinin-B\/Gastrin Receptors in Human Medullary Thyroid Carcinomas","volume":"67","author":"Reubi","year":"1996","journal-title":"Int. J. Cancer"},{"key":"ref_2","first-page":"1377","article-title":"Cholecystokinin(CCK)-A and CCK-B\/Gastrin Receptors in Human Tumors","volume":"57","author":"Reubi","year":"1997","journal-title":"Cancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Biersack, H.-J., and Gr\u00fcnwald, F. (2001). Thyroid Cancer, Springer.","DOI":"10.1007\/978-3-662-04610-4"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"78","DOI":"10.6004\/jnccn.2013.0011","article-title":"Small Cell Lung Cancer","volume":"11","author":"Kalemkerian","year":"2013","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2134","DOI":"10.1002\/cncr.22244","article-title":"Prognosis of Medullary Thyroid Carcinoma","volume":"107","author":"Roman","year":"2006","journal-title":"Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/s13045-019-0736-3","article-title":"Emerging Therapies for Small Cell Lung Cancer","volume":"12","author":"Yang","year":"2019","journal-title":"J. Hematol. Oncol."},{"key":"ref_7","first-page":"287","article-title":"Radiolabeled Gastrin\/CCK Analogs in Tumor Diagnosis: Towards Higher Stability and Improved Tumor Targeting","volume":"59","author":"Kaloudi","year":"2015","journal-title":"Q. J. Nucl. Med. Mol. Imaging"},{"key":"ref_8","unstructured":"(2021, April 11). Clinical Trial NCT02088645, S.-N. 177Lu-PP-F11N for Receptor Targeted Therapy and Imaging of Metastatic Thyroid Cancer. (Lumed), Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02088645?term=8.%09NCT02088645&draw=2&rank=1."},{"key":"ref_9","unstructured":"(2021, April 11). Clinical Trial NCT03246659, S.-N. Radiolabelled CCK-2\/Gastrin Receptor Analogue for Personalized Theranostic Strategy in Advanced MTC (GRAN-T-MTC), Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03246659?term=NCT03246659&draw=2&rank=1."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"520","DOI":"10.2967\/jnumed.119.233031","article-title":"Cholecystokinin-2 Receptor Agonist 177Lu-PP-F11N for Radionuclide Therapy of Medullary Thyroid Carcinoma\u2014Results of the Lumed Phase 0a Study","volume":"61","author":"Rottenburger","year":"2020","journal-title":"J. Nucl. Med."},{"key":"ref_11","first-page":"S268","article-title":"Gallium-68 Labelled Minigastrin Analogue for High Sensitivity PET Imaging of Cholecystokinin-2 Receptor Expressing Tumours","volume":"46","author":"Klingler","year":"2019","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1053\/snuc.2002.31028","article-title":"Cholecystokinin-B\/Gastrin Receptor-Targeting Peptides for Staging and Therapy of Medullary Thyroid Cancer and other Cholecystokinin-B Receptor-Expressing Malignancies","volume":"32","author":"Behr","year":"2002","journal-title":"Semin. Nucl. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.2967\/jnumed.110.075101","article-title":"Renal Toxicity of Radiolabeled Peptides and Antibody Fragments: Mechanisms, Impact on Radionuclide Therapy, and Strategies for Prevention","volume":"51","author":"Vegt","year":"2010","journal-title":"J. Nucl. Med."},{"key":"ref_14","first-page":"20","article-title":"Improving the In Vivo Profile of Minigastrin Radiotracers: A Comparative Study Involving the Neutral Endopeptidase Inhibitor Phosphoramidon","volume":"31","author":"Kaloudi","year":"2016","journal-title":"Cancer Biother. Radiopharm."},{"key":"ref_15","first-page":"1","article-title":"Impact of Clinically Tested NEP\/ACE Inhibitors on Tumor Uptake of [111In-DOTA]MG11\u2014First Estimates for Clinical Translation","volume":"6","author":"Kaloudi","year":"2016","journal-title":"Eur. J. Nucl. Med. Mol. Imaging Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4484","DOI":"10.1021\/acs.jmedchem.9b01936","article-title":"Triazolo-Peptidomimetics: Novel Radiolabeled Minigastrin Analogs for Improved Tumor Targeting","volume":"63","author":"Grob","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4496","DOI":"10.1021\/acs.jmedchem.9b01937","article-title":"Design of Radiolabeled Analogs of Minigastrin by Multiple Amide-to-Triazole Substitutions","volume":"63","author":"Grob","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2143","DOI":"10.1021\/acs.bioconjchem.5b00444","article-title":"1,2,3-Triazole Stabilized Neurotensin-Based Radiopeptidomimetics for Improved Tumor Targeting","volume":"26","author":"Mascarin","year":"2015","journal-title":"Bioconjug. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"8957","DOI":"10.1002\/anie.201303108","article-title":"1,2,3-Triazoles as Amide Bond Mimics: Triazole Scan Yields Protease-Resistant Peptidomimetics for Tumor Targeting","volume":"52","author":"Valverde","year":"2013","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"7475","DOI":"10.1021\/acs.jmedchem.5b00994","article-title":"Probing the Backbone Function of Tumor Targeting Peptides by an Amide-to-Triazole Substitution Strategy","volume":"58","author":"Valverde","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_21","unstructured":"Behe, M., and Schibli, R. (2015). Mini-Gastrin Analogue, in Particular for Use in CCK2 Receptor Positive Tumour Diagnosis and\/or Treatment. (WO2015067473 A1)."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1021\/acs.bioconjchem.5b00187","article-title":"Stereochemistry of Amino Acid Spacers Determines the Pharmacokinetics of 111In\u2013DOTA\u2013Minigastrin Analogues for Targeting the CCK2\/Gastrin Receptor","volume":"26","author":"Tamma","year":"2015","journal-title":"Bioconjug. Chem."},{"key":"ref_23","first-page":"485","article-title":"In Vitro and In Vivo Evaluation of 111In-DTPAGlu-G-CCK8 for Cholecystokinin-B Receptor Imaging","volume":"45","author":"Aloj","year":"2004","journal-title":"J. Nucl. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1021\/acs.bioconjchem.8b00849","article-title":"Elucidating the Structure\u2013Activity Relationship of the Pentaglutamic Acid Sequence of Minigastrin with Cholecystokinin Receptor Subtype 2","volume":"30","author":"Ritler","year":"2019","journal-title":"Bioconjug. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.2967\/jnumed.118.221283","article-title":"DOTA-MGS5, a New Cholecystokinin-2 Receptor Targeting Peptide Analog with Optimized Targeting Profile for Theranostic Use","volume":"60","author":"Klingler","year":"2019","journal-title":"J. Nucl. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.ejps.2016.05.011","article-title":"Preclinical Pharmacokinetics, Biodistribution, Radiation Dosimetry and Toxicity Studies Required for Regulatory Approval of a Phase I Clinical Trial with 111In-CP04 in Medullary Thyroid Carcinoma Patients","volume":"91","author":"Maina","year":"2016","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1021\/acsmedchemlett.0c00636","article-title":"1,5-Disubstituted 1,2,3-Triazoles as Amide Bond Isosteres Yield Novel Tumor-Targeting Minigastrin Analogs","volume":"12","author":"Grob","year":"2021","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1007\/s00259-011-1818-9","article-title":"Comparison of Biological Stability and Metabolism of CCK2 Receptor Targeting Peptides, a Collaborative Project under COST BM0607","volume":"38","author":"Ocak","year":"2011","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"121","DOI":"10.2967\/jnumed.113.129411","article-title":"\u201cTo Serve and Protect\u201d: Enzyme Inhibitors as Radiopeptide Escorts Promote Tumor Targeting","volume":"55","author":"Nock","year":"2014","journal-title":"J. Nucl. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"393","DOI":"10.2967\/jnumed.118.207845","article-title":"Targeting of the Cholecystokinin-2 Receptor with the Minigastrin Analog 177Lu-DOTA-PP-F11N: Does the Use of Protease Inhibitors Further Improve In Vivo Distribution?","volume":"60","author":"Sauter","year":"2019","journal-title":"J. Nucl. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.nucmedbio.2019.01.006","article-title":"Mini-review: Targeted radiopharmaceuticals incorporating reversible, low molecular weight albumin binders","volume":"70","author":"Brandt","year":"2019","journal-title":"Nucl. Med. Biol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/11\/2629\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:08:50Z","timestamp":1760162930000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/11\/2629"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,27]]},"references-count":31,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["cancers13112629"],"URL":"https:\/\/doi.org\/10.3390\/cancers13112629","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,27]]}}}