{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T22:24:10Z","timestamp":1787005450799,"version":"build-2736575974"},"reference-count":36,"publisher":"American Chemical Society (ACS)","issue":"9","license":[{"start":{"date-parts":[[2019,8,8]],"date-time":"2019-08-08T00:00:00Z","timestamp":1565222400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2019,8,8]],"date-time":"2019-08-08T00:00:00Z","timestamp":1565222400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2019,8,8]],"date-time":"2019-08-08T00:00:00Z","timestamp":1565222400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/100011272","name":"FP7 Health","doi-asserted-by":"publisher","award":["602812"],"award-info":[{"award-number":["602812"]}],"id":[{"id":"10.13039\/100011272","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,9,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The glucagon-like peptide-1 receptor (GLP-1R) is highly and specifically expressed on the pancreatic \u03b2-cells. It plays an important role in glucose metabolism as well as in \u03b2-cell-derived diseases like diabetes, insulinoma, or congenital and adult hyperinsulinemic hypoglycemia. Radiolabeled exendin-4, a ligand of GLP-1R, has routinely been used in clinics to image insulinomas. However, its major drawback is the high kidney accumulation. Here, we show that the addition of an albumin-binding moiety (ABM) to radiolabeled exendin-4 results in a significant reduction of kidney uptake while retaining its high affinity and specificity to GLP-1R. The four tested peptides were shown to have high affinity to the GLP-1 receptor (IC50 of 3.7 \u00b1 0.6 to 15.1 \u00b1 0.8 nM). The radiolabeled derivatives were taken up into cells efficiently, internalizing between 39 \u00b1 2 and 56 \u00b1 2% after 2 h. Thus, the derivatives with ABM outperformed the reference peptide with its IC50 of 22.5 \u00b1 2.9 nM and internalization of 41 \u00b1 4%. Stability in human blood plasma was slightly enhanced by the addition of the albumin binder. In biodistribution studies, the radioligands exhibited an improved target-to-kidney ratio in comparison to the reference peptide of up to seven-fold. This was confirmed qualitatively in single-photon-emission computed tomography (SPECT)\/CT imaging. This study demonstrated in vitro and in vivo that the addition of an ABM to radiolabeled exendin-4 strongly decreased kidney accumulation while retaining affinity to GLP-1R. Thus, exendin-4 derivatives with an albumin-binding moiety could present a viable class of diagnostic tracers for the detection of insulinomas and other GLP-1R-positive tissue in clinical application.<\/jats:p>","DOI":"10.1021\/acs.molpharmaceut.9b00271","type":"journal-article","created":{"date-parts":[[2019,8,8]],"date-time":"2019-08-08T13:24:47Z","timestamp":1565270687000},"page":"3760-3769","source":"Crossref","is-referenced-by-count":25,"title":["Exendin\u20114 Derivatives with an Albumin-Binding\nMoiety Show Decreased Renal Retention and Improved GLP\u20111 Receptor\nTargeting"],"prefix":"10.1021","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4449-6952","authenticated-orcid":true,"given":"Simon\nA. M.","family":"Kaeppeli","sequence":"first","affiliation":[{"name":"Paul Scherrer Institut , , ,","place":["Villigen, Switzerland, 5232"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Jodal","sequence":"additional","affiliation":[{"name":"Paul Scherrer Institut , , ,","place":["Villigen, Switzerland, 5232"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Gotthardt","sequence":"additional","affiliation":[{"name":"Radboud University Medical Center , , ,","place":["Nijmegen, The Netherlands, 6525"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"Schibli","sequence":"additional","affiliation":[{"name":"Paul Scherrer Institut , , ,","place":["Villigen, Switzerland, 5232"]},{"name":"ETH Zurich , , ,","place":["Zurich, Switzerland, 8092"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1110-2665","authenticated-orcid":true,"given":"Martin","family":"Be\u0301he\u0301","sequence":"additional","affiliation":[{"name":"Paul Scherrer Institut , , ,","place":["Villigen, Switzerland, 5232"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2019,8,8]]},"reference":[{"key":"2026081717214563800_cit1","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1016\/j.bpg.2012.12.003","article-title":"Pancreatic neuroendocrine tumors:\nclinical features, diagnosis and medical treatment: advances","volume":"26","author":"Ito","year":"2012","journal-title":"Best Pract. Res., Clin. Gastroenterol."},{"key":"2026081717214563800_cit2","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.2967\/jnumed.115.157768","article-title":"Localization of Hidden Insulinomas with 68Ga-DOTA-Exendin-4\nPET\/CT: A Pilot Study","volume":"56","author":"Antwi","year":"2015","journal-title":"J. Nucl. Med."},{"key":"2026081717214563800_cit3","doi-asserted-by":"publisher","first-page":"821","DOI":"10.1007\/s12020-015-0633-7","article-title":"Preoperative\nlocalization of adult\nnesidioblastosis using 68Ga-DOTA-exendin-4-PET\/CT","volume":"50","author":"Christ","year":"2015","journal-title":"Endocrine"},{"key":"2026081717214563800_cit4","doi-asserted-by":"publisher","first-page":"715","DOI":"10.2967\/jnumed.115.167445","article-title":"Glucagon-Like Peptide-1\nReceptor PET\/CT with 68Ga-NOTA-Exendin-4\nfor Detecting Localized Insulinoma: A Prospective Cohort Study","volume":"57","author":"Luo","year":"2016","journal-title":"J. Nucl. Med."},{"key":"2026081717214563800_cit5","doi-asserted-by":"publisher","first-page":"1519","DOI":"10.1210\/jc.2013-3541","article-title":"Detection\nof Metastatic Insulinoma by Positron Emission Tomography With [68Ga]\u00adExendin-4\ue5f8A Case Report","volume":"99","author":"Eriksson","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2026081717214563800_cit6","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.1056\/NEJMc1004547","article-title":"GLP-1-receptor scanning for imaging\nof human beta cells transplanted in muscle","volume":"363","author":"Pattou","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"2026081717214563800_cit7","doi-asserted-by":"publisher","first-page":"821","DOI":"10.1007\/s12020-015-0633-7","article-title":"Preoperative\nlocalization of adult\nnesidioblastosis using 68Ga-DOTA-exendin-4-PET\/CT","volume":"50","author":"Christ","year":"2015","journal-title":"Endocrine"},{"key":"2026081717214563800_cit8","unstructured":"68Ga-NODAGA-exendin-4 PET\/CT for Diagnostic\nImaging in AHH. https:\/\/ClinicalTrials.gov\/show\/NCT03189953."},{"key":"2026081717214563800_cit9","doi-asserted-by":"publisher","first-page":"706","DOI":"10.1007\/s00125-005-0128-9","article-title":"Exendin-4,\nbut not glucagon-like\npeptide-1, is cleared exclusively by glomerular filtration in anaesthetised\npigs","volume":"49","author":"Simonsen","year":"2006","journal-title":"Diabetologia"},{"key":"2026081717214563800_cit10","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1016\/j.nucmedbio.2007.05.002","article-title":"Renal uptake and retention of radiolabeled\nsomatostatin, bombesin, neurotensin, minigastrin and CCK analogues:\nspecies and gender differences","volume":"34","author":"Melis","year":"2007","journal-title":"Nucl. Med. Biol."},{"key":"2026081717214563800_cit11","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1007\/s00259-014-2946-9","article-title":"68Ga-NOTA-exendin-4\nPET\/CT in detection of occult insulinoma and evaluation of physiological\nuptake","volume":"42","author":"Luo","year":"2015","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"2026081717214563800_cit12","doi-asserted-by":"publisher","first-page":"4398","DOI":"10.1210\/jc.2009-1082","article-title":"Glucagon-like peptide-1\nreceptor imaging for localization\nof insulinomas","volume":"94","author":"Christ","year":"2009","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2026081717214563800_cit13","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1111\/dom.12596","article-title":"Review of\nhead-to-head comparisons of glucagon-like peptide-1 receptor agonists","volume":"18","author":"Madsbad","year":"2016","journal-title":"Diabetes, Obes. Metab."},{"key":"2026081717214563800_cit14","doi-asserted-by":"publisher","first-page":"1979","DOI":"10.1021\/acs.molpharmaceut.6b00143","article-title":"Cu-64- and Ga-68-Based PET Imaging\nof Folate Receptor -Positive Tumors: Development and Evaluation of\nan Albumin -Binding NODAGA-Folate","volume":"13","author":"Farkas","year":"2016","journal-title":"Mol. Pharmaceutics"},{"key":"2026081717214563800_cit15","doi-asserted-by":"publisher","first-page":"124","DOI":"10.2967\/jnumed.112.107235","article-title":"DOTA conjugate with\nan albumin-binding entity enables\nthe first folic acid-targeted 177Lu-radionuclide tumor\ntherapy in mice","volume":"54","author":"Muller","year":"2013","journal-title":"J. Nucl. Med."},{"key":"2026081717214563800_cit16","doi-asserted-by":"publisher","first-page":"934","DOI":"10.1021\/acs.molpharmaceut.7b00877","article-title":"Albumin-Binding\nPSMA Ligands: Optimization of the Tissue Distribution Profile","volume":"15","author":"Benes\u030cova\u0301","year":"2018","journal-title":"Mol. Pharmaceutics"},{"key":"2026081717214563800_cit17","doi-asserted-by":"publisher","first-page":"3196","DOI":"10.1002\/anie.200704936","article-title":"A portable albumin binder from a\nDNA-encoded chemical library","volume":"47","author":"Dumelin","year":"2008","journal-title":"Angew. Chem.,\nInt. Ed."},{"key":"2026081717214563800_cit18","doi-asserted-by":"publisher","first-page":"5526","DOI":"10.1016\/j.bbagen.2013.04.023","article-title":"Albumin\nas a versatile platform for\ndrug half-life extension","volume":"1830","author":"Sleep","year":"2013","journal-title":"Biochim. Biophys.\nActa, Gen. Subj."},{"key":"2026081717214563800_cit19","doi-asserted-by":"publisher","first-page":"2883","DOI":"10.1016\/S0960-894X(02)00610-8","article-title":"Albumin\naffinity tags increase peptide\nhalf-life in vivo","volume":"12","author":"Koehler","year":"2002","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"2026081717214563800_cit20","doi-asserted-by":"publisher","DOI":"10.1186\/s13550-014-0031-9","article-title":"A comparison\nof three 67\/68Ga-labelled exendin-4 derivatives for beta-cell\nimaging on the GLP-1 receptor: the influence of the conjugation site\nof NODAGA as chelator","volume":"4","author":"Jodal","year":"2014","journal-title":"EJNMMI Res."},{"key":"2026081717214563800_cit21","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0123443","article-title":"Evaluation\nof 111In-labelled exendin-4 derivatives\ncontaining different meprin beta-specific cleavable linkers","volume":"10","author":"Jodal","year":"2015","journal-title":"PLoS One"},{"key":"2026081717214563800_cit22","doi-asserted-by":"publisher","first-page":"736","DOI":"10.2967\/jnumed.106.038679","article-title":"GLP-1 receptor expression\nin human tumors and human normal tissues: potential for in vivo targeting","volume":"48","author":"Ko\u0308rner","year":"2007","journal-title":"J. Nucl. Med."},{"key":"2026081717214563800_cit23","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1007\/978-3-319-40525-4_25","article-title":"Congenital Hyperinsulinism","volume-title":"Pediatric\nDigestive Surgery","author":"Boroni","year":"2017"},{"key":"2026081717214563800_cit24","first-page":"109","article-title":"Dosimetry of [177Lu]-DO3A-VS-Cys\u00ad(40)-Exendin-4\n- impact on the feasibility\nof insulinoma internal radiotherapy","volume":"5","author":"Velikyan","year":"2015","journal-title":"Am. J.\nNucl. Med. Mol. Imaging"},{"key":"2026081717214563800_cit25","doi-asserted-by":"publisher","first-page":"950","DOI":"10.1007\/s00125-014-3166-3","article-title":"Non-invasive\nquantification of the beta cell mass by SPECT with 111In-labelled\nexendin","volume":"57","author":"Brom","year":"2014","journal-title":"Diabetologia"},{"key":"2026081717214563800_cit26","doi-asserted-by":"publisher","first-page":"1324","DOI":"10.2337\/db14-1212","article-title":"111In-exendin uptake in the pancreas correlates\nwith the beta-cell mass\nand not with the alpha-cell mass","volume":"64","author":"Brom","year":"2015","journal-title":"Diabetes"},{"key":"2026081717214563800_cit27","doi-asserted-by":"publisher","first-page":"158","DOI":"10.3389\/fendo.2012.00158","article-title":"Glucagon-like peptide-1\nreceptor overexpression in cancer and its impact on clinical applications","volume":"3","author":"Ko\u0308rner","year":"2012","journal-title":"Front. Endocrinol."},{"key":"2026081717214563800_cit28","doi-asserted-by":"publisher","first-page":"3891","DOI":"10.2337\/db13-1169","article-title":"Exendin-4,\na GLP-1\nreceptor agonist, attenuates prostate cancer growth","volume":"63","author":"Nomiyama","year":"2014","journal-title":"Diabetes"},{"key":"2026081717214563800_cit29","doi-asserted-by":"publisher","first-page":"1282","DOI":"10.2967\/jnumed.115.168948","article-title":"Approaches\nto improve the pharmacokinetics of radiolabeled GLP-1 receptor ligands\nusing antagonistic tracers","volume":"57","author":"Rylova","year":"2016","journal-title":"J. Nucl. Med."},{"key":"2026081717214563800_cit30","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0170435","article-title":"Radioiodinated Exendin-4 Is Superior\nto the Radiometal-Labelled\nGlucagon-Like Peptide-1 Receptor Probes Overcoming Their High Kidney\nUptake","volume":"12","author":"La\u0308ppchen","year":"2017","journal-title":"PLoS One"},{"key":"2026081717214563800_cit31","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.nucmedbio.2005.08.004","article-title":"Antiepidermal\ngrowth factor variant III scFv fragment: effect of radioiodination\nmethod on tumor targeting and normal tissue clearance","volume":"33","author":"Shankar","year":"2006","journal-title":"Nucl. Med. Biol."},{"key":"2026081717214563800_cit32","doi-asserted-by":"publisher","first-page":"2447","DOI":"10.2174\/0929867033456666","article-title":"Approaches\nto improve cellular retention\nof radiohalogen labels delivered by internalising tumour-targeting\nproteins and peptides","volume":"10","author":"Tolmachev","year":"2003","journal-title":"Curr. Med. Chem."},{"key":"2026081717214563800_cit33","first-page":"829","article-title":"Intracellular fate\nof radiometals","volume":"38","author":"Duncan","year":"1997","journal-title":"J. Nucl. Med."},{"key":"2026081717214563800_cit34","doi-asserted-by":"publisher","first-page":"976","DOI":"10.1067\/msy.2002.128615","article-title":"Concurrent resections of pancreatic islet cell cancers\nwith synchronous hepatic metastases: outcomes of an aggressive approach","volume":"132","author":"Sarmiento","year":"2002","journal-title":"Surgery"},{"key":"2026081717214563800_cit35","doi-asserted-by":"publisher","DOI":"10.1186\/s13550-016-0243-2","article-title":"Low kidney uptake of\nGLP-1R-targeting, beta cell-specific PET tracer, 18F-labeled\n[Nle14,Lys40]\u00adexendin-4 analog, shows promise for clinical imaging","volume":"6","author":"Mikkola","year":"2016","journal-title":"EJNMMI Res."},{"key":"2026081717214563800_cit36","doi-asserted-by":"publisher","first-page":"1059","DOI":"10.2967\/jnumed.110.074914","article-title":"Exendin-4\u2013Based\nRadiopharmaceuticals\nfor Glucagonlike Peptide-1 Receptor PET\/CT and SPECT\/CT","volume":"51","author":"Wild","year":"2010","journal-title":"J. Nucl. Med."}],"container-title":["Molecular Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.molpharmaceut.9b00271","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/mpohbp\/article-pdf\/16\/9\/3760\/13583854\/mp9b00271.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/mpohbp\/article-pdf\/16\/9\/3760\/13583854\/mp9b00271.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T21:26:03Z","timestamp":1787001963000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/mpohbp\/article\/16\/9\/3760\/507308\/Exendin-4-Derivatives-with-an-Albumin-Binding"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,8,8]]},"references-count":36,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2019,8,8]]},"published-print":{"date-parts":[[2019,9,3]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.molpharmaceut.9b00271","relation":{},"ISSN":["1543-8384","1543-8392"],"issn-type":[{"value":"1543-8384","type":"print"},{"value":"1543-8392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,8,8]]}}}