title: Neuroendocrine tumor targeting: study of novel gallium-labeled somatostatin radiopeptides in a rat pancreatic tumor model.
abstract: Somatostatin analogs labeled with radionuclides are of considerable interest in the diagnosis and therapy of SSTR-expressing tumors, such as gastroenteropancreatic, small cell lung, breast and frequently nervous system tumors. In view of the favorable physical characteristics of the Ga isotopes (67)Ga and (68)Ga, enabling conventional tumor scintigraphy, PET and possibly internal radiotherapy, we focused on the development of a Ga-labeled somatostatin analog suitable for targeting SSTR-expressing tumors. For this purpose, 3 somatostatin analogs, OC, TOC and TATE were conjugated to the metal chelator DOTA and labeled with the radiometals (111)In, (90)Y and (67)Ga. They were then evaluated for their performance in the AR4-2J pancreatic tumor model by testing SSTR2-binding affinity, internalization/externalization in isolated cells and biodistribution in tumor-bearing nude mice. Surprisingly, we found that, compared to (111)In or (90)Y, labeling with (67)Ga considerably improved the biologic performance of the tested somatostatin analogs with respect to SSTR2 affinity and tissue distribution. (67)Ga-labeled DOTA-somatostatin analogs were rapidly excreted from nontarget tissues, leading to excellent tumor-to-nontarget tissue uptake ratios. Of interest for radiotherapeutic application, [(67)Ga]DOTATOC was strongly internalized by AR4-2J cells. Furthermore, our results suggest a link between the radioligand charge and its kidney retention. The excellent tumor selectivity of Ga-DOTA somatostatin analogs together with the different applications of Ga in nuclear oncology suggests that Ga-DOTA somatostatin analogs will become an important tool in the management of SSTR-positive tumors.
authors.affiliation: Department of Research-ZLF, University Hospital and University Children's Hospital, University of Basel, Basel, Switzerland. sylvie.froidevaux@unibas.ch
authors.forename: Sylvie
authors.initials: S
authors.lastname: Froidevaux
authors.forename: Alex N
authors.initials: AN
authors.lastname: Eberle
authors.forename: Martine
authors.initials: M
authors.lastname: Christe
authors.forename: Lazar
authors.initials: L
authors.lastname: Sumanovski
authors.forename: Axel
authors.initials: A
authors.lastname: Heppeler
authors.forename: Jörg S
authors.initials: JS
authors.lastname: Schmitt
authors.forename: Klaus
authors.initials: K
authors.lastname: Eisenwiener
authors.forename: Christoph
authors.initials: C
authors.lastname: Beglinger
authors.forename: Helmut R
authors.initials: HR
authors.lastname: Mäcke
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000737:chemistry / Q000493:pharmacokinetics; D018278:Carcinoma, Neuroendocrine / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D005260:Female; D005710:Gallium Radioisotopes / Q000493:pharmacokinetics; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D006801:Humans; D007205:Indium Radioisotopes / Q000493:pharmacokinetics; D007668:Kidney / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D015282:Octreotide / Q000737:chemistry / Q000493:pharmacokinetics; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed; D015021:Yttrium Radioisotopes / Q000493:pharmacokinetics
chemical_list: D018931:Antineoplastic Agents, Hormonal; D005710:Gallium Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; D007205:Indium Radioisotopes; D019275:Radiopharmaceuticals; D015021:Yttrium Radioisotopes; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D015282:Octreotide