title: Design, synthesis, and biological evaluation of somatostatin-based radiopeptides.
abstract: The prototypes for tumor targeting with radiolabeled peptides are derivatives of somatostatin. Usually, they primarily have high affinity for somatostatin receptor subtype 2 (sst2), and they have moderate affinity for sst5. We aimed at developing analogs that recognize different somatostatin receptor subtypes for internal radiotherapy in order to extend the present range of accessible tumors. We synthesized DOTA-octapeptides based on octreotide by replacing Phe3 mainly with unnatural amino acids. The affinity profile was determined by using cell lines transfected with sst1-5. Internalization was determined by using AR42J, HEK-sst3, and HEK-sst5 cell lines, and biodistribution was studied in rat tumor models. Two of the derivatives thus obtained showed an improved binding affinity profile, enhanced internalization into cells expressing sst2 and sst3, respectively, and better tumor:kidney ratios in animals.
authors.affiliation: Division of Radiological Chemistry, Department of Radiology, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Ginj
authors.forename: Jörg S
authors.initials: JS
authors.lastname: Schmitt
authors.forename: Jianhua
authors.initials: J
authors.lastname: Chen
authors.forename: Beatrice
authors.initials: B
authors.lastname: Waser
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Reubi
authors.forename: Marion
authors.initials: M
authors.lastname: de Jong
authors.forename: Stefan
authors.initials: S
authors.lastname: Schulz
authors.forename: Helmut R
authors.initials: HR
authors.lastname: Maecke
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007205:Indium Radioisotopes; D008297:Male; D008968:Molecular Conformation; D009368:Neoplasm Transplantation; D015282:Octreotide / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D017481:Receptors, Somatostatin / Q000187:drug effects; D013004:Somatostatin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D013997:Time Factors; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D015021:Yttrium Radioisotopes
chemical_list: D006573:Heterocyclic Compounds, 1-Ring; D007205:Indium Radioisotopes; D017481:Receptors, Somatostatin; D015021:Yttrium Radioisotopes; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D013004:Somatostatin; D015282:Octreotide