title: Toward stable N4-modified neurotensins for NTS1-receptor-targeted tumor imaging with 99mTc.
abstract: A series of Gly-neurotensin(8-13) analogues modified at the N-terminus by acyclic tetraamines (Demotensin 1-4) were obtained by solid-phase peptide synthesis techniques. Strategic replacement of amino acids and/or reduction of sensitive peptide bonds were performed to enhance conjugate resistance against proteolytic enzymes. During 99mTc-labeling, single species radiopeptides, [99mTc]Demotensin 1-4, were easily obtained in high yields and typical specific activities of 1 Ci/micromol. Peptide conjugates displayed a high affinity binding to the human neurotensin subtype 1 receptor (NTS1-R) expressed in colon adenocarcinoma HT-29 or WiDr cells and/or in human tumor sections. [99mTc]Demotensin 1-4 internalized very rapidly in HT-29 or WiDr cells by a NTS1-R-mediated process. [99mTc]Demotensin 3 and 4, which remained stable during 1 h incubation in murine plasma, were selectively studied in nude mice bearing human HT-29 and WiDr xenografts. After injection, [99mTc]Demotensin 3 and 4 effectively and specifically localized in the experimental tumors and were rapidly excreted via the kidneys into the urine, exhibiting overall biodistribution patterns favorable for NTS1-R-targeted tumor imaging in man.
authors.affiliation: Institute of Radioisotopes - Radiodiagnostic Products, National Center for Scientific Research Demokritos, 15310 Athens, Greece.
authors.forename: Berthold A
authors.initials: BA
authors.lastname: Nock
authors.forename: Anastasia
authors.initials: A
authors.lastname: Nikolopoulou
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Reubi
authors.forename: Veronique
authors.initials: V
authors.lastname: Maes
authors.forename: Peter
authors.initials: P
authors.lastname: Conrath
authors.forename: Dirk
authors.initials: D
authors.lastname: Tourwé
authors.forename: Theodosia
authors.initials: T
authors.lastname: Maina
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000000981:diagnostic imaging / Q000378:metabolism; D045744:Cell Line, Tumor; D004355:Drug Stability; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism; D009496:Neurotensin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D015609:Organotechnetium Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D018028:Receptors, Neurotensin / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
chemical_list: D009842:Oligopeptides; D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; D018028:Receptors, Neurotensin; C114036:neurotensin type 1 receptor; D009496:Neurotensin