title: [(99m)Tc]Demomedin C, a radioligand based on human gastrin releasing peptide(18-27): synthesis and preclinical evaluation in gastrin releasing peptide receptor-expressing models.
abstract: The synthesis and preclinical evaluation of [(99m)Tc]Demomedin C in GRPR-expressing models are reported. Demomedin C resulted by coupling a Boc-protected N(4)-chelator to neuromedin C (human GRP(18-27)), which, after (99m)Tc-labeling, afforded [(99m)Tc]Demomedin C. Demomedin C showed high affinity and selectivity for the GRPR during receptor autoradiography on human cancer samples (IC(50) in nM: GRPR, 1.4 ± 0.2; NMBR, 106 ± 18; and BB(3)R, >1000). It triggered GRPR internalization in HEK-GRPR cells and Ca(2+) release in PC-3 cells (EC(50) = 1.3 nM). [(99m)Tc]Demomedin C rapidly and specifically internalized at 37 °C in PC-3 cells and was stable in mouse plasma. [(99m)Tc]Demomedin C efficiently and specifically localized in human PC-3 implants in mice (9.84 ± 0.81%ID/g at 1 h pi; 6.36 ± 0.85%ID/g at 4 h pi, and 0.41 ± 0.07%ID/g at 4 h pi block). Thus, human GRP-based radioligands, such as [(99m)Tc]Demomedin C, can successfully target GRPR-expressing human tumors in vivo while displaying attractive biological features--e.g. higher GRPR-selectivity--vs their frog-homologues.
authors.affiliation: Molecular Radiopharmacy, Institute of Radioisotopes-Radiodiagnostic Products, National Center for Scientific Research Demokritos, Ag. Paraskevi Attikis, GR-153 10 Athens, Greece.
authors.forename: Berthold A
authors.initials: BA
authors.lastname: Nock
authors.forename: Renzo
authors.initials: R
authors.lastname: Cescato
authors.forename: Eleni
authors.initials: E
authors.lastname: Ketani
authors.forename: Beatrice
authors.initials: B
authors.lastname: Waser
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Reubi
authors.forename: Theodosia
authors.initials: T
authors.lastname: Maina
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001001:Anura; D001345:Autoradiography; D001667:Binding, Competitive; D001839:Bombesin / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D001984:Bronchial Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007078:Ileal Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D015609:Organotechnetium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D018004:Receptors, Bombesin / Q000819:agonists / Q000378:metabolism*; D013045:Species Specificity; D013329:Structure-Activity Relationship; D013667:Technetium; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
chemical_list: D008024:Ligands; D009842:Oligopeptides; D015609:Organotechnetium Compounds; D010446:Peptide Fragments; D019275:Radiopharmaceuticals; D018004:Receptors, Bombesin; C577115:technetium 99m demomedin C; D013667:Technetium; C040794:neuromedin C; D001839:Bombesin; D002118:Calcium