title: Metal-ion-dependent biological properties of a chelator-derived somatostatin analogue for tumour targeting.
abstract: Somatostatin-based radioligands have been shown to have sensitive imaging properties for neuroendocrine tumours and their metastases. The potential of [(55)Co(dotatoc)] (dotatoc =4,7,10-tricarboxymethyl-1,4,7,10-tetraazacyclododecane-1-ylacetyl-D-Phe-(Cys-Tyr-D-Trp-Lys-Thr-Cys)-threoninol (disulfide bond)) as a new radiopharmaceutical agent for PET has been evaluated. (57)Co was used as a surrogate of the positron emitter (55)Co and the pharmacokinetics of [(57)Co(dotatoc)] were investigated by using two nude mouse models. The somatostatin receptor subtype (sst1-sst5) affinity profile of [(nat)Co(dotatoc)] on membranes transfected with human somatostatin receptor subtypes was assessed by using autoradiographic methods. These studies revealed that [(57)Co(dotatoc)] is an sst2-specific radiopeptide which presents the highest affinity ever found for the sst2 receptor subtype. The rate of internalisation into the AR4-2J cell line also was the highest found for any somatostatin-based radiopeptide. Biodistribution studies, performed in nude mice bearing an AR4-2J tumour or a transfected HEK-sst2 cell-based tumour, showed high and specific uptake in the tumour and in other sst-receptor-expressing tissues, which reflects the high receptor binding affinity and the high rate of internalisation. The pharmacologic differences between [(57)Co(dotatoc)] and [(67)Ga(dotatoc)] are discussed in terms of the structural parameters found for the chelate models [Co(II)(dota)](2-) and [Ga(III)(dota)](-) whose X-ray structures have been determined. Both chelates show six-fold coordination in pseudo-octahedral arrangements.
authors.affiliation: Division of Radiological Chemistry, University Hospital of Basel, 4031 Basel, Switzerland.
authors.forename: Axel
authors.initials: A
authors.lastname: Heppeler
authors.forename: João P
authors.initials: JP
authors.lastname: André
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Buschmann
authors.forename: Xuejuan
authors.initials: X
authors.lastname: Wang
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Reubi
authors.forename: Michael
authors.initials: M
authors.lastname: Hennig
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Kaden
authors.forename: Helmut R
authors.initials: HR
authors.lastname: Maecke
mesh_terms: D000818:Animals; D002614:Chelating Agents / Q000737:chemistry / Q000493:pharmacokinetics; D003037:Cobalt Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D018360:Crystallography, X-Ray; D006801:Humans; D007553:Isotope Labeling; D007700:Kinetics; D008024:Ligands; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000000981:diagnostic imaging*; D009942:Organometallic Compounds / Q000737:chemistry / Q000493:pharmacokinetics; D011869:Radioligand Assay; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D012680:Sensitivity and Specificity; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000737:chemistry; D013816:Thermodynamics; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D002614:Chelating Agents; D003037:Cobalt Radioisotopes; D008024:Ligands; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; D013004:Somatostatin