Metal-ion-dependent biological properties of a chelator-derived somatostatin analogue for tumour targeting

Chemistry. 2008;14(10):3026-34. doi: 10.1002/chem.200701264.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chelating Agents* / chemistry
  • Chelating Agents* / pharmacokinetics
  • Cobalt Radioisotopes* / chemistry
  • Cobalt Radioisotopes* / pharmacokinetics
  • Crystallography, X-Ray
  • Humans
  • Isotope Labeling
  • Kinetics
  • Ligands
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Molecular Structure
  • Neoplasms / diagnostic imaging*
  • Organometallic Compounds* / chemistry
  • Organometallic Compounds* / pharmacokinetics
  • Radioligand Assay
  • Radionuclide Imaging
  • Radiopharmaceuticals* / chemistry
  • Radiopharmaceuticals* / pharmacokinetics
  • Rats
  • Sensitivity and Specificity
  • Somatostatin / analogs & derivatives*
  • Somatostatin / chemistry
  • Thermodynamics
  • Tissue Distribution
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Chelating Agents
  • Cobalt Radioisotopes
  • Ligands
  • Organometallic Compounds
  • Radiopharmaceuticals
  • Somatostatin