N-terminal sugar conjugation and C-terminal Thr-for-Thr(ol) exchange in radioiodinated Tyr3-octreotide: effect on cellular ligand trafficking in vitro and tumor accumulation in vivo

J Med Chem. 2005 Apr 21;48(8):2778-89. doi: 10.1021/jm040794i.


For effective targeting of somatostatin receptor (sst) expressing tumors by radiolabeled octreotide analogues, high ligand uptake into sst-positive cells is mandatory. To optimize it, two modifications have been introduced into [(125)I]Tyr(3)-octreotide ([(125)I]TOC): C-terminal Thr-for-Thr(ol) exchange (leading to Tyr(3)-octreotate (TOCA)) and N-terminal derivatization with different carbohydrates. Both have significant impact on radioligand uptake into sst(2)-expressing cells in vitro and in vivo. Glucose conjugation via Amadori reaction by itself led to improved tumor uptake of [(123)I]Gluc-TOC in vivo, which is based on an enhancement of peptide internalization despite a reduction in receptor affinity. In the case of the doubly modified analogues [(123)I]Gluc-TOCA, [(123)I]Gluc-S-TOCA, and [(123)I]Gal-S-TOCA, a cumulative effect of both structural modifications was observed, leading up to a 5-fold increased uptake of these compounds in sst-expressing tumors compared to [(125)I]TOC. Thus, glycosylation with small carbohydrates was found to be a suitable tool to enhance receptor-mediated uptake of radiolabeled octreotide analogues into sst-positive malignancies, leading to tracers with excellent characteristics for in vivo sst-imaging applications.

MeSH terms

  • Animals
  • Biological Transport
  • Cell Line
  • Cricetinae
  • Cricetulus
  • Female
  • Glucose / chemistry*
  • Glycosylation
  • Humans
  • Iodine Radioisotopes
  • Isotope Labeling
  • Ligands
  • Maltose / chemistry*
  • Mice
  • Mice, Nude
  • Neoplasms, Experimental / metabolism
  • Octreotide / analogs & derivatives*
  • Octreotide / chemical synthesis*
  • Octreotide / chemistry
  • Octreotide / pharmacokinetics
  • Radiopharmaceuticals / chemical synthesis*
  • Radiopharmaceuticals / chemistry
  • Radiopharmaceuticals / pharmacokinetics
  • Receptors, Somatostatin / metabolism
  • Structure-Activity Relationship
  • Trisaccharides / chemistry*


  • Iodine Radioisotopes
  • Ligands
  • Radiopharmaceuticals
  • Receptors, Somatostatin
  • Trisaccharides
  • 3-Tyr-octreotide
  • maltotriose
  • Maltose
  • Glucose
  • Octreotide