NMR studies reveal structural differences between the gallium and yttrium complexes of DOTA-D-Phe1-Tyr3-octreotide

J Med Chem. 2005 Mar 10;48(5):1506-14. doi: 10.1021/jm0496335.

Abstract

The somatostatin analogue DOTATOC, DOTA-[Tyr(3)]octreotide, is used for in vivo diagnosis and targeted therapy of somatostatin-receptor-positive tumors. DOTATOC consists of a disulfide-bridged octapeptide, d-Phe(1)-Cys(2)-Tyr(3)-d-Trp(4)-Lys(5)-Thr(6)-Cys(7)-Thr(8)-ol, connected to the metal chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). Two metal complexes, Ga(III)- and Y(III)-DOTATOC, were reported to differ significantly in somatostatin receptor affinity and tumor uptake. Our (1)H and (13)C solution NMR data and modeling studies of both compounds are in agreement with a fast conformational equilibrium of the peptide part, as previously reported for octreotide itself. However, the different coordination geometry of Ga(3+) and Y(3+) (6-fold and 8-fold, respectively, as known from model compounds) causes pronounced differences for the d-Phe(1) residue. For Y(III)-DOTATOC this leads to two conformers exchanging slowly on the NMR time scale. From various NMR measurements, they could be identified as cis-trans isomers at the amide bond between DOTA chelator and first residue (d-Phe(1)H(N)) of the peptide.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Gallium*
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Molecular Conformation
  • Molecular Structure
  • Octreotide / analogs & derivatives*
  • Octreotide / chemistry*
  • Organometallic Compounds / chemistry*
  • Stereoisomerism
  • Yttrium*

Substances

  • Ga(III)-DOTATOC
  • Organometallic Compounds
  • Yttrium
  • Gallium
  • Octreotide
  • Edotreotide