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

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 H-1 and C-13 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 Ga3+ and Y3+ (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.