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

The somatostatin analogue DOTATOC, DOTA-[Tyr³]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-Cys²-Tyr³-D-Trp⁴-Lys ⁵-Thr⁶-Cys⁷-Thr⁸-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 ¹H and ¹³C 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 Y ³⁺ (6-fold and 8-fold, respectively, as known from model compounds) causes pronounced differences for the D-Phe¹ 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-Phe¹H^N) of the peptide.