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 (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.
Deshmukh
Mandar V
MV
Department Chemie, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany.
Voll
Georg
G
Kühlewein
Angelika
A
Mäcke
Helmut
H
Schmitt
Jörg
J
Kessler
Horst
H
Gemmecker
Gerd
G
D005708:Gallium; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D015282:Octreotide / Q000031:analogs & derivatives* / Q000737:chemistry*; D009942:Organometallic Compounds / Q000737:chemistry*; D013237:Stereoisomerism; D015019:Yttrium
C499142:Ga(III)-DOTATOC; D009942:Organometallic Compounds; D015019:Yttrium; D005708:Gallium; D015282:Octreotide; C106246:Edotreotide