DOTA-D-Tyr(1)-octreotate: a somatostatin analogue for labeling with metal and halogen radionuclides for cancer imaging and therapy.
The goal of this study was to evaluate a somatostatin receptor ligand, DOTA-D-Tyr(1)-octreotate (DOTA-DY1-TATE), that has the chelator 1,4,7,10-tetraazacyclotetradecane-N,N',N'',N'"-tetraacetic acid (DOTA) attached to the D-Tyr(1) residue, allowing radiolabeling with both radiohalogens and radiometals. A potential advantage of having a chelator attached to the Tyr(1) residue is that halogen radiolabels may residualize or remain trapped in tumor cells rather than clear from the tumor. DOTA-DY1-TATE was synthesized by solid-phase methods and radiolabeled with (61)Cu, (64)Cu, and (125)I in high radiochemical purity and specific activity. A competitive binding assay demonstrated that (nat)Cu-DOTA-DY1-TATE and DOTA-(nat)I-DY1-TATE had comparable affinity to (nat)In-DTPA-OC in AR42J rat pancreatic tumor cells membranes. (61)Cu-DOTA-DY1-TATE had a dissociation constant (K(d)) of 176.4 pM and a receptor concentration (B(max)) of 244.4 fmol/mg. A tumor uptake of 1.515 %ID/g was determined for (64)Cu-DOTA-DY1-TATE and 0.814 %ID/g for DOTA-(125)I-DY1-TATE in AR42J tumor bearing Lewis rats at 1 h postinjection. DOTA-(125)I-DY1-TATE remained in the tumor at a higher concentration out to 4 h postinjection, suggesting that the iodine may have residualized in the tumor cells. MicroPET imaging of (64)Cu-DOTA-DY1-TATE in AR42J tumor bearing rats and SCID mice at 2 h postinjection showed significant uptake and good contrast in the thigh tumors in the rat model and in the neck and thigh tumors of the mouse. This study demonstrates that DOTA-DY1-TATE is a somatostatin analogue that can be labeled with both metal and halogen radionuclides, and its (64)Cu- and (125)I-radiolabeled compounds showed somatostatin receptor-mediated uptake in normal and tumor tissues.
Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Wen Ping
WP
Li
Jason S
JS
Lewis
Joonyoung
J
Kim
Joseph E
JE
Bugaj
Michael A
MA
Johnson
Jack L
JL
Erion
Carolyn J
CJ
Anderson
D000818:Animals; D005260:Female; D006219:Halogens / Q000627:therapeutic use; D006573:Heterocyclic Compounds, 1-Ring / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008024:Ligands; D008297:Male; D008670:Metals / Q000627:therapeutic use; D051379:Mice; D016513:Mice, SCID; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000532:radiotherapy*; D015282:Octreotide / Q000031:analogs & derivatives; D009928:Organ Specificity; D010456:Peptides, Cyclic / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011485:Protein Binding; D011868:Radioisotopes / Q000627:therapeutic use; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051381:Rats; D011917:Rats, Inbred Lew; D017481:Receptors, Somatostatin / Q000378:metabolism; D013004:Somatostatin / Q000031:analogs & derivatives*; D014055:Tomography, Emission-Computed; D016896:Treatment Outcome
C476041:DOTA-Tyr(1)-octreotate; D006219:Halogens; D006573:Heterocyclic Compounds, 1-Ring; D008024:Ligands; D008670:Metals; D010456:Peptides, Cyclic; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D017481:Receptors, Somatostatin; D013004:Somatostatin; D015282:Octreotide