DOTA-D-Tyr1-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 (CU)-C-61, Cu-64, and I-125 in high radiochemical purity and specific activity. A competitive binding assay demonstrated that Cu-nat-DOTA-DY1-TATE and DOTA-I-nat-DY1-TATE had comparable affinity to In-nat-DTPA-OC in AR42J rat pancreatic tumor cells membranes. Cu-61-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 Cu-64-DOTA-DY1-TATE and 0.814 %ID/g for DOTA-I-125-DY1-TATE in AR42J tumor bearing Lewis rats at 1 h postinjection. DOTA-I-125-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 Cu-64-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 Cu-64-and I-125-radiolabeled compounds showed somatostatin receptor-mediated uptake in normal and tumor tissues.