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-Tyr¹-octreotate (DOTA-DY1-TATE), that has the chelator 1,4,7,10-tetraazacyclotetradecane-N,N‘,N‘ ‘,N‘ ‘‘-tetraacetic acid (DOTA) attached to the d-Tyr¹ residue, allowing radiolabeling with both radiohalogens and radiometals. A potential advantage of having a chelator attached to the Tyr¹ 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 ⁶¹Cu, ⁶⁴Cu, and ¹²⁵I in high radiochemical purity and specific activity. A competitive binding assay demonstrated that ^natCu-DOTA-DY1-TATE and DOTA-^natI-DY1-TATE had comparable affinity to ^natIn-DTPA-OC in AR42J rat pancreatic tumor cells membranes. ⁶¹Cu-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 ⁶⁴Cu-DOTA-DY1-TATE and 0.814 %ID/g for DOTA-¹²⁵I-DY1-TATE in AR42J tumor bearing Lewis rats at 1 h postinjection. DOTA-¹²⁵I-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 ⁶⁴Cu-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 ⁶⁴Cu- and ¹²⁵I-radiolabeled compounds showed somatostatin receptor-mediated uptake in normal and tumor tissues.