Tyr3-octreotide and Tyr3-octreotate radiolabeled with 177Lu or 90Y:: Peptide receptor radionuclide therapy results in vitro

Somatostatin analogs promising for peptide receptor scintigraphy (PRS) and peptide receptor radionuclide therapy (PRRT) are D-Phe-c(Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr(ol) (Tyr(3)-octreotide) and D-Phe-c(Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr (Tyr(3)-octreotate). For radiotherapeutic applications these peptides are being labeled with the beta(-) particle emitters Lu-177 or Y-90. We evaluated the therapeutic effects of these analogs chelated with tetra-azacyclododecatatro-acetic acid (DOTA) and labeled with Y-90 or Lu-177 in an in vitro colony-forming assay using the rat pancreatic tumor cell line CA20948. Furthermore, we investigated the effects of incubation time, radiation dose, and specific activity of [Lu-177-DOTA]-D-Phe(1)-c (Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr (Lu-177-octreotate). Lu-177-octreotate could reduce tumor growth to 100% cell kill and effects were dependent on radiation dose, incubation time, and specific activity used. Similar concentrations of Lu-177-DOTA, which is not bound to the cells, had a less pronounced effect on the tumor cell survival. Both Tyr(3)-octreotide and Tyr(3)-octreotate labeled with either Lu-177 or Y-90, using DOTA as chelator, were able to control tumor growth in a dose-dependent manner. In all concentrations used radiolabeled Tyr(3)-octreotate had a higher tumor kill compared to radiolabeled Tyr(3)-octreotide, labeled with Lu-177 or Y-90. This is in accordance with the higher affinity of Tyr(3)-octreotate for the subtype 2 (sst(2))-receptor compared to Tyr(3)-octreotide, leading to a higher amount of cell-associated radioactivity, resulting in a significantly higher tumor radiation dose. In conclusion, Tyr(3)-octreotate labeled with Lu-177 or Y-90 is the most promising analog for PRRT.