Tyr 3 -Octreotide and Tyr 3 -Octreotate Radiolabeled with 177 Lu or 90 Y: Peptide Receptor Radionuclide Therapy Results In Vitro

Abstract

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(tyr³-octreotate). For radiotherapeutic applications these peptides are being labeled with the β^- particle emitters ¹⁷⁷Lu or ⁹⁰Y. We evaluated the therapeutic effects of these analogs chelated with tetra-azacyclododecatatro-acetic acid (DOTA) and labeled with ⁹⁰Y or ¹⁷⁷Lu 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 [¹⁷⁷Lu-DOTA]-D-Phe¹-c (Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr (¹⁷⁷Lu-octreotate). ¹⁷⁷Lu-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 ¹⁷⁷Lu-DOTA, which is not bound to the cells, had a less pronounced effect on the tumor cell survival. Both tyr³-octreotide and tyr³-octreotate labeled with either ¹⁷⁷Lu or ⁹⁰Y, using DOTA as chelator, were able to control tumor growth in a dose-dependent manner. In all concentrations used radiolabeled tyr³-octreotate had a higher tumor kill compared to radiolabeled tyr³-octreotide, labeled with ¹⁷⁷Lu or ⁹⁰Y. This is in accordance with the higher affinity of tyr³-octreotate for the subtype 2 (sst₂)-receptor compared to tyr³-octreotide, leading to a higher amount of cell-associated radioactivity, resulting in a significantly higher tumor radiation dose. In conclusion, tyr³-octreotate labeled with ¹⁷⁷Lu or ⁹⁰Y is the most promising analog for PRRT.