Preclinical evaluation of tumor dose effects of Terbium-161 and Lutetium-177 with DOTA-TATE and DOTA-JR11 in a NETs model

[ 177 Lu]Lu-DOTA-TATE is well established for the treatment of neuroendocrine tumors. However, further optimization of targeted radionuclide therapy remains necessary. In this context, terbium-161 has emerged as a promising alternative due to the emission of significant quantities of Auger and conversion electrons, which may enhance dose deposition at short ranges. The contribution of these electrons is not completely understood and may depend on the absorbed dose and targeting strategy. Therefore, this study aimed to compare the dose-dependent effects of a somatostatin receptor agonist (DOTA-TATE) and antagonist (DOTA-JR11) when labeled with either terbium-161 or lutetium-177 in mice bearing SSTR2-H69 xenografts. DOTA-TATE and DOTA-JR11 were radiolabeled with terbium-161 and lutetium-177 and evaluated for radiochemical yield, purity, competition binding, cellular uptake, and internalization. All four radiopharmaceuticals were obtained with high radiochemical yields (> 98%) and purities (> 95%), and showed comparable in vitro binding, uptake and internalization profiles irrespective of the radionuclide used. Therapeutic efficacy and toxicity were subsequently assessed in mice bearing SSTR2-H69 xenograft at tumor absorbed doses 20 and 30 Gy, which were determined by preceding biodistribution studies and dosimetry simulations. At 20 Gy, median survival was comparable among all treatment groups. At 30 Gy, terbium-161 labeled radiopharmaceuticals demonstrated improved therapeutic efficacy compared with their lutetium-177 counterparts without evidence of renal toxicity. At matched absorbed tumor doses, terbium-161 labeled radiopharmaceuticals demonstrated equivalent or improved therapeutic efficacy compared with lutetium-177, particularly for antagonist-based targeting at higher dose levels. These findings support further investigation of terbium-161 as a therapeutic radionuclide and suggest that the Auger and conversion electrons of terbium-161 enhance therapeutic effect when targeting the membrane.