Terbium-161 Shows Dose-Dependent Edge Over Lutetium-177 in Mouse Neuroendocrine Tumor Model

Terbium-161, a radionuclide that emits large quantities of Auger and conversion electrons, has delivered equivalent or better tumor control than the clinically established lutetium-177 in a preclinical mouse model of neuroendocrine tumors, according to a study published in EJNMMI Radiopharmacy and Chemistry. The work compared two somatostatin receptor targeting agents, the agonist DOTA-TATE and the antagonist DOTA-JR11, each labeled with either terbium-161 or lutetium-177, in mice bearing SSTR2-H69 xenografts. Because lutetium-177 DOTA-TATE is already well established for treating neuroendocrine tumors, the researchers set out to test whether terbium-161’s short-range electron emissions could enhance dose deposition and therapeutic effect at matched absorbed tumor doses.

The team first characterized all four radiopharmaceuticals in the laboratory. Each was produced with high radiochemical yields above 98 percent and purities above 95 percent, and the compounds showed comparable binding, uptake and internalization profiles in vitro regardless of which radionuclide was attached. This matching mattered for the in vivo comparison: with chemistry and receptor binding held essentially constant, differences in tumor response could be attributed to the radionuclide’s radiation emission properties rather than to different targeting behavior. Tumor absorbed doses of 20 and 30 Gy were then selected on the basis of preceding biodistribution studies and dosimetry simulations, allowing a dose-controlled head-to-head evaluation.

The therapeutic results divided cleanly by dose level. At 20 Gy, median survival was comparable across all treatment groups, indicating no advantage for either radionuclide at the lower absorbed dose. The authors concluded that at matched absorbed tumor doses, terbium-161 performed equivalently or better than lutetium-177, with the advantage particularly evident for antagonist-based targeting at the higher dose level.

The study’s interpretation of why terbium-161 outperformed lutetium-177 centers on its emission spectrum. The authors suggest these electrons enhance therapeutic effect when targeting the membrane, while noting that the contribution of such electrons is not completely understood and may depend on both the absorbed dose and the targeting strategy used. The finding that the benefit appeared only at 30 Gy, and was especially pronounced with the antagonist DOTA-JR11, is consistent with the idea that the added short-range dose component becomes meaningful only once a sufficient baseline absorbed dose has been delivered.

Several caveats frame these results. The work is entirely preclinical: it was conducted in mice bearing human SSTR2-expressing xenografts, not in patients, and therapeutic efficacy and toxicity were assessed at only two tumor dose levels in a single tumor model. The authors themselves position the findings as supporting further investigation of terbium-161 as a therapeutic radionuclide rather than as evidence of clinical benefit. The article was also shared early as a peer-reviewed, accepted manuscript subject to further editing before the final version of record. Even so, the dose-matched design, the verified radiochemical equivalence of the four tracers, and the absence of renal toxicity signals give the comparison unusual internal control for a preclinical radiopharmaceutical study, and they sharpen the specific question that clinical translation must now answer: whether terbium-161’s Auger electron payload can be converted into a survival advantage for neuroendocrine tumor patients.

Subject of Research: Preclinical comparison of terbium-161 and lutetium-177 labeled somatostatin agonist and antagonist radiopharmaceuticals in a mouse neuroendocrine tumor model

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

Article References: Ntihabose, C. M., Handula, M., Piet, A., Beekman, S., Eskandari, N., Stuurman, D., de Ridder, C., Li, L., Ma, H., van de Merwe, I., Sabatella, M., Groningen, M. C. C.-V., Brabander, T., Koolen, S. L. W., Konijnenberg, M., Nonnekens, J., Seimbille, Y., & de Blois, E. (2026). Preclinical evaluation of tumor dose effects of Terbium-161 and Lutetium-177 with DOTA-TATE and DOTA-JR11 in a NETs model. EJNMMI Radiopharmacy and Chemistry. https://doi.org/10.1186/s41181-026-00499-z

Image Credits: AI Generated

DOI: 10.1186/s41181-026-00499-z

Keywords: terbium-161, lutetium-177, DOTA-TATE, DOTA-JR11, neuroendocrine tumors, peptide receptor radionuclide therapy, Auger electrons, dosimetry, preclinical study, xenograft model, somatostatin receptor antagonist, renal toxicity