Comparison of the tolerability of 161Tb- and 177Lu-labeled somatostatin analogues in the preclinical setting.

Purpose: [¹⁷⁷Lu]Lu-DOTATATE is an established somatostatin receptor (SSTR) agonist for the treatment of metastasized neuroendocrine neoplasms, while the SSTR antagonist [¹⁷⁷Lu]Lu-DOTA-LM3 has only scarcely been employed in clinics. Impressive preclinical data obtained with [¹⁶¹Tb]Tb-DOTA-LM3 in tumor-bearing mice indicated the potential of terbium-161 as an alternative to lutetium-177. The aim of the present study was to compare the tolerability of ¹⁶¹Tb- and ¹⁷⁷Lu-based DOTA-LM3 and DOTATATE in immunocompetent mice.

Methods: Dosimetry calculations were performed based on biodistribution data of the radiopeptides in immunocompetent mice. Treatment-related effects on blood cell counts were assessed on Days 10, 28 and 56 after application of [¹⁶¹Tb]Tb-DOTA-LM3 or [¹⁶¹Tb]Tb-DOTATATE at 20 MBq per mouse. These radiopeptides were also applied at 100 MBq per mouse and the effects compared to those observed after application of the ¹⁷⁷Lu-labeled counterparts. Bone marrow smears, blood plasma parameters and organ histology were assessed at the end of the study.

Results: The absorbed organ dose was commonly higher for the SSTR antagonist than for the SSTR agonist and for terbium-161 over lutetium-177. Application of a therapeutic activity level of 20 MBq [¹⁶¹Tb]Tb-DOTA-LM3 or [¹⁶¹Tb]Tb-DOTATATE was well tolerated without major hematological changes. The injection of 100 MBq of the ¹⁶¹Tb- and ¹⁷⁷Lu-based somatostatin analogues affected the blood cell counts, however. The lymphocytes were 40-50% lower in treated mice compared to the untreated controls on Day 10 irrespective of the radionuclide employed. At the same timepoint, thrombocyte and erythrocyte counts were 30-50% and 6-12% lower, respectively, after administration of the SSTR antagonist (p < 0.05) while changes were less pronounced in mice injected with the SSTR agonist. All blood cell counts were in the normal range on Day 56. Histological analyses revealed minimal abnormalities in the kidneys, liver and spleen of treated mice. No correlation was observed between the organ dose and frequency of the occurrence of abnormalities.

Conclusion: Hematologic changes were more pronounced in mice treated with the SSTR antagonist than in those treated with the SSTR agonist. Despite the increased absorbed dose delivered by terbium-161 over lutetium-177, [¹⁶¹Tb]Tb-DOTA-LM3 and [¹⁶¹Tb]Tb-DOTATATE should be safe at activity levels that are recommended for their respective ¹⁷⁷Lu-based analogues.