Comparison of the tolerability of 161 Tb- and 177 Lu-labeled somatostatin analogues in the preclinical setting
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Purpose
[ 177 Lu]Lu-DOTATATE is an established somatostatin receptor (SSTR) agonist for the treatment of metastasized neuroendocrine neoplasms, while the SSTR antagonist [ 177 Lu]Lu-DOTA-LM3 has only scarcely been employed in clinics. Impressive preclinical data obtained with [ 161 Tb]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 161 Tb- and 177 Lu-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 [ 161 Tb]Tb-DOTA-LM3 or [ 161 Tb]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 177 Lu-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 [ 161 Tb]Tb-DOTA-LM3 or [ 161 Tb]Tb-DOTATATE was well tolerated without major hematological changes. The injection of 100 MBq of the 161 Tb- and 177 Lu-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, [ 161 Tb]Tb-DOTA-LM3 and [ 161 Tb]Tb-DOTATATE should be safe at activity levels that are recommended for their respective 177 Lu-based analogues.
