[161Tb]Tb-DOTATATE as a potential treatment option for neuroblastoma

Background Neuroblastoma is an aggressive paediatric malignancy with poor outcomes in high-risk patients despite multimodal therapy. [ 177 Lu]Lu-DOTATATE, targeting somatostatin receptor 2 (SSTR2), is under clinical investigation for neuroblastoma. Terbium-161 ( 161 Tb) shares chemical characteristics and a similar half-life with lutetium-177 ( 177 Lu) but offers advantages through its higher emission of Auger and conversion electrons, which may enhance therapeutic efficacy especially for micrometastases and recurrent disease. This study investigates [ 161 Tb]Tb-DOTATATE as a potential complement for treatment of SSTR2-expressing neuroblastoma. Results DOTATATE was successfully radiolabelled with 161 Tb, achieving high radiochemical yield and stability. [ 161 Tb]Tb-DOTATATE demonstrated clear SSTR2-specific binding in vitro, as well as biodistribution and tumour uptake comparable to [ 177 Lu]Lu-DOTATATE in vivo. Treatment with [ 161 Tb]Tb-DOTATATE reduced tumour growth in an activity-dependent manner, and demonstrated stronger early tumour control compared to [ 177 Lu]Lu-DOTATATE at comparable administered activities (**p < 0.01 at day 9). Tumour doubling times were longest in the 6 MBq [ 161 Tb]Tb-DOTATATE group (29 vs. 18 days in controls), while the 3 MBq [ 161 Tb]Tb-DOTATATE group showed similar doubling times to 4 MBq [ 177 Lu]Lu-DOTATATE (21 vs. 22 days). This was also reflected in survival, where 6 MBq [ 161 Tb]Tb-DOTATATE achieved the greatest effect (50% increase in median survival), followed by 4 MBq [ 161 Tb]Tb-DOTATATE (36%), while 3 MBq [ 161 Tb]Tb-DOTATATE and 4 MBq [ 177 Lu]Lu-DOTATATE showed more modest improvements (23%). All treatment regimens were well tolerated, and no signs of treatment-related toxicity were observed. Conclusion [ 161 Tb]Tb-DOTATATE demonstrates favourable targeting properties and activity-dependent therapeutic efficacy in preclinical neuroblastoma models without detectable toxicity. These findings encourage us to explore its potential as a complement to [ 177 Lu]Lu-DOTATATE, particularly for targeting minimal residual disease and micrometastases, and warrant further preclinical and clinical evaluation.