Combination of terbium-161 with somatostatin receptor antagonists—a potential paradigm shift for the treatment of neuroendocrine neoplasms

PURPOSE: The β(¯)-emitting terbium-161 also emits conversion and Auger electrons, which are believed to be effective in killing single cancer cells. Terbium-161 was applied with somatostatin receptor (SSTR) agonists that localize in the cytoplasm (DOTATOC) and cellular nucleus (DOTATOC-NLS) or with a SSTR antagonist that localizes at the cell membrane (DOTA-LM3). The aim was to identify the most favorable peptide/terbium-161 combination for the treatment of neuroendocrine neoplasms (NENs). METHODS: The capability of the (161)Tb- and (177)Lu-labeled somatostatin (SST) analogues to reduce viability and survival of SSTR-positive AR42J tumor cells was investigated in vitro. The radiopeptides’ tissue distribution profiles were assessed in tumor-bearing mice. The efficacy of terbium-161 compared to lutetium-177 was investigated in therapy studies in mice using DOTATOC or DOTA-LM3, respectively. RESULTS: In vitro, [(161)Tb]Tb-DOTA-LM3 was 102-fold more potent than [(177)Lu]Lu-DOTA-LM3; however, (161)Tb-labeled DOTATOC and DOTATOC-NLS were only 4- to fivefold more effective inhibiting tumor cell viability than their (177)Lu-labeled counterparts. This result was confirmed in vivo and demonstrated that [(161)Tb]Tb-DOTA-LM3 was significantly more effective in delaying tumor growth than [(177)Lu]Lu-DOTA-LM3, thereby, prolonging survival of the mice. A therapeutic advantage of terbium-161 over lutetium-177 was also manifest when applied with DOTATOC. Since the nuclear localizing sequence (NLS) compromised the in vivo tissue distribution of DOTATOC-NLS, it was not used for therapy. CONCLUSION: The use of membrane-localizing DOTA-LM3 was beneficial and profited from the short-ranged electrons emitted by terbium-161. Based on these preclinical data, [(161)Tb]Tb-DOTA-LM3 may outperform the clinically employed [(177)Lu]Lu-DOTATOC for the treatment of patients with NENs. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00259-021-05564-0.