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Limited experiments have compared the treatment effects of repetitive cycles of radiolabelled somatostatin (SST) analogues. In vitro and in vivo experiments were conducted in an AR42J cancer cell model, comparing the antagonist [ 177 Lu]Lu-satoreotide tetraxetan with the agonist [ 177 Lu]Lu-DOTA-TATE in terms of their binding properties, biodistribution, anti-tumour activity and toxicity. Histopathological and immunohistochemical examinations were performed at different timepoints. In the in vitro assays, [ 177 Lu]Lu-satoreotide tetraxetan recognised twice as many SST 2 binding sites as [ 177 Lu]Lu-DOTA-TATE. In mice treated once a week for four consecutive weeks, [ 177 Lu]Lu-satoreotide tetraxetan (15 MBq) revealed a significantly greater median time taken to reach a tumour volume of 850 mm 3 (68 days) compared to [ 177 Lu]Lu-DOTA-TATE at 15 MBq (43 days) or 30 MBq (48 days). This was associated with a higher tumour uptake, enhanced DNA damage and no or mild effects on body weight, haematological toxicity, or renal toxicity with [ 177 Lu]Lu-satoreotide tetraxetan (15 MBq). At the end of the study, complete tumour senescence was noted in 20% of animals treated with [ 177 Lu]Lu-satoreotide tetraxetan, in 13% of those treated with [ 177 Lu]Lu-DOTA-TATE at 30 MBq, and in none of those treated with [ 177 Lu]Lu-DOTA-TATE at 15 MBq. In conclusion, repeated administrations of [ 177 Lu]Lu-satoreotide tetraxetan were able to potentiate peptide receptor radionuclide therapy with a higher tumour uptake, longer median survival, and enhanced DNA damage, with a favourable efficacy/safety profile compared to [ 177 Lu]Lu-DOTA-TATE.

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Comparison of the Anti-Tumour Activity of the Somatostatin Receptor (SST) Antagonist [177Lu]Lu-Satoreotide Tetraxetan and the Agonist [177Lu]Lu-DOTA-TATE in Mice Bearing AR42J SST2-Positive Tumours