First preclinical evaluation of [ 225 Ac]Ac-DOTA-JR11 and comparison with [ 177 Lu]Lu-DOTA-JR11, alpha versus beta radionuclide therapy of NETs

Background The [ 177 Lu]Lu-DOTA-TATE mediated peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors (NETs) is sometimes leading to treatment resistance and disease recurrence. An interesting alternative could be the somatostatin antagonist, [ 177 Lu]Lu-DOTA-JR11, that demonstrated better biodistribution profile and higher tumor uptake than [ 177 Lu]Lu-DOTA-TATE. Furthermore, treatment with alpha emitters showed improvement of the therapeutic index of PRRT due to the high LET offered by the alpha particles compared to beta emitters. Therefore, [ 225 Ac]Ac-DOTA-JR11 can be a potential candidate to improve the treatment of NETs (Graphical abstract). DOTA-JR11 was radiolabeled with [ 225 Ac]Ac(NO 3 ) 3 and [ 177 Lu]LuCl 3 . Stability studies were performed in phosphate buffered saline (PBS) and mouse serum. In vitro competitive binding assay has been carried out in U2OS-SSTR2 + cells for nat La-DOTA-JR11, nat Lu-DOTA-JR11 and DOTA-JR11. Ex vivo biodistribution studies were performed in mice inoculated with H69 cells at 4, 24, 48 and 72 h after injection of [ 225 Ac]Ac-DOTA-JR11. A blocking group was included to verify uptake specificity. Dosimetry of selected organs was determined for [ 225 Ac]Ac-DOTA-JR11 and [ 177 Lu]Lu-DOTA-JR11. Results [ 225 Ac]Ac-DOTA-JR11 has been successfully prepared and obtained in high radiochemical yield (RCY; 95%) and radiochemical purity (RCP; 94%). [ 225 Ac]Ac-DOTA-JR11 showed reasonably good stability in PBS (77% intact radiopeptide at 24 h after incubation) and in mouse serum (~ 81% intact radiopeptide 24 h after incubation). [ 177 Lu]Lu-DOTA-JR11 demonstrated excellent stability in both media (> 93%) up to 24 h post incubation. Competitive binding assay revealed that complexation of DOTA-JR11 with nat La and nat Lu did not affect its binding affinity to SSTR2. Similar biodistribution profiles were observed for both radiopeptides, however, higher uptake was noticed in the kidneys, liver and bone for [ 225 Ac]Ac-DOTA-JR11 than [ 177 Lu]Lu-DOTA-JR11. Conclusion [ 225 Ac]Ac-DOTA-JR11 showed a higher absorbed dose in the kidneys compared to [ 177 Lu]Lu-DOTA-JR11, which may limit further studies with this radiopeptide. However, several strategies can be explored to reduce nephrotoxicity and offer opportunities for future clinical investigations with [ 225 Ac]Ac-DOTA-JR11.