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

Background: The [¹⁷⁷Lu]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, [¹⁷⁷Lu]Lu-DOTA-JR11, that demonstrated better biodistribution profile and higher tumor uptake than [¹⁷⁷Lu]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, [²²⁵Ac]Ac-DOTA-JR11 can be a potential candidate to improve the treatment of NETs (Graphical abstract). DOTA-JR11 was radiolabeled with [²²⁵Ac]Ac(NO₃)₃ and [¹⁷⁷Lu]LuCl₃. 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 ^natLa-DOTA-JR11, ^natLu-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 [²²⁵Ac]Ac-DOTA-JR11. A blocking group was included to verify uptake specificity. Dosimetry of selected organs was determined for [²²⁵Ac]Ac-DOTA-JR11 and [¹⁷⁷Lu]Lu-DOTA-JR11. Results: [²²⁵Ac]Ac-DOTA-JR11 has been successfully prepared and obtained in high radiochemical yield (RCY; 95%) and radiochemical purity (RCP; 94%). [²²⁵Ac]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). [¹⁷⁷Lu]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 ^natLa and ^natLu 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 [²²⁵Ac]Ac-DOTA-JR11 than [¹⁷⁷Lu]Lu-DOTA-JR11. Conclusion: [²²⁵Ac]Ac-DOTA-JR11 showed a higher absorbed dose in the kidneys compared to [¹⁷⁷Lu]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 [²²⁵Ac]Ac-DOTA-JR11.