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.

Increasing attention is given to personalized tumour therapy, where α-emitters can potentially play an important role. Alpha particles are ideal for localized cell killing because of their high linear energy transfer and short ranges. However, upon the emission of an α particle the daughter nuclide experiences a recoil energy large enough to ensure decoupling from any chemical bond. These ‘free’ daughter nuclides are no longer targeted to the tumour and can accumulate in normal tissue. In this paper, we used polymersomes as model carrier to evaluate the retention of recoiling daughters of ²²⁵Ac in vivo, and assessed their suitability as therapeutic agents. Vesicles containing ²²⁵Ac were injected intravenously in healthy mice, and intratumourally in tumour-bearing mice, and the relocation of free ²¹³Bi was assessed in different organs upon the injection [²²⁵Ac]Ac-polymersomes. The therapeutic effect of ²²⁵Ac-containing vesicles was studied upon intratumoural injection, where treatment groups experienced no tumour-related deaths over a 115 day period. While polymersomes containing ²²⁵Ac could be suitable agents for long-term irradiation of tumours without causing significant renal toxicity, there is still a significant re-distribution of daughter nuclides throughout the body, signifying the importance of careful evaluation of the effect of daughter nuclides in targeted alpha therapy.