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

The standard peptide receptor radionuclide therapy (PRRT) for neuroendocrine tumors (NETs) based on [177Lu]Lu-DOTA-TATE can lead to treatment resistance and disease recurrence. The somatostatin antagonist, [177Lu]Lu-DOTA-JR11, exhibits better biodistribution profile and higher tumor uptake. Besides, targeted alpha therapy (TAT) can improve 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. Methods DOTA-JR11 has been 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.

HANDULA Maryana;  BEEKMAN Savane;  KONIJNENBERG M.W.;  STUURMAN Debra;  DE RIDDER Corrina;  BRUCHERTSEIFER Frank;  MORGENSTERN Alfred;  DENKOVA A.G.;  DE BLOIS Erik;  SEIMBILLE Yann; 

2023-10-11

Springer Science and Business Media Deutschland GmbH

JRC134426

2365-421X (online),   

https://ejnmmipharmchem.springeropen.com/articles/10.1186/s41181-023-00197-0,    https://publications.jrc.ec.europa.eu/repository/handle/JRC134426,   

10.1186/s41181-023-00197-0 (online),