Preclinical Evaluation of Gastrin-Releasing Peptide Receptor Antagonists Labeled with ¹⁶¹Tb and ¹⁷⁷Lu: A Comparative...

To elucidate potential benefits of the Auger-electron-emitting radionuclide ¹⁶¹Tb, we compared the preclinical performance of the gastrin-releasing peptide receptor antagonists RM2 (DOTA-Pip⁵-d-Phe⁶-Gln⁷-Trp⁸-Ala⁹-Val¹⁰-Gly¹¹-His¹²-Sta¹³-Leu¹⁴-NH₂) and AMTG (α-Me-Trp⁸-RM2), each labeled with both ¹⁷⁷Lu and ¹⁶¹Tb. Methods: ¹⁶¹Tb/¹⁷⁷Lu labeling (90°C, 5 min) and cell-based experiments (PC-3 cells) were performed. In vivo stability (30 min after injection) and biodistribution studies (1-72 h after injection) were performed on PC-3 tumor-bearing CB17-SCID mice. Results: Gastrin-releasing peptide receptor affinity was high for all compounds (half-maximal inhibitory concentration [nM]: [¹⁶¹Tb]Tb-RM2, 2.46 ± 0.16; [¹⁶¹Tb]Tb-AMTG, 2.16 ± 0.09; [¹⁷⁷Lu]Lu-RM2, 3.45 ± 0.18; [¹⁷⁷Lu]Lu-AMTG, 3.04 ± 0.08), and 75%-84% of cell-associated activity was receptor-bound. In vivo, both AMTG analogs displayed distinctly higher stability (30 min after injection) and noticeably higher tumor retention than their RM2 counterparts. Conclusion: On the basis of preclinical results, [¹⁶¹Tb]Tb-/[¹⁷⁷Lu]Lu-AMTG might reveal a higher therapeutic efficacy than [¹⁶¹Tb]Tb-/[¹⁷⁷Lu]Lu-RM2, particularly [¹⁶¹Tb]Tb-AMTG because of additional Auger-electron emissions at the cell membrane level.