Preclinical evaluation of gastrin-releasing peptide receptor antagonists labeled with 161Tb and 177Lu: A comparative study

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-Pip ⁵-DPhe ⁶-Gln ⁷-Trp ⁸-Ala ⁹-Val ¹⁰-Gly ¹¹-His ¹²-Sta ¹³-Leu ¹⁴-NH ₂) and AMTG (a-Me-Trp ⁸-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 6 0.16; [ ¹⁶¹Tb]Tb-AMTG, 2.16 6 0.09; [ ¹⁷⁷Lu]Lu-RM2, 3.45 6 0.18; [ ¹⁷⁷Lu]Lu-AMTG, 3.04 6 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.