Preclinical Evaluation of Gastrin-Releasing Peptide Receptor Antagonists Labeled with<sup>161</sup>Tb and<sup>177</sup>Lu: A Comparative Study
Nadine Holzleitner, Tatjana Cwojdzinski, Roswitha Beck, Nicole Urtz-Urban, Colin C. Hillhouse, Pascal V. Grundler, Nicholas P. van der Meulen, Zeynep Talip, Stijn Ramaekers, Michiel Van de Voorde, Bernard Ponsard, Angela Casini, Thomas Günther
Abstract
To elucidate potential benefits of the Auger-electron–emitting radionuclide <sup>161</sup>Tb, we compared the preclinical performance of the gastrin-releasing peptide receptor antagonists RM2 (DOTA-Pip<sup>5</sup>-d-Phe<sup>6</sup>-Gln<sup>7</sup>-Trp<sup>8</sup>-Ala<sup>9</sup>-Val<sup>10</sup>-Gly<sup>11</sup>-His<sup>12</sup>-Sta<sup>13</sup>-Leu<sup>14</sup>-NH<sub>2</sub>) and AMTG (α-Me-Trp<sup>8</sup>-RM2), each labeled with both <sup>177</sup>Lu and <sup>161</sup>Tb. <b>Methods:</b><sup>161</sup>Tb/<sup>177</sup>Lu 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. <b>Results:</b> Gastrin-releasing peptide receptor affinity was high for all compounds (half-maximal inhibitory concentration [nM]: [<sup>161</sup>Tb]Tb-RM2, 2.46 ± 0.16; [<sup>161</sup>Tb]Tb-AMTG, 2.16 ± 0.09; [<sup>177</sup>Lu]Lu-RM2, 3.45 ± 0.18; [<sup>177</sup>Lu]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. <b>Conclusion:</b> On the basis of preclinical results, [<sup>161</sup>Tb]Tb-/[<sup>177</sup>Lu]Lu-AMTG might reveal a higher therapeutic efficacy than [<sup>161</sup>Tb]Tb-/[<sup>177</sup>Lu]Lu-RM2, particularly [<sup>161</sup>Tb]Tb-AMTG because of additional Auger-electron emissions at the cell membrane level.