Background Recent data on 161Tb-labeled radiopharmaceuticals indicate a benefit in treatment efficacy due to the emission of high-energy Auger and conversion electrons in addition to β particles. We aimed to investigate differences in therapeutic potential of the gastrin-releasing peptide receptor (GRPR) antagonists RM2 (DOTA-Pip5-D-Phe6-Gln7-Trp8-Ala9-Val10-Gly11-His12-Sta13-Leu14-NH2) and AMTG (DOTA-Pip5-D-Phe6-Gln7-α-Me-Trp8-Ala9-Val10-Gly11-His12-Sta13-Leu14-NH2) radiolabeled with 161Tb and 177Lu in PC-3 tumor-bearing mice. We hypothesized that the superior in vivo stability of AMTG in combination with 161Tb would result in improved tumor control and overall survival as compared to RM2 and 177Lu counterparts. Methods Treatment studies in PC-3 tumor-bearing Nu/J mice were initiated once tumor volume was ~ 100 mm3. 161Tb- and 177Lu-Labeling was completed at 90 °C within 10 min (1.0 M sodium acetate buffer, pH = 5.5, molar activity of ~ 50 MBq/nmol). Radiolabeled GRPR ligands were administered in treatment (PC-3 tumor-bearing, n = 6–7 per group) and toxicity (healthy animals, n = 3 per group) animals on day 0 and day 7 of the experiment (~ 15 MBq each). Treatment animals were sacrificed once tumor volume surpassed 1,500 mm3. Toxicity animals were sacrificed 45 d after injection and analyzed for complete blood count and metabolic panel. Results Animals were assigned to five groups (control, [177Lu]Lu-RM2, [177Lu]Lu-AMTG, [161Tb]Tb-RM2, [161Tb]Tb-AMTG). Each treatment group received a total activity amount of 26–31 MBq of the respective radiolabeled compound. All treatments resulted in improved tumor control and overall survival related to vehicle animals. [161Tb]Tb-AMTG had the longest median overall survival of 58.1 ± 5.4 d after initiation of treatment. No signs of long-term toxicity were observed during this study in any treatment group. Conclusion The combination of Auger electrons with high in vivo stability of [161Tb]Tb-AMTG resulted in substantially improved tumor control and overall survival in PC-3 tumor-bearing mice, thus expanding the therapeutic potential of GRPR antagonists in GRPR-expressing malignancies. Graphical Abstract

Evaluation of treatment efficacy of the ¹⁶¹Tb- and ¹⁷⁷Lu-Labeled GRPR antagonists AMTG and RM2 in a mouse model of prostate cancer

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2026年7月10日

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Thomas Günther,
Abraham S. Moses,
Elisabeth Günther,
Madeleine R. Landry,
Stijn Ramaekers,
Michiel Van de Voorde,
Maarten Ooms,
Bernard Ponsard,
Corinne Beinat

摘要

Background

Recent data on ¹⁶¹Tb-labeled radiopharmaceuticals indicate a benefit in treatment efficacy due to the emission of high-energy Auger and conversion electrons in addition to β particles. We aimed to investigate differences in therapeutic potential of the gastrin-releasing peptide receptor (GRPR) antagonists RM2 (DOTA-Pip⁵-D-Phe⁶-Gln⁷-Trp⁸-Ala⁹-Val¹⁰-Gly¹¹-His¹²-Sta¹³-Leu¹⁴-NH₂) and AMTG (DOTA-Pip⁵-D-Phe⁶-Gln⁷-α-Me-Trp⁸-Ala⁹-Val¹⁰-Gly¹¹-His¹²-Sta¹³-Leu¹⁴-NH₂) radiolabeled with ¹⁶¹Tb and ¹⁷⁷Lu in PC-3 tumor-bearing mice. We hypothesized that the superior in vivo stability of AMTG in combination with ¹⁶¹Tb would result in improved tumor control and overall survival as compared to RM2 and ¹⁷⁷Lu counterparts.

Methods

Treatment studies in PC-3 tumor-bearing Nu/J mice were initiated once tumor volume was ~ 100 mm³. ¹⁶¹Tb- and ¹⁷⁷Lu-Labeling was completed at 90 °C within 10 min (1.0 M sodium acetate buffer, pH = 5.5, molar activity of ~ 50 MBq/nmol). Radiolabeled GRPR ligands were administered in treatment (PC-3 tumor-bearing, n = 6–7 per group) and toxicity (healthy animals, n = 3 per group) animals on day 0 and day 7 of the experiment (~ 15 MBq each). Treatment animals were sacrificed once tumor volume surpassed 1,500 mm³. Toxicity animals were sacrificed 45 d after injection and analyzed for complete blood count and metabolic panel.

Results

Animals were assigned to five groups (control, [¹⁷⁷Lu]Lu-RM2, [¹⁷⁷Lu]Lu-AMTG, [¹⁶¹Tb]Tb-RM2, [¹⁶¹Tb]Tb-AMTG). Each treatment group received a total activity amount of 26–31 MBq of the respective radiolabeled compound. All treatments resulted in improved tumor control and overall survival related to vehicle animals. [¹⁶¹Tb]Tb-AMTG had the longest median overall survival of 58.1 ± 5.4 d after initiation of treatment. No signs of long-term toxicity were observed during this study in any treatment group.

Conclusion

The combination of Auger electrons with high in vivo stability of [¹⁶¹Tb]Tb-AMTG resulted in substantially improved tumor control and overall survival in PC-3 tumor-bearing mice, thus expanding the therapeutic potential of GRPR antagonists in GRPR-expressing malignancies.

Graphical Abstract

Evaluation of treatment efficacy of the 161Tb- and 177Lu-Labeled GRPR antagonists AMTG and RM2 in a mouse model of prostate cancer

摘要

Evaluation of treatment efficacy of the ¹⁶¹Tb- and ¹⁷⁷Lu-Labeled GRPR antagonists AMTG and RM2 in a mouse model of prostate cancer