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

Background Recent data on 161 Tb-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-Pip 5 -D-Phe 6 -Gln 7 -Trp 8 -Ala 9 -Val 10 -Gly 11 -His 12 -Sta 13 -Leu 14 -NH 2 ) and AMTG (DOTA-Pip 5 -D-Phe 6 -Gln 7 - α -Me-Trp 8 -Ala 9 -Val 10 -Gly 11 -His 12 -Sta 13 -Leu 14 -NH 2 ) radiolabeled with 161 Tb and 177 Lu in PC-3 tumor-bearing mice. We hypothesized that the superior in vivo stability of AMTG in combination with 161 Tb would result in improved tumor control and overall survival as compared to RM2 and 177 Lu counterparts. Methods Treatment studies in PC-3 tumor-bearing Nu/J mice were initiated once tumor volume was ~ 100 mm 3 . 161 Tb- and 177 Lu-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 mm 3 . 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, [ 177 Lu]Lu-RM2, [ 177 Lu]Lu-AMTG, [ 161 Tb]Tb-RM2, [ 161 Tb]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. [ 161 Tb]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 [ 161 Tb]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.