Multimodal Imaging of 2-Cycle PRRT with 177Lu-DOTA-JR11 and 177Lu-DOTATOC in an Orthotopic Neuroendocrine Xenograft Tumor Mouse Model

Peptide receptor radionuclide therapy (PRRT) using radiolabeled somatostatin receptor (SSTR) analogs is a common approach in advanced neuroendocrine neoplasms. Recently, SSTR antagonists have shown promising results for imaging and therapy due to a higher number of binding sites than in commonly used agonists. We evaluated PRRT with SSTR agonist Lu-177-DOTATOC and antagonist Lu-177-DOTA-JR11 longitudinally in an orthotopic murine pancreatic neuroendocrine neoplasm model expressing human SSTR2. Morphologic and metabolic changes during treatment were assessed using multimodal imaging, including hybrid PET/MRI and SPECT/CT. Methods: In vitro radioligand binding and internalization assays and cell-cycle analysis were performed. SSTR2-transfected BON cells (BON-SSTR2) were used for in vivo experiments. Tumor-bearing mice received 2 intravenous injections of 100 mu L of saline, 30 MBq of Lu-177-DOTATOC, or 20 MBq of Lu-177-DOTA-JR11 with an interval of 3 wk. Weekly T2-weighted MRI was performed for tumor monitoring. Viability of the tumor tissue was assessed by F-18-FDG PET/MRI once after PRRT. Tumor and kidney uptake of the respective radiopharmaceuticals was measured 24 h after injection by SPECT/CT. Results: Compared with Lu-177-DOTATOC, Lu-177-DOTA-JR11 treatment resulted in an increased accumulation of cells in G2/M phase. Animals treated with the SSTR antagonist showed a significant reduction in tumor size (P < 0.001) and an increased median survival (207 d; interquartile range [IQR], 132-228) compared with Lu-177-DOTATOC (126 d; IQR, 118-129). SPECT/CT revealed a 4-fold higher median tumor uptake for the antagonist and a 3-fold higher tumor-to-kidney ratio in the first treatment cycle. During the second therapy cycle, tumor uptake of Lu-177-DOTATOC was significantly lower (P = 0.01) whereas Lu-177-DOTA-JR11 uptake remained stable. Imaging of tumor morphology indicated comparatively larger necrotic fractions for Lu-177-DOTA-JR11 despite further tumor growth. These results were confirmed by F-18-FDG PET, revealing the least amount of viable tumor tissue in Lu-177-DOTA-JR11-treated animals, at 6.2% (IQR, 2%-23%). Conclusion: Lu-177-DOTA-JR11 showed a higher tumor to-kidney ratio and a more pronounced cytotoxic effect than did Lu-177-DOTATOC. Additionally, tumor uptake was more stable over the course of 2 treatment cycles.

Automated summary

Peptide receptor radionuclide therapy (PRRT) using radiolabeled somatostatin receptor (SSTR) analogs is a common approach in advanced neuroendocrine neoplasms. Recently, SSTR antagonists have shown promising results for imaging and therapy due to a higher number of binding sites than in commonly used agonists. Lu-177-DOTA-JR11 exhibited a higher tumor-to-kidney ratio, increased G2/M phase accumulation of cells, decreased tumor size, prolonged median survival, and stable tumor uptake over 2 treatment cycles compared to Lu-177-DOTATOC.