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

Abstract

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 ¹⁷⁷Lu-DOTATOC and antagonist ¹⁷⁷Lu-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. <b>Methods:</b> 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 μL of saline, 30 MBq of ¹⁷⁷Lu-DOTATOC, or 20 MBq of ¹⁷⁷Lu-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 ¹⁸F-FDG PET/MRI once after PRRT. Tumor and kidney uptake of the respective radiopharmaceuticals was measured 24 h after injection by SPECT/CT. <b>Results:</b> Compared with ¹⁷⁷Lu-DOTATOC, ¹⁷⁷Lu-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 (<i>P</i> < 0.001) and an increased median survival (207 d; interquartile range [IQR], 132-228) compared with ¹⁷⁷Lu-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 ¹⁷⁷Lu-DOTATOC was significantly lower (<i>P</i> = 0.01) whereas ¹⁷⁷Lu-DOTA-JR11 uptake remained stable. Imaging of tumor morphology indicated comparatively larger necrotic fractions for ¹⁷⁷Lu-DOTA-JR11 despite further tumor growth. These results were confirmed by ¹⁸F-FDG PET, revealing the least amount of viable tumor tissue in ¹⁷⁷Lu-DOTA-JR11-treated animals, at 6.2% (IQR, 2%-23%). <b>Conclusion:</b>¹⁷⁷Lu-DOTA-JR11 showed a higher tumor-to-kidney ratio and a more pronounced cytotoxic effect than did ¹⁷⁷Lu-DOTATOC. Additionally, tumor uptake was more stable over the course of 2 treatment cycles.