Evaluation of agonist and antagonist radioligands for somatostatin receptor imaging of breast cancer using positron emission tomography

Background: The somat ace, resulting in higher tumor uptake and improved sensitivity. We compared the tumor uptake and biodistribution of the antagonist68Ga-NODAGA-JR11 with two agonists68Ga-DOTA-Tyr3-octreotide (68Ga-DOTATOC) and68Ga-DOTA-Tyr3-octreotate (68Ga-DOTATATE), in the human, sstr2-positive, luminal breast cancer model: ZR-75-1. Results: Peptides were assayed for binding affinity using a filtration-based competitive assay to sstr2.natGa-DOTATOC andnatGa-DOTATATE had excellent affinity (inhibition constant Ki: 0.9 ± 0.1 nM and 1.4 ± 0.3 nM respectively) compared tonatGa-NODAGA-JR11 (25.9 ± 0.2 nM). The number of binding sites on ZR-75-1 cells was determined in vitro by saturation assays. Agonist67/ natGa-DOTATOC bound to 6.64 ± 0.39 × 104 sites/cells, which was 1.5-fold higher than67/ natGa-NODAGA-JR11 and 2.3-fold higher than67/ natGa-DOTATATE. All three 68Ga-labeled peptides were obtained in good decay-corrected radiochemical yield (61-68%) and were purified by high performance liquid chromatography to ensure high specific activity (137 – 281 MBq/nmol at the end of synthesis). NOD scid gamma mice bearing ZR-75-1 tumors were injected intravenously with the labeled peptides and used for PET/CT imaging and biodistribution at 1 h post-injection. We found that68Ga-DOTATOC had the highest tumor uptake (18.4 ± 2.9%ID/g), followed by68Ga-DOTATATE (15.2 ± 2.2%ID/g) and68Ga-NODAGA-JR11 (12.2 ± 0.8%ID/g). Tumor-to-blood and tumor-to-muscle ratios were also higher for the agonists (>40 and >150 respectively), compared to the antagonist (15.6 ± 2.2 and 45.2 ± 11.6 respectively). Conclusions: The antagonist68Ga-NODAGA-JR11 had the lowest tumor uptake and contrast compared to agonists68Ga-DOTATOC and68Ga-DOTATATE in ZR-75-1 xenografts. The main contributing factor to this result could be the use of an endogenously expressing cell line, which may differ from previously published transfected models in the number of low-affinity, antagonist-specific binding sites. The relative merit of agonists versus antagonists for sstr2 breast cancer imaging warrants further investigation, first in preclinical models with other sstr2-positive breast cancer xenografts, and ultimately in luminal breast cancer patients. © The Author(s) 2017.