An orthotopic model of pancreatic somatostatin receptor (SSTR)-positive tumors allows bimodal imaging studies using 3T MRI and animal PET-based molecular imaging of SSTR expression

Abstract

Somatostatin receptor (SSTR) scintigraphy is currently used as one standard imaging modality in neuroendocrine tumors (NETs). However, future optimization of NET imaging may be achieved with positron emission tomography based methods utilizing more sensitive and specific tracers in combination with computed tomography or magnetic resonance imaging. Here we established an orthotopic mouse model that reflects relevant aspects of human pancreatic NETs such as SSTR expression, dense vascularization and metastatic disease. This model was then utilized to test the feasibility of combined magnetic resonance imaging and animal positron emission tomography. Orthotopic implantation of amphicrine, SSTR-positive pancreatic AR42J cells resulted in rapidly growing tumors, with concomitant metastatic spread into abdominal lymph nodes and peritoneal cavity. Primary tumors as well as their metastases expressed the neuroendocrine markers chromogranin A and synaptophysin. For imaging experiments, the SSTR ligands (68)Ga-DOTATOC or (68)Ga-DOTANOC were injected intravenously, and animals were subsequently examined in an animal positron emission tomography scanner and a clinical 3T (tesla) magnetic resonance imager. All animals showed radionuclide accumulation in the primary tumor. Definite anatomical correlation was achieved using digital image fusion of the positron emission tomography and magnetic resonance imaging data. (68)Ga-DOTANOC strongly accumulated in the tumor tissue (mean 6.6-fold vs. control tissues) when compared to (68)Ga-DOTATOC, which showed a higher renal clearance. In good agreement with the biodistribution data, the kidney-to-tumor ratio was higher for (68)Ga-DOTATOC (2.43-fold vs. 1.75-fold). Consequently, (68)Ga-DOTANOC achieved better signal enhancement in the primary tumor and allowed for detection of metastatic lesions. In summary, we established a novel orthotopic pancreatic SSTR-positive tumor model and used this model to provide proof of principle for the diagnostic combination of SSTR-based molecular imaging and magnetic resonance imaging. Specifically, the animal model allowed the comparative evaluation of (68)Ga-DOTANOC and (68)Ga-DOTATOC, with (68)Ga-DOTANOC providing better tumor-specific accumulation and renal activity. We conclude that this animal model will be of innovative value for further investigation in the imaging of NETs.