Development of a Quantitative PET/MRI Method to Simultaneously Measure β-cell Mass and Function

Abstract

The goal of this project was the development of a PET/MRI method to simultaneously measure BCM and function. Towards the establishment of in vivo ME-MRI, a VFA T1 mapping protocol was optimized in vitro and in vivo. Simultaneous PET/MRI was shown to quantify and correlate radiolabeled Ex4 and Mn uptake throughout the pancreas of healthy and transgenic RIP1-Tag2 mice, a spontaneous model of pancreatic neuroendocrine tumors. Most importantly, the validation of in vivo imaging methods was performed by combining ex vivo autoradiography and LA-ICP-MS imaging. In this regard, the distribution of Mn in the pancreas was cross-validated with the accumulation of the PET tracer and with the endogenous levels of calcium and zinc at both early and late time points post injection. The research findings indicated that Mn accumulated at higher binding affinity in the exocrine pancreas during the early distribution of the contrast agent. By contrast, the retained amount of Mn measured in the pancreas was localized within the native islet cells and insulinomas, suggesting that late MRI measurements of Mn might be linked with β-cell function. The accumulation of Mn was also associated with the accumulation of the PET tracer and the endogenous levels of calcium and zinc. Using a similar procedure in the methodologies, the specificity of Mn uptake was validated in a transplanted mouse model. In this regard, longitudinal measurements by using a combined PET/MRI approach was shown to provide useful information on the viability of engrafted islets between 1 and 4 weeks after the transplantation. By using a different approach, the pharmacokinetics of radioactive 52Mn was investigated on healthy animals. The results obtained from the PET measurements confirmed previous reports regarding the higher safety of MnDPDP, especially regarding the lower tracer uptake that was observed in off-target tissues, such as the heart and specific regions of the brain. In parallel, different approaches were investigated to non-invasively determine the effects of quinoxaline on the modulation of the uptake of radiolabelled Ex4. In vivo PET studies conducted in different animal model could not discern a significant effect of quinoxaline. Nevertheless, a dynamic PET protocol is a promising method to monitor the modulation of the PET tracer uptake.