| Islet cell loss in the pancreas results in diabetes. A noninvasive method that measures islet cell loss and also tracks the fate of transplanted islets would facilitate the development of novel therapeutics and improve the management of diabetes. The aim of this dissertation is to describe a novel dopamine D2/D3 receptor (D2/D3)-based PET method to study islet cells in the rat pancreas and in islet cell transplantation. We show that in vitro 18F-fallypride, a D 2/D3 receptor imaging agent, bound to isolated islet cells and pancreatic sections with an endocrine to exocrine selectivity of approximately 4. Binding selectivity was reduced by the D2/D3 receptor antagonist haloperidol, suggesting that binding was D2/D3 R-specific. In chapter 2, rat islets transplanted into the spleen were visualized in vivo by 18F-fallypride and confirmed by immunostaining. The ratio of activity in spleen-transplanted islets to the erector spinae muscle was greater than 5, compared with a ratio of 2.8 in non-transplanted rats. In Chapter 3, a streptozotocin-treated diabetic rat model was used to study localization of 18F-fallypride in the pancreas in vivo. Chemical destruction of islets by streptozotocin decreased 18F-fallypride binding in pancreas by greater than 50%, paralleling the decrease in insulin immunostaining and the elevated blood glucose levels which are typical of diabetic subjects. Uptake of 18F-fallypride in the normal pancreas was confirmed by radiochromatography and was 0.05% of the injected dose/cm3 as measured by PET/CT. 18F-Fallypride binding has been successfully measured in isolated islets, transplanted islets, whole pancreas sections, and in pancreata of a rodent model of Type 1 Diabetes using ex vivo micropet, in vitro autoradiography and by in vivo PET/CT. These studies demonstrate the potential utility of 18F-fallypride as a PET imaging agent for islet cells. |
