¹⁸F-Fallypride PET of Pancreatic Islets: In Vitro and In Vivo Rodent Studies

Abstract

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. We describe a novel dopamine D 2 /D 3 receptor (D 2 /D 3 R)-based PET method to study islet cells in the rat pancreas and in islet cell transplantation. Methods: 18 F-fallypride binding to isolated rat islets and pancreas was evaluated in the absence and presence of the D 2 /D 3 R inhibitor haloperidol. After intravenous 18 F-fallypride (28-37 MBq) administration, normal rats and rats pretreated with haloperidol were imaged in a PET/CT scanner and subsequently studied ex vivo for 18 F-fallypride localization in the pancreas. A streptozotocin-treated diabetic rat model was used to study localization of 18 F-fallypride in the pancreas, in vitro and ex vivo. Rat islet cells were transplanted into the spleen and visualized using 18 F-fallypride PET. Results: 18 Ffallypride bound to isolated islet cells and pancreatic sections with an endocrine or exocrine selectivity of approximately 4; selectivity was reduced by haloperidol, suggesting that binding was D 2 /D 3 R-specific. Chemical destruction of islets by streptozotocin decreased 18 F-fallypride binding in pancreas by greater than 50%, paralleling the decrease in insulin immunostaining. Uptake of 18 F-fallypride in the pancreas was confirmed by radiochromatography and was 0.05% injected dose/cm 3 as measured by PET/CT. The ratio of 18 F-fallypride uptake in the pancreas to reference tissue (erector spinae muscle) was 5.5. Rat islets transplanted into the spleen were visualized in vivo by 18 F-fallypride and confirmed by immunostaining. The ratio of spleen-transplanted islets to erector spinae muscle was greater than 5, compared with a ratio of 2.8 in untransplanted rats.Conclusion: These studies demonstrate the potential utility of 18 F-fallypride as a PET agent for islet cells.

Imaging Pancreas in Healthy and Diabetic Rodent Model Using [18F]Fallypride Positron Emission Tomography/Computed Tomography

“…2A). Consistent with our previous results, 4 these data indicate that [ 18 F]fallypride uptake occurs in the pancreas in vivo and that the tracer binds to dopamine D2/D3 receptors.…”

“…Pancreatic sections were immunostained for insulin as previously described. 4 All animal studies were approved by the Institutional Animal Health Care and Use Committee of University of California-Irvine. Healthy male Sprague-Dawley rats (8 weeks old; weighing 250 g; n = 6) were used for the study, which included two PET/CT scans.…”

“…4 The objective of this preliminary report was to extend in vivo imaging of pancreas in a streptozotocin (STZ) rodent model of type 1 diabetes mellitus.…”

“…3 Our goal is to develop a noninvasive method for imaging rodent islet cells using dopamine D2/D3 receptor imaging with [ 18 F]fallypride positron emission tomography (PET)/computed tomography (CT). 4 […”

Translational Molecular Imaging of Diabetes

“…It is sensitive in the picoto nanomolar range and its results can be deconvoluted into quantitation of ligand or receptor concentration. Several targets have been tested so far for nuclear imaging of BCM including the sulfonylurea receptor (SUR) [30][31][32][33], somatostatin receptor type-2 (SSTR2) [34,35], serotonin receptor [36,37], glucagon like peptide-1 receptor (GLP-1R) [38][39][40][41], IC2 antigen [42], dopamine D-2 receptor [43], type 2 vesicular monoamine transporter (VMAT2) [44][45][46][47][48][49], and presynaptic vesicular acetylcholine transporter [50 • ]. Among these targets, translational clinical studies have been developed for imaging VMAT2 and the presynaptic vesicular acetylcholine transporter.…”