Diabetes mellitus is characterized by the selective destruction of insulin-producing beta-cells, which leads to a deficiency in insulin secretion and as a result, to hyperglycemia. A promising treatment for type I diabetes is pancreatic islet transplantation which is currently in clinical trials. It is clear now that in order to follow the fate of transplanted islets, reliable non-invasive methods are required. Unfortunately, such non-invasive techniques are currently not available. However, if developed, these methods would provide spatial and temporal information regarding location, function and viability of transplanted islets. Continuing development of molecular imaging probes and non-invasive imaging methods could be successfully applied to labeling and imaging of transplanted pancreatic islets. This would allow evaluating the outcome of human islet transplantation in animal models and ultimately in a clinical setting. Based on our prior experience in imaging autoimmune attack in pancreatic islets using crosslinked superparamagnetic iron oxide nanoparticles (CLIO) and their derivatives (1; 2), we propose to utilize these compounds for labeling human pancreatic islets with subsequent detection by magnetic resonance imaging (MRJ) upon islet transplantation. Furthermore, by conjugating CLIO with a near-infrared probe (Cy5.5 dye), we will be able to confirm MR imaging results using another non-invasive modality - near-infrared optical imaging (NIRF). Multi-modal imaging probes that combine the advantages of both methods have been successfully used in our laboratory (3). Therefore, the overall goal of this application is two-fold. First, we seek to determine the feasibility of labeling human pancreatic islets with a multi-modal imaging probe (CLIO-Cy5.5). We will also study islet function and viability upon labeling. Second, we will investigate if labeled islets can be visualized non-invasively after their transplantation using high-resolution magnetic resonance imaging (MRI) and near-infrared optical imaging in an animal model of diabetes. If successful, this research can be further translated into human studies as similar imaging probes are already in clinical trials (4).