Beta-cell mass (BCM)and the functional state of islets are critical measures in assessing the magnitude of autoimmune destruction in type 1 diabetes. Progressive loss of BCM is also responsible for the secondary failure of currently available drugs (lack of durability) in type 2 diabetes. Serum tests such as insulin/C- peptide and others do not reliably measure BCM,and currently the only accepted gold standard of measurement is autopsy. It is generally believed that imaging could ultimately be used to a) better understand the history of the islet and the pathophysiology of diabetes, b) enable earlier diagnosis of type 1 diabetes (T1DM), c) allow monitoring of therapeutic efficacy and durability (including islet transplantation), and d) reveal image-able biomarkers useful in the discovery of new therapies. Unfortunately, the necessary tools to quantify BCM are still largely missing. The overall goal of this project is therefore to develop novel in vivo imaging methods and agents with specificity for p-cells, in order to non-invasively visualize the target of autoimmune attack in type 1 diabetes. This will be done using powerful library, small-molecule combinatorial and genetic approaches. In close collaboration with the Mathis and Benoist groups, we will validate the most promising agents using accepted gold standards and mouse models. Specifically, we will ask the following questions: 1) what is the in vivo behavior and the putative binding partners of the new affinity ligands ? 2) what is the correlation between imaging signal and BCM ? and 3) what are the sources of error in measurements, and how can they be reduced ? The progress to date (newfluorescent mouse models, imaging techniques such as FPT and IVM and new leads from screens to be converted into imaging agents) has been remarkable. The developed agents and strategies will be designed to be clinically translatable, and should add to our previously developed clinical data on imaging islet dysfunction.