? The function of pancreatic beta-cell cells is a key issue in diabetes mellitus, but can only be assessed indirectly. Currently, several aspects regarding beta-cell mass remain to be elucidated, for example: (1) Is the total beta-cell mass at the onset of type 2 diabetes diminished or not, (2) how does the beta-cell mass develop during the course of the disease, (3) which factors affect beta-cell mass, and (4) how does beta-cell mass relate to the response to therapy. Futhermore, it would be of great interest to measure beta-cell mass after islet-transplantation. Research is hampered by the fact that no reliable methods exist to assess and quantify human beta-cell mass in vivo. If beta-cell mass could be determined by a non-invasive method, this would be of a tremendous asset in advancing this field of research. ? We have developed a radiolabeled agent (DOTA-Lys40-Exendin 4) that allows specific beta-cell imaging. In mice the tracer shows uptake of approximately 9% of the injected activity per gram of pancreas tissue. This specific tracer is therefore a promising tool for in vivo beta-cell imaging in humans.Under this grant proposal, we will develop a Ga-68 labeled DOTA-Exendin compound for imaging of beta-cells in vivo with positron emission tomography (PET). The use of a positron emitter such as Ga-68 will offer a number of advantages over conventional nuclear medicine imaging: 1. high spatial resolution, 2. accurate quantification, 3. exact localization of the pancreas / the beta-cell areas by use of an integrated PET/CT scanner (CT=computed tomography), even if pancreatic tracer uptake is decreased after beta-cell loss. In comparison to Magnetic Resonance Imaging (MRI), the approach is very sensitive and will not require direct labeling of beta-cells for imaging purposes. Direct labeling (for example with iron) can only be done in beta-cell transplantation (prior to islet transplantation) but is not suitable for imaging of pancreatic beta-cells in vivo. ? In this project, we will investigate the correlation of uptake of the Ga-68-labeled DOTA-Exendin and beta-cell mass in different animal models of diabetes. Upon succesful pre-clinical development of the tracer, pilot studies in humans will be conducted. Apart from proof-of-principle studies in healthy volunteers and diabetes type I and II patients, a dosimetric method will be established to simply and reliably quantify beta-cell mass by PET imaging. ? ?
