A hallmark of diabetes is the progressive loss of the beta-cell mass (BCM) and function. Most of the diagnostic methods for diabetes are mostly reflective of the beta-cell function, whereas current methodologies for studying the beta-cell mass are limited to post-mortem biopsies or highly invasive methods. Positron-emission tomography (PET) is a highly sensitive and quantitative medical imaging technique that was suggested as a tool for non-invasive imaging of the pancreas and quantification of the BCM. 

GPR44 is a membrane protein recently identified as a promising beta-cell biomarker highly expressed in beta cells, but not in other exocrine or endocrine tissues within the pancreas. Paper I describes the preclinical evaluation of the carbon-11 labeled GPR44 antagonist [¹¹C]MK-7246 using cell lines and pigs. We have demonstrated strong binding of [¹¹C]MK-7246 to the GPR44 receptor as well as its specificity to the pig pancreas. Based on the success of this study, we have initiated the clinical translation of [¹¹C]MK-7246 to first-in-man BCM imaging studies in diabetic patients. As a direct continuation to paper I, paper II focused on the preclinical evaluation of MK-7246 labeled with a different isotope, namely fluorine-18. Additional characterizations were obtained such as the binding affinity and specificity to endocrine pancreatic fractions. Proof of concept in vivo GPR44 directed imaging has been demonstrated as well using an immunodeficient mouse model grafted with GPR44 expressing cells.

Paper III is focused on the development and screening of first-in-class affibody molecules targeting DGCR2, another biomarker specific to beta cells. After binding and biodistribution assessments, the affibody molecule Z_DGCR2:AM106 has been retained as the lead candidate for DGCR2 targeted imaging. In Paper IV, we have labeled  the affibody molecule Z_DGCR2:AM106 screened from paper III using fluorine-18, and the resulting [¹⁸F]Z_DGCR2:AM106 has been assessed for in vivo PET imaging of stem-cells derived pancreatic islets grafts. 

In conclusion, this thesis describes the preclinical evaluation of several PET imaging radiotracers with the end goal of in vivo imaging of the BCM.