Imaging of the Glucagon Receptor in Subjects with Type 2 Diabetes

Despite the importance of the glucagon receptor (GCGR) in disease and in pharmaceutical drug development, there is a lack of specific and sensitive biomarkers of its activation in humans. The PET radioligand ⁶⁸Ga-DO3A-VS-Tuna-2 (⁶⁸Ga-Tuna-2) was developed to yield a noninvasive imaging marker for GCGR target distribution and drug target engagement in humans. Methods: The biodistribution and dosimetry of ⁶⁸Ga-Tuna-2 was assessed by PET/CT in 13 individuals with type 2 diabetes as part of a clinical study assessing the occupancy of the dual GCGR/glucagon like peptide-1 receptor agonist SAR425899. Binding of ⁶⁸Ga-Tuna-2 in liver and reference tissues was evaluated and correlated to biometrics (e.g., weight or body mass index) or other biomarkers (e.g., plasma glucagon levels). Results:⁶⁸Ga-Tuna-2 binding was seen primarily in the liver, which is in line with the strong expression of GCGR on hepatocytes. The kidneys demonstrated high excretion-related retention, whereas all other tissue demonstrated rapid washout. The SUV_{55 min} (SUV during the last 10-min time frame, 50–60 min after administration) uptake endpoint was sensitive to endogenous levels of glucagon. ⁶⁸Ga-Tuna-2 exhibited a safe dosimetry profile and no adverse events after intravenous administration. Conclusion:⁶⁸Ga-Tuna-2 can be used for safe and accurate assessment of the GCGR in human. It may serve as an important tool in understanding the in vivo pharmacology of novel drugs engaging the GCGR.