Imaging of the glucagon receptor in subjects with type 2 diabetes

Abstract

Rationale: 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 human. The Positron Emission Tomography (PET) radioligand ⁶⁸Ga-DO3A-VS-Tuna-2 (⁶⁸Ga-Tuna-2) was developed to yield a non-invasive 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/Computed Tomography (CT) in n = 13 individuals with Type 2 Diabetes (T2D) as part of a clinical study assessing the occupancy of dual GCGR/Glucagon Like Peptide-1 Receptor (GLP-1R) agonist SAR425899. Binding of ⁶⁸Ga-Tuna-2 in liver and reference tissues was evaluated and correlated to biometrics (e.g. weight or BMI) 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. Kidney demonstrated high excretion related retention, while all other tissue demonstrated rapid washout. The Standardized Uptake Value (SUV)55min 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.