Amina Khalil: PET Imaging of Incretin Receptors and Pancreatic Islets

Abstract

Diabetes is a complex metabolic disease characterised by impaired regulation of blood glucose and, in some forms, loss or dysfunction of insulin-producing pancreatic beta cells. Incretin receptors, particularly the glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR), have become important therapeutic targets in diabetes and obesity. At the same time, the ability to non-invasively visualise pancreatic islets remains an important need, particularly for monitoring islet replacement therapies.

This thesis explores the development and application of positron emission tomography (PET) imaging to study incretin receptors and pancreatic islets, with the overall aim of improving our understanding of diabetes biology and emerging, incretin based, therapeutic strategies. In Paper I, the GIPR-targeting PET tracer [68Ga]Ga-DOTA-GIP1234 was developed with a fatty acid modification designed to prolong blood circulation time through albumin binding and improve receptor accessibility. The tracer demonstrated specific GIPR binding, although its prolonged circulation was accompanied by high blood and liver activity. In Paper II, PET imaging was used to investigate target engagement of the dual incretin agonist tirzepatide and the triple agonist SAR441255 in healthy pigs. Dose-dependent GLP-1R occupancy was demonstrated in the pancreas, pituitary and medial hypothalamic region, showing the potential of using PET to quantify incretin drug–target engagement in vivo. In Paper III, the small-molecule tracer [11C]Methyl-V-0219 was developed for imaging GLP-1R in the brain. Although the tracer crossed the blood–brain barrier, no specific GLP-1R binding could be demonstrated in vivo, highlighting important challenges for brain GLP-1R PET imaging. In Paper IV, a 68Ga-labelled nanobody targeting DPP6 was developed for PET imaging of pancreatic islets. The tracer enabled sensitive detection of transplanted human islets and stem cell-derived islets in mice, supporting DPP6 as a promising target for monitoring islet replacement therapies.

In conclusion, this thesis demonstrates the versatility of PET imaging for studying incretin receptor and pancreatic islet biology. The developed approaches provide tools for investigating where and to what extent some of incretin-based drugs engage their targets, while also advancing the possibility of non-invasive monitoring of transplanted insulin-producing cells.