Glucagon-like Peptide-1 Receptor as Emerging Target: Will It Make It to the Clinic?

The glucagon-like peptide-1 receptor (GLP-1R) is an emerging target due to its high expression in benign insulinomas as well as in islet cell hypertrophia/hyperplasia (nesidioblastosis) and pancreatic β-cells. In 2008, occult insulinomas were localized for the first time in men using the metabolically stable radiolabeled glucagon-like peptide-1 (GLP-1) agonist [Lys⁴⁰(Ahx-DTPA-¹¹¹In)NH₂]-exendin-4 (¹¹¹In-DTPA-exendin-4). Afterward, several radiopharmaceuticals for GLP-1R PET/CT imaging were synthesized and evaluated, for example, [Nle¹⁴,Lys⁴⁰(Ahx-DOTA-⁶⁸Ga)NH₂]-exendin-4 (⁶⁸Ga-DOTA-exendin-4), [Cys⁴⁰(MAL-NOTA-⁶⁸Ga)NH₂]-exendin-4 (⁶⁸Ga-NOTA-exendin-4), and [Lys⁴⁰(NODAGA-⁶⁸Ga)NH₂]-exendin-4 (⁶⁸Ga-NODAGA-exendin-4). Several prospective comparison studies provided evidence that GLP-1R PET/CT is significantly more sensitive than contrast-enhanced MRI (ceMRI), contrast-enhanced CT (ceCT), GLP-1R SPECT/CT, somatostatin receptor PET/CT, and SPECT/CT in the detection of benign insulinomas, and insulinomas in the context of multiple endocrine neoplasia type 1. As a result, the European Neuroendocrine Tumor Society guidelines recommend GLP-1R imaging or selective intraarterial calcium stimulation and venous sampling (ASVS) in patients for whom there is a clinical suspicion of having an insulinoma but who have a negative ceMRI/ceCT or negative endoscopic ultrasound. Furthermore, there is growing evidence that GLP-1R PET/CT can visualize and localize adult nesidioblastosis. This is clinically relevant as the distinction between focal and diffuse nesidioblastosis is critical in directing a therapeutic strategy in these patients. Prospective studies have proven the clinical relevance of GLP-1R imaging as it is often the only imaging modality able to localize the insulinoma or nesidioblastosis. It is therefore likely that this noninvasive imaging modality will replace the invasive localization of insulinomas using ASVS. More experimental indications for GLP-1R imaging include the diagnosis of an insulinoma/nesidioblastosis in patients with postprandial hypoglycemia after bariatric bypass surgery and monitoring β-cells in patients with brittle type 1 diabetes after islet-cell transplantation. We believe that these indications and possibly future indications will bring GLP-1R imaging to the clinic.