Wild, D.; (2011) Glucagon-like peptide-1 receptor imaging probes translation of molecular biology into clinical application including insulinoma and islet cell imaging. Doctoral thesis , UCL (University College London).

Abstract

Strong over-expression of Glucagon-like Peptide-1 receptors (GLP-1-R) in human pancreatic β cells and in insulinoma provide an attractive target for imaging. This is relevant since the preoperative localisation of insulinomas remains a challenge whilst serial measurements of functional β cell mass (BCM) may improve monitoring of novel diabetes therapies such as islet cell replacement. The aim of the thesis was to develop and evaluate GLP-1-R imaging probes and translate these into clinical applications, including insulinoma and β cell imaging. After extensive preclinical evaluation (internalization, externalization, biodistribution, pharmacokinetic, imaging and detailed dosimetry studies) of different GLP-1-R imaging tracers, the most promising probe, [Lys40(Ahx-DOTA-111In)NH2]-exendin-4, was selected for a first in man study. This novel probe was then prospectively evaluated in the management setting of benign and malignant insulinoma. An additional proof of concept study was performed in a patient after intramuscular transplantation of islet cells. The GLP-1-R planar imaging study showed focally raised tracer uptake in functional β cells transplanted into the brachioradialis muscle of a 48 years old woman. In patients with benign insulinomas GLP-1-R imaging was superior to conventional imaging (CT, MRI, somatostatin receptor imaging and endoscopic ultrasound) and detected the insulinoma in all 6 patients pre- and intra-operatively. This is in contrast to patients with malignant insulinoma where conventional imaging (CT and somatostatin receptor imaging) was superior to GLP-1-R imaging, which detected the primary tumour and metastases in only 4/11 patients. In conclusion, these data, based on the development and evaluation of a novel probe, strongly suggest that GLP-1-R imaging offers a new approach to localise benign insulinomas. With further refinements of the labelling agent and the imaging methodology, it is expected that GLP-1-R imaging may have the potential for non-invasive imaging of pancreatic islets and the early diagnosis of β cell graft rejection. This thesis has led to six original publications and one review article. These are listed at the end of each chapter. For a full list please see appendix.

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