Molecular Imaging in Noninvasive Assessment of Diabetes Progression
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Molecular imaging is a recently emerged multidisciplinary scientific field comprised of diverse technologies. The goal of this branch of science is to understand molecular mechanism of diseases and facilitate drug development, namely the interplay of non-invasive imaging techniques with molecular biology and medicine. The goal of this dissertation is to reflect the roles of molecular imaging in biomedical applications by longitudinal and non-invasive detection of the initiation and progression of diabetes. Diabetes is a chronic disease caused by a gradual loss of pancreatic β-cell mass (BCM). The current clinical diagnosis measures the parameters of the β-cell function (BCF) post the onset of the disease, which cannot accurately reflect the BCM loss during the initiation and progression of the disease. Therefore, a non-invasive imaging technique that enables the direct assessment of BCM change would be highly desirable. In this dissertation, Positron Emission Tomography (PET) imaging was conducted to non-invasively and longitudinally monitor the change of glucagon-like peptide 1 receptor (GLP-1R), a specific biomarker of pancreatic β-cell, during disease progression. Through a two-fold screening method, a modified bicyclic GLP-1 analog, which enhances biological stability while maintaining the receptor binding affinity, was selected. An imaging probe was therefore developed based on this selected stable GLP-1 analog for noninvasive imaging assessment of BCM. In vivo evaluation was carried out to determine the BCM targeting properties of the probe followed by ex vivo PET imaging and histology. Further, a reliable and reproducible multimodality imaging technique was developed by combining PET imaging with the GLP-1R targeted probe with anatomical imaging techniques including BaSO4-enhanced CT and MRI for quantitative analysis of BCM imaging in mouse models. To test the potential of the imaging technique for longitudinal monitoring of BCM change during the diabetes initiation and progression, a serial PET/CT imaging was performed in a streptozotocin (STZ)-induced diabetic mouse model. With the successful development of the BCM imaging probe, a valid imaging technique has been established for noninvasive assessment of the progression of diabetes, which may find applications in early diagnosis of diabetes and monitoring therapeutic interventions of the disease.