64 Cu-Labeled Lys 40(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)NH 2–conjugated exendin-4

In: Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004–2013.
[updated ].


Autoimmune processes and other environmental factors that destroy β-cells located in the pancreatic islet cells are known to promote the development of insulin-dependent diabetes mellitus (type 1 diabetes) in individuals genetically predisposed to the disease (1). Due to this destruction, the net mass of the β-cells in the islet cells of the pancreas is reduced, which leads to decreased production of insulin in the individual, and the maintenance of blood glucose at proper physiological levels is impaired. Type 2 diabetes is the most common form of the disease and is primarily caused by insulin resistance as a consequence of low insulin secretion by the β-cells. This form of diabetes can often be corrected with exercise, diet control, and/or medication (2). Upon diagnosis of diabetes, it is important to determine the individual's β-cell mass (BCM) or volume to devise a successful treatment regimen for the condition (3). Changes in the BCM during the onset of diabetes is poorly understood, and only an indirect method that measures the amount of stimulated insulin secretion by the pancreas is used to quantify the BCM in humans (4). However, the β-cells appear to have a reserved capacity to produce insulin, so the use of insulin secretion as a determinant of BCM is of limited value (4). As an alternative to determine insulin secretion to quantify BCM, investigators have evaluated the use of noninvasive positron emission tomography (PET) imaging techniques to determine the BCM in rats with the use of 11C- or 18F-labeled dihydrotetrabenazine, which is an antagonist of the vesicular monoamine transporter type 2 (VMAT2) in the islet cells (5). Careful evaluation of results obtained with the VMAT2 antagonists has revealed that a large proportion of these radiolabeled compounds tend to reside in the exocrine pancreas, indicating that these radiotracers are not suitable for the determination of BCM with PET imaging (6). Recently, some G-protein–coupled receptors (e.g., the glucagon-like peptide 1 (GLP 1) receptor (GLP-1R)), which show a selective location in the β-cells compared to the surrounding exocrine pancreatic cells, were identified by database mining and immunohistochemical staining of pancreatic tissue (6-8). On the basis of these observations and the known involvement of GLP-1R in β-cell function and biology (for details, see Baggio and Drucker (9)), this receptor was identified as a possible target of radiolabeled probes that can be used to quantify the BCM. Although GLP-1 is the natural ligand for the GLP-1R, a major drawback of using this peptide to measure the BCM is that it is rapidly inactivated (half-life, ~2 min) by proteolytic enzymes while in circulation. As a consequence, investigators identified and have used radiolabeled Exendin-4 or its analogs (Exendin is a peptide of 39 amino acids that has a 54% homology with GLP-1, acts as an agonist of the GLP-1R, and is not inactivated by proteolytic enzymes) for the measurement of BCM with noninvasive molecular imaging techniques (6, 8). Connolly et al. evaluated the use of 64Cu-labeled Lys40(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)NH2–conjugated exendin-4 ([64Cu](Lys40(DOTA)NH2)Exendin-4) for the in vivo imaging and measurement of the BCM in rats and investigated its biodistribution in these animals (6).

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