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Review

18 F-Labeled exendin(9-39)

In: Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004–2013.
[updated ].
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18 F-Labeled exendin(9-39)

Arvind Chopra.
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Excerpt

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 (2). 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 (3). 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 (4). Changes in the BCM during the onset of diabetes is poorly understood, and an indirect method that measures the amount of stimulated insulin secretion by the pancreas is currently used to quantify the BCM in humans (5). 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 (5). 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 (6). 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 (7). 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 (1, 7, 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 by dipeptidyl peptidase, a proteolytic enzyme, while in circulation (half-life, ~2 min). 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 with a Kd of ~1.4 × 10−10 M for this receptor, is not inactivated by proteolytic enzymes, and has a circulation half-life of ~2 h) for the measurement of BCM with noninvasive molecular imaging techniques (1, 7). 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 for the in vivo imaging and measurement of the BCM in rats; however, because this tracer accumulated in the kidneys of the rodents, the pancreas was masked in the PET images and the BCM in the animals could not be quantified (7). Radionuclide-labeled Exendin(9-39) (Ex(9-39)), a truncated version of Exendin, which acts as an antagonist of the GLP-1R and exhibits a high affinity for the receptor (Kd, ~3 × 10−9 M) has also been used by investigators for the visualization of the GLP-1R (1). In an effort to develop a GLP-1R imaging agent, investigators labeled Ex(9-39) with [18F]fluoride using N-succinimidyl-4-[18F]fluorobenzoate ([18F]FB) (1). However, the 18F-succinimidyl ester reacts with all of the primary amine groups available in a peptide, and the final labeled product is a mixture of the labeled peptide molecules that have [18F]FB attached randomly on the primary amine groups of amino acids that constitute the peptide. Therefore, the exact structure of 18F-labeled FB-conjugated Ex(9-39) is not well defined. In addition, during the labeling reaction the radionuclide may be introduced on an important amine group of the peptide, which can result in the loss of its biological activity. In order to develop a 18F-labeled Ex(9-39) with a defined structure, Wang et al. used a site-specific technique to introduce 18F into the molecule (1). To achieve this, [18F]-4-fluorobenzaldehyde ([18F]FBA) was conjugated with a 6-hydrazinonicotinyl group (6-HYNIC) located on the ε-amine of Lys27 in the Ex(9-39) molecule to generate [18F]Ex(9-39). To evaluate the GLP-1R imaging ability of the labeled peptide, Sprague-Dawley (SD) rats and BioBreeding diabetes-prone (BB-DP) rats were injected with [18F]Ex(9-39), and the time-activity curves for the pancreas, kidney, and the liver of the animals were obtained with PET imaging. Data generated with PET images of the pancreas were then correlated with insulin expressed by β-cells of the organ.

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