64 Cu-Labeled 1,4,7-tris(acetic acid)-10-vinylsulfone-1,4,7,10-tetraazacyclododecane Conjugated to Cys 40-Exendin-4

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


A characteristic clinical feature of diabetes, an autoimmune disease, is diminished secretion and/or function of insulin and little or no glycemic control (1-3). The onset of diabetes is a complex process, and the pathophysiology of this disease is not completely understood (4). Diabetes has been classified into two types: Type 1 (T1D) and Type 2 (T2D). Among these, T1D is the chronic form of the disorder and is usually triggered by environmental factors in young people (<30 years of age) who are genetically predisposed to it; however, some individuals >30 years of age may also develop T1D (5). T1D is also known as juvenile-onset diabetes. People develop T2D because their muscles and adipose tissue are resistant to insulin, and it usually manifests in older (>50 years of age) and/or obese individuals (5). Although exercise and diet can alleviate this disorder to some extent, the blood glucose levels of individuals who suffer from diabetes have to be monitored several times a day or on a regular basis (weekly or monthly). Drugs (such as recombinant insulin) that are available to treat diabetes must be used lifelong after diagnosis, and a treatment(s) that can effectively prevent the disease is not yet available (6). In humans, insulin is produced by the β cells that are located in the islets of Langerhans of the pancreas. Approximately 80% of the islet cells are composed of the β cells, and reduced or the absence of function of these cells (due to T-cell–mediated destruction) in individuals with diabetes leads to low or a complete lack of insulin secretion. Transplantation of islet cells is considered to be the most suitable treatment for diabetes, but only 10%–15% of the patients who undergo this procedure remain insulin-independent beyond 5 years. Reasons for the loss of the grafted islet cell functions are not completely understood (7). Currently, only indirect methods are used to monitor the functioning of the transplanted islet cells, and usually by the time the loss in function is apparent it is too late to rescue the transplanted islets. In addition, noninvasive imaging probes that have been evaluated to monitor the β cells produced suboptimal results, and agents that may produce accurate images of the transplanted cells are still under development (1, 7). The β cells have a high expression of the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R), and the GLP-1R ligand (on binding to the receptor it enhances insulin secretion from the β cells) can be a suitable probe for the visualization of these cells in the pancreas. A major limitation of using this peptide for imaging purposes is its rapid degradation under physiological conditions (1). Exendin-4, a peptide hormone isolated from the saliva of the gila monster, has properties similar to those of GLP-1, is more stable than GLP-1 in vivo, and has a high affinity for the GLP-1R (1). Previously, investigators labeled derivatives of Exendin-4 with radionuclides such as 111In, 125I, 68Ga, etc., and used the probes with single-photon emission computed tomography (SPECT) to visualize GLP-1R–positive insulinomas in preclinical studies (1) and in humans (8, 9). However, positron emission tomography (PET) imaging is known to have a higher resolution and sensitivity compared to SPECT and can be used to accurately investigate various biological processes in living systems. Wu et al. developed a 64Cu-labeled Exendin analog (64Cu-labeled 1,4,7-tris(acetic acid)-10-vinylsulfone-1,4,7,10-tetraazacyclododecane (DO3A) conjugated to Cys40-Exendin-4 (64Cu-DO3A-VS-Cys40-Exendin-4)) and investigated its biodistribution in mice bearing subcutaneous INS-1 cell tumors (a rat insulinoma cell line that overexpresses GLP-1R) (1). The probe was also evaluated for the PET visualization of INS-1 cell xenograft tumors and islet cells transplanted into the liver of the animals.

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