Systematic screening of potential β-cell imaging agents

Sweet, Ian R.; Cook, Daniel L.; Lernmark, Åke; Greenbaum, Carla J.; Wallen, Angela R.; Marcum, Erin S; Stekhova, S. A.; Krohn, Kenneth A.

doi:10.1016/j.bbrc.2003.12.182

Cited by 92 publications

(75 citation statements)

References 18 publications

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“…The pancreatic uptake of 111 In-labelled exendin was clearly decreased in patients with type 1 diabetes, with marked differences between diabetic patients and healthy individuals. To date, no other radiotracer tested for BCM determination has shown such large maximum differences between healthy individuals and patients with type 1 diabetes, nor has such a high interindividual variability of the uptake been reported previously [37][38][39][40][41][42][43][44]. A recent study in healthy individuals and patients with type 1 diabetes, involving PET after injection of [ 18 F]fluoropropyl-dihydrotetrabenazine ([ 18 F]FP-(+)-DTBZ), showed a maximum difference in pancreatic uptake of <40% [45].…”

Section: Discussionmentioning

confidence: 96%

Non-invasive quantification of the beta cell mass by SPECT with 111In-labelled exendin

et al. 2014

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Aims/hypothesis A reliable method for in vivo quantification of pancreatic beta cell mass (BCM) could lead to further insight into the pathophysiology of diabetes. The glucagonlike peptide 1 receptor, abundantly expressed on beta cells, may be a suitable target for imaging. We investigated the potential of radiotracer imaging with the GLP-1 analogue exendin labelled with indium-111 for determination of BCM in vivo in a rodent model of beta cell loss and in patients with type 1 diabetes and healthy individuals. MethodsThe targeting of 111 In-labelled exendin was examined in a rat model of alloxan-induced beta cell loss. Rats were injected with 15 MBq 111 In-labelled exendin and single photon emission computed tomography (SPECT) acquisition was performed 1 h post injection, followed by dissection, biodistribution and ex vivo autoradiography studies of pancreatic sections. BCM was determined by morphometric analysis after staining with an anti-insulin antibody. For clinical evaluation SPECT was acquired 4, 24 and 48 h after injection of 150 MBq 111 In-labelled exendin in five patients with type 1 Maarten Brom and Wietske Woliner-van der Weg contributed equally to this study. Diabetologia (2014) 57:950-959 DOI 10.1007 diabetes and five healthy individuals. The tracer uptake was determined by quantitative analysis of the SPECT images. Results In rats, 111 In-labelled exendin specifically targets the beta cells and pancreatic uptake is highly correlated with BCM. In humans, the pancreas was visible in SPECT images and the pancreatic uptake showed high interindividual variation with a substantially lower uptake in patients with type 1 diabetes. Conclusions/interpretation These studies indicate that 111 Inlabelled exendin may be suitable for non-invasive quantification of BCM.

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Section: Discussionmentioning

confidence: 96%

Non-invasive quantification of the beta cell mass by SPECT with 111In-labelled exendin

et al. 2014

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“…Alloxan, however, is a well-known diabetogenic agent itself; thus, the clinical utility of this approach remains unproven [15]. Dithizone and sulfonylurea receptor ligands (e.g., 3 H glibenclamide) have been studied as possible imaging agents [16], but some show broad tissue distributions of uptake contraindicating feasibility [17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Visualizing pancreatic β-cell mass with [11C]DTBZ

Simpson

Souza

Witkowski

et al. 2006

Nuclear Medicine and Biology

109

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Abstractβ-Cell mass (BCM) influences the total amount of insulin secreted, varies by individual and by the degree of insulin resistance, and is affected by physiologic and pathologic conditions. The islets of Langerhans, however, appear to have a reserve capacity of insulin secretion and, overall, assessments of insulin and blood glucose levels remain poor measures of BCM, β-cell function and progression of diabetes. Thus, novel noninvasive determinations of BCM are needed to provide a quantitative endpoint for novel therapies of diabetes, islet regeneration and transplantation. Built on previous gene expression studies, we tested the hypothesis that the targeting of vesicular monoamine transporter 2 (VMAT2), which is expressed by β cells, with [ 11 C]dihydrotetrabenazine ([ 11 C]DTBZ), a radioligand specific for VMAT2, and the use of positron emission tomography (PET) can provide a measure of BCM. In this report, we demonstrate decreased radioligand uptake within the pancreas of Lewis rats with streptozotocininduced diabetes relative to their euglycemic historical controls. These studies suggest that quantitation of VMAT2 expression in β cells with the use of [ 11 C]DTBZ and PET represents a method for noninvasive longitudinal estimates of changes in BCM that may be useful in the study and treatment of diabetes.

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“…Previously developed β-cell-specific imaging agents have included labeled glucose analogs (or other small molecules) (1,2), antibodies (3), sulfonylureas (2,4), and vesicular monoamine transporter receptor agonists (5,6). In addition, a variety of transgenic strategies have been applied to mouse models (7,8).…”

mentioning

confidence: 99%

“…Some of these compounds have already been tested clinically with PET imaging (1,9,10). However, a prevailing problem with most injectable agents has been the inability of whole-body imaging studies to achieve a target-to-background ratio sufficiently high to detect the <2% of the pancreatic volume composed of β-cells (2). Recent developments in this area have been summarized in several reviews (11)(12)(13).…”

mentioning

confidence: 99%

Accurate measurement of pancreatic islet β-cell mass using a second-generation fluorescent exendin-4 analog

Reiner

Thurber

Gaglia³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

111

126

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The hallmark of type 1 diabetes is autoimmune destruction of the insulin-producing β-cells of the pancreatic islets. Autoimmune diabetes has been difficult to study or treat because it is not usually diagnosed until substantial β-cell loss has already occurred. Imaging agents that permit noninvasive visualization of changes in β-cell mass remain a high-priority goal. We report on the development and testing of a near-infrared fluorescent β-cell imaging agent. Based on the amino acid sequence of exendin-4, we created a neopeptide via introduction of an unnatural amino acid at the K 12 position, which could subsequently be conjugated to fluorophores via bioorthogonal copper-catalyzed click-chemistry. Cell assays confirmed that the resulting fluorescent probe (E4 ×12 -VT750) had a high binding affinity (∼3 nM). Its in vivo properties were evaluated using high-resolution intravital imaging, histology, whole-pancreas visualization, and endoscopic imaging. According to intravital microscopy, the probe rapidly bound to β-cells and, as demonstrated by confocal microscopy, it was internalized. Histology of the whole pancreas showed a close correspondence between fluorescence and insulin staining, and there was an excellent correlation between imaging signals and β-cell mass in mice treated with streptozotocin, a β-cell toxin. Individual islets could also be visualized by endoscopic imaging. In short, E4 ×12 -VT750 showed strong and selective binding to glucose-like peptide-1 receptors and permitted accurate measurement of β-cell mass in both diabetic and nondiabetic mice. This near-infrared imaging probe, as well as future radioisotope-labeled versions of it, should prove to be important tools for monitoring diabetes, progression, and treatment in both experimental and clinical contexts.

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Systematic screening of potential β-cell imaging agents

Cited by 92 publications

References 18 publications

Non-invasive quantification of the beta cell mass by SPECT with 111In-labelled exendin

Non-invasive quantification of the beta cell mass by SPECT with 111In-labelled exendin

Visualizing pancreatic β-cell mass with [11C]DTBZ

Accurate measurement of pancreatic islet β-cell mass using a second-generation fluorescent exendin-4 analog

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