A new technique for in vivo imaging of specific GLP-1 binding sites: First results in small rodents

Gotthardt, Martin; Lalyko, Georg; Eerd-Vismale, Julliëtte van; Keil, Boris; Schurrat, Tino; Hower, Michael; Laverman, Peter; Behr, Thomas M.; Boerman, Otto C.; Göke, Burkhard; Béhé, Martin

doi:10.1016/j.regpep.2006.07.005

Cited by 83 publications

(74 citation statements)

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“…Ideally, two basic criteria should be met for adequate beta cell imaging [6]: (1) beta cells should retain the tracer 100-to 1,000-fold more than the exocrine cells; and (2) agents that label beta cell surface proteins should do this at high enough concentrations to overcome imaging signals arising from unbound tracer retained in the extracellular and vascular spaces, and from tracer bound to the other tissues surrounding the pancreas. Agents being tested currently for BCM imaging include glibenclamide [6], glucagon-like peptide 1 receptor [7,8], sulfonylurea receptor [6], vesicular monoamine transporter 2 (VMAT2) [9][10][11][12][13] and gangliosides [14]. Unfortunately, the uptake/binding of these agents to beta cells, compared with exocrine pancreas and non-beta cells, is insufficient to allow reliable imaging of the BCM [6,15].…”

Section: Introductionmentioning

confidence: 99%

A genomic-based approach identifies FXYD domain containing ion transport regulator 2 (FXYD2)γa as a pancreatic beta cell-specific biomarker

et al. 2010

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Aims/hypothesis Non-invasive imaging of the pancreatic beta cell mass (BCM) requires the identification of novel and specific beta cell biomarkers. We have developed a systems biology approach to the identification of promising beta cell markers. Methods We followed a functional genomics strategy based on massive parallel signal sequencing (MPSS) and microarray data obtained in human islets, purified primary rat beta cells, non-beta cells and INS-1E cells to identify promising beta cell markers. Candidate biomarkers were validated and screened using established human and macaque (Macacus cynomolgus) tissue microarrays.Results After a series of filtering steps, 12 beta cell-specific membrane proteins were identified. For four of the proteins we selected or produced antibodies targeting specifically the human proteins and their splice variants; all four candidates were confirmed as islet-specific in human D. Flamez and I. Roland contributed equally to this study. Electronic supplementary materialThe online version of this article

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Section: Introductionmentioning

confidence: 99%

A genomic-based approach identifies FXYD domain containing ion transport regulator 2 (FXYD2)γa as a pancreatic beta cell-specific biomarker

et al. 2010

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“…vesicular monoamine transporter 2) and transporter molecules (e.g. glucose transporter 2), have been evaluated for their suitability as potential islet-imaging targets [3][4][5][6][7][8][9][10][11]. The properties of the tracer probes (e.g.…”

Section: Introductionmentioning

confidence: 99%

In vitro phage display in a rat beta cell line: a simple approach for the generation of a single-chain antibody targeting a novel beta cell-specific epitope

et al. 2010

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Aims/hypothesis The aim of the present study was to evaluate in vitro phage display in a beta cell line as a novel strategy for the isolation of beta cell-specific agents/ biomarkers. Methods A single-chain antibody (SCA) library was preincubated with AR42J cells in order to eliminate SCAs with exocrine binding properties. It was then panned against INS-1 cells to select beta cell-targeted antibodies.Results By these means, we isolated a novel antibody, SCA B5, that binds rapidly (6.0 min) and with a 450-fold higher specificity to beta cells relative to exocrine cells. We estimated for SCA B5 a binding affinity in the low μmol/l range and 858 binding sites per beta cell. Confocal microscopy showed binding to the beta cell surface and confirmed subsequent internalisation. Moreover, staining of rat and human pancreatic tissue sections with SCA B5 suggests that the target epitope is presented in pancreatic beta cells of different origins. Infrared imaging revealed that labelling of beta cells with tracer SCA B5 is strictly dependent on beta cell mass. With competition assays we excluded insulin, glutamate decarboxylase, C-peptide and islet amyloid polypeptide as SCA B5 targets. In accordance with these predictions, SCA B5 homed in vivo highly selectively to normal beta cells and dysfunctional beta cells of diabetic rats. Moreover, accumulation of radioactively labelled SCA B5 in the pancreas was reduced by 80% after pre-injection with unlabelled SCA B5, thereby confirming the specific uptake in the pancreas. Conclusions/interpretation We report a simple strategy for the generation of an SCA targeting a novel beta cellspecific epitope.

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“…Especially in benign insulinoma, the GLP-1 receptor density is high, with almost 100% incidence (8). Consequently, GLP-1 receptor-avid radioligands have been developed and evaluated (15,16). Preclinical animal studies have shown the ability of [Lys 40 (Ahx [6-aminohexanoic acid]-DTPA-111 In)NH 2 ]-exendin-4 to successfully localize small insulinomas in the Rip1Tag2 mouse tumor model (17).…”

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Exendin-4–Based Radiopharmaceuticals for Glucagonlike Peptide-1 Receptor PET/CT and SPECT/CT

et al. 2010

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Tc/EDDA)NH 2 ]-exendin-4 did not result in inferior tumor-to-organ ratios or reduced image quality. All radiopeptides tested showed a high tumor-to-background ratio, resulting in the visualization of small tumors (maximum diameter between 1.0 and 3.2 mm) by SPECT and PET. The only exception was the kidneys, which also showed high uptake. This uptake could be reduced by 49%278% using poly-glutamic acid, Gelofusine, or a combination of the 2. The estimated effective radiation dose was 3.7 mSv/MBq for [Lys 40

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A new technique for in vivo imaging of specific GLP-1 binding sites: First results in small rodents

Cited by 83 publications

References 28 publications

A genomic-based approach identifies FXYD domain containing ion transport regulator 2 (FXYD2)γa as a pancreatic beta cell-specific biomarker

A genomic-based approach identifies FXYD domain containing ion transport regulator 2 (FXYD2)γa as a pancreatic beta cell-specific biomarker

In vitro phage display in a rat beta cell line: a simple approach for the generation of a single-chain antibody targeting a novel beta cell-specific epitope

Exendin-4–Based Radiopharmaceuticals for Glucagonlike Peptide-1 Receptor PET/CT and SPECT/CT

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