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

Wild, Damian; Wicki, Andreas; Mansi, Rosalba; Béhé, Martin; Keil, Boris; Bernhardt, Peter; Christofori, Gerhard; Ell, Peter J.; Mäcke, Helmut R.

doi:10.2967/jnumed.110.074914

Cited by 142 publications

(162 citation statements)

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“…Biodistribution studies of 111 In-EG4 and 68 Ga-EG4 showed fast blood clearance and specific targeting of INR1G9-hGIPr xenografts. The washout from the tumor is not yet understood and is contrary to the GLP-1 receptor-targeting radiopeptides, which impress by a long tumor retention time (12,13 (12)(13)(14). Uptake of radiolabeled peptides in kidneys is a major problem because of the nephrotoxicity caused by the accumulated activity.…”

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confidence: 99%

“…A new and promising family of G-proteincoupled receptors is the incretin receptor family (8,10,11). The imaging of tumors overexpressing the glucagonlike peptide 1 (GLP-1) receptor was proven to be successful in insulinoma preclinically (12)(13)(14)(15)(16)(17) and clinically (18,19). Recently, it was found that the second member of the incretin receptor family, the glucose-dependent insulinotropic polypeptide (GIP) receptor, is overexpressed in specific NETs.…”

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confidence: 99%

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The Glucose-Dependent Insulinotropic Polypeptide Receptor: A Novel Target for Neuroendocrine Tumor Imaging—First Preclinical Studies

Gourni

Waser

Clerc³

et al. 2014

J Nucl Med

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A new family of peptide receptors, the incretin receptor family, overexpressed on many neuroendocrine tumors (NETs) is of great importance because it may enable the in vivo peptide-based receptor targeting of a category of NETs that does not express the somatostatin receptor. Impressive in vivo diagnostic data were published for glucagonlike peptide 1 receptor-targeting radiopeptides. Recently, promising in vitro data have appeared for the second member of the incretin family, the glucose-dependent insulinotropic polypeptide (GIP) receptor. This prompted us to develop and evaluate a new class of radioligands with the potential to be used for the in vivo targeting of GIP receptor-positive tumors. Methods: GIP(1-42) was modified C-terminally, and the truncated peptides showed high affinity toward GIP receptor for the GIP conjugates. Specific in vitro internalization was found, and almost the entire cellassociated activity was internalized (.90% of the cell-bound activity), supporting the agonist potency of the 111 In-EG4 and 68 Ga-EG4 were shown to specifically target INR1G9-hGIPr xenografts, with tumor uptake of 10.4% ± 2.2% and 17.0% ± 4.4% injected activity/g, 1 h after injection, respectively. Kidneys showed the highest uptake, which could be reduced by approximately 40%-50% with a modified-fluid-gelatin plasma substitute or an inhibitor of the serine protease dipeptidyl peptidase 4. The PET images clearly visualized the tumor. Conclusion: The evaluation of EG4 as a proof-ofprinciple radioligand indicated the feasibility of imaging GIP receptorpositive tumors. These results prompt us to continue the development of this family of radioligands for imaging of a broad spectrum of NETs.

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The Glucose-Dependent Insulinotropic Polypeptide Receptor: A Novel Target for Neuroendocrine Tumor Imaging—First Preclinical Studies

Gourni

Waser

Clerc³

et al. 2014

J Nucl Med

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“…A potential target for measurement of the BCM is the glucagon-like peptide 1 receptor (GLP-1R) as it is abundantly expressed in rat, mouse and human pancreatic beta cells but not in α, δ and pp cells [13,14]. Exendin is a stable agonist of the GLP-1R and it has been used for in vivo targeting of the GLP-1R after labelling with various radionuclides [15][16][17][18][19]. Exendin labelled with indium-111 could be used to determine the BCM in vivo by SPECT.…”

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confidence: 99%

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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“…Although the development of several radiolabeled Exendin-4 analogs has been reported, the GLP-1 receptor affinities of these analogs, assessed in various cell lines do not differ significantly [8,12,[19][20][21][22]. However, so far, there is no published data on the GLP-1 receptor affinity of the oxidized form of Exendin-4.…”

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confidence: 99%

“…This new tracer was efficient in localizing the pancreatic tumors and insulinomas, which had previously not been identified using conventional methods [10,11] Tc/EDDA)NH 2 ]-Exendin-4 did not result in the inferior tumor-to-organ ratio or reduced image quality [12]. This prompted us to further develop this tracer into the clinically suitable formulation.…”

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Oxidation of methionine — is it limiting the diagnostic properties of 99mTc-labeled Exendin-4, a Glucagon-Like Peptide-1 receptor agonist?

et al. 2016

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

Cited by 142 publications

References 36 publications

The Glucose-Dependent Insulinotropic Polypeptide Receptor: A Novel Target for Neuroendocrine Tumor Imaging—First Preclinical Studies

The Glucose-Dependent Insulinotropic Polypeptide Receptor: A Novel Target for Neuroendocrine Tumor Imaging—First Preclinical Studies

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

Oxidation of methionine — is it limiting the diagnostic properties of 99mTc-labeled Exendin-4, a Glucagon-Like Peptide-1 receptor agonist?

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