Congenital Hyperinsulinism

Boroni, Giovanni; Parolini, Filippo; Alberti, Daniele

doi:10.1007/978-3-319-40525-4_25

Cited by 1 publication

(2 citation statements)

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“…The main focus of this study was to reduce the kidney uptake of radiolabeled exendin-4 to address the unmet need for an improved diagnostic tool for the differential diagnosis of focal and diffuse CHI and insulinoma. 23 The high kidney uptake has an impact on the diagnostic accuracy of lesions located close to the kidneys and on the dose delivered to the kidneys mainly in infant patients with the need of repeated diagnostic examination. Currently, radiolabeled exendin-4 is used to detect AHH in clinical trials, 7 but in particular for neonates being imaged for CHI, the high renal accumulation should be avoided for the aforementioned reason.…”

Section: ■ Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Exendin-4 Derivatives with an Albumin-Binding Moiety Show Decreased Renal Retention and Improved GLP-1 Receptor Targeting

et al. 2019

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The glucagon-like peptide-1 receptor (GLP-1R) is highly and specifically expressed on the pancreatic β-cells. It plays an important role in glucose metabolism as well as in β-cell-derived diseases like diabetes, insulinoma, or congenital and adult hyperinsulinemic hypoglycemia. Radiolabeled exendin-4, a ligand of GLP-1R, has routinely been used in clinics to image insulinomas. However, its major drawback is the high kidney accumulation. Here, we show that the addition of an albumin-binding moiety (ABM) to radiolabeled exendin-4 results in a significant reduction of kidney uptake while retaining its high affinity and specificity to GLP-1R. The four tested peptides were shown to have high affinity to the GLP-1 receptor (IC50 of 3.7 ± 0.6 to 15.1 ± 0.8 nM). The radiolabeled derivatives were taken up into cells efficiently, internalizing between 39 ± 2 and 56 ± 2% after 2 h. Thus, the derivatives with ABM outperformed the reference peptide with its IC50 of 22.5 ± 2.9 nM and internalization of 41 ± 4%. Stability in human blood plasma was slightly enhanced by the addition of the albumin binder. In biodistribution studies, the radioligands exhibited an improved target-to-kidney ratio in comparison to the reference peptide of up to seven-fold. This was confirmed qualitatively in single-photon-emission computed tomography (SPECT)/CT imaging. This study demonstrated in vitro and in vivo that the addition of an ABM to radiolabeled exendin-4 strongly decreased kidney accumulation while retaining affinity to GLP-1R. Thus, exendin-4 derivatives with an albumin-binding moiety could present a viable class of diagnostic tracers for the detection of insulinomas and other GLP-1R-positive tissue in clinical application.

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Section: ■ Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%