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

Molecular Pharmaceutics
Simon A M KaeppeliMartin Béhé

Abstract

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 sev...Continue Reading

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Citations

May 27, 2020·Clinical Nuclear Medicine·Kerstin MichalskiJuri Ruf
Feb 17, 2021·PET Clinics·Yaping Luo, Xiaoyuan Chen
Apr 12, 2021·Drug Discovery Today·Seyed Ebrahim Alavi, Hasan Ebrahimi Shahmabadi
Jul 30, 2021·Current Opinion in Chemical Biology·Dora Mugoli ChigohoSophie Hernot

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