New Radiolabeled Exendin Analogues Show Reduced Renal Retention
| Autor: | Joosten, L., Frielink, C., Jansen, T.J.P., Lobeek, D., Andreae, F., Konijnenberg, M.W., Heskamp, S., Gotthardt, M., Brom, M. |
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| Rok vydání: | 2023 |
| Předmět: |
All institutes and research themes of the Radboud University Medical Center
Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14] Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9] Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19] |
| Zdroj: | Molecular Pharmaceutics, 20, 7, pp. 3519-3528 |
| Popis: | Contains fulltext : 294525.pdf (Publisher’s version ) (Open Access) PET imaging of the glucagon-like peptide-1 receptor (GLP-1R) using radiolabeled exendin is a promising imaging method to detect insulinomas. However, high renal accumulation of radiolabeled exendin could hamper the detection of small insulinomas in proximity to the kidneys and limit its use as a radiotherapeutic agent. Here, we report two new exendin analogues for GLP-1R imaging and therapy, designed to reduce renal retention by incorporating a cleavable methionine-isoleucine (Met-Ile) linker. We examined the renal retention and insulinoma targeting properties of these new exendin analogues in a nude mouse model bearing subcutaneous GLP-1R-expressing insulinomas. NOTA or DOTA was conjugated via a methionine-isoleucine linker to the C-terminus of exendin-4 (NOTA-MI-exendin-4 or DOTA-MI-exendin-4). NOTA- and DOTA-exendin-4 without the linker were used as references. The affinity for GLP-1R was determined in a competitive binding assay using GLP-1R transfected cells. Biodistribution of [(68)Ga]Ga-NOTA-exendin-4, [(68)Ga]Ga-NOTA-MI-exendin-4, [(177)Lu]Lu-DOTA-exendin-4, and [(177)Lu]Lu-DOTA-MI-exendin-4 was determined in INS-1 tumor-bearing BALB/c nude mice, and PET/CT was acquired to visualize renal retention and tumor targeting. For all tracers, dosimetric calculations were performed to determine the kidney self-dose. The affinity for GLP-1R was in the low nanomolar range ( |
| Databáze: | OpenAIRE |
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