Radioiodinated Exendin-4 Is Superior to the Radiometal-Labelled Glucagon-Like Peptide-1 Receptor Probes Overcoming Their High Kidney Uptake
| Autor: | Roswitha Tönnesmann, Jos Eersels, Philipp T. Meyer, Helmut R. Maecke, Tilman Läppchen, Svetlana N. Rylova |
|---|---|
| Přispěvatelé: | Supporting clinical sciences, Radiology and nuclear medicine, Amsterdam Neuroscience - Brain Imaging |
| Rok vydání: | 2016 |
| Předmět: |
lcsh:Medicine
Pharmacology Kidney Lung and Intrathoracic Tumors 030218 nuclear medicine & medical imaging Diagnostic Radiology Iodine Radioisotopes Mice 0302 clinical medicine Positron Emission Tomography Computed Tomography Medicine and Health Sciences Tissue Distribution lcsh:Science Internalization Receptor 610 Medicine & health Endocrine Tumors Tomography media_common Thyroid Liquid Chromatography Mice Inbred BALB C Multidisciplinary Chemistry Radiology and Imaging Stomach Chromatographic Techniques Oncology 030220 oncology & carcinogenesis Heterografts Female Anatomy Research Article Agonist Biodistribution medicine.medical_specialty medicine.drug_class Imaging Techniques media_common.quotation_subject Mice Nude Gallium Radioisotopes Neuroimaging Endocrine System Research and Analysis Methods Glucagon-Like Peptide-1 Receptor 03 medical and health sciences Exocrine Glands In vivo Diagnostic Medicine Internal medicine Cell Line Tumor Journal Article medicine Animals Humans Insulinoma Pancreas Venoms lcsh:R Kidney metabolism Biology and Life Sciences Cancers and Neoplasms Kidneys Renal System medicine.disease In vitro High Performance Liquid Chromatography Pancreatic Neoplasms Gastrointestinal Tract Endocrinology Exenatide lcsh:Q Radiopharmaceuticals Peptides Digestive System Positron Emission Tomography Neuroscience |
| Zdroj: | PLoS ONE Läppchen, Tilman; Tönnesmann, Roswitha; Eersels, Jos; Meyer, Philipp T; Maecke, Helmut R; Rylova, Svetlana N (2017). Radioiodinated Exendin-4 Is Superior to the Radiometal-Labelled Glucagon-Like Peptide-1 Receptor Probes Overcoming Their High Kidney Uptake. PLoS ONE, 12(1), e0170435. Public Library of Science 10.1371/journal.pone.0170435 PLoS ONE, 12(1):e0170435. Public Library of Science Läppchen, T, Tönnesmann, R, Eersels, J, Meyer, P T, Maecke, H R & Rylova, S N 2017, ' Radioiodinated exendin-4 is superior to the radiometal-labelled glucagon-like peptide-1 receptor probes overcoming their high kidney uptake ', PLoS ONE, vol. 12, no. 1, e0170435 . https://doi.org/10.1371/journal.pone.0170435 PLoS ONE, Vol 12, Iss 1, p e0170435 (2017) |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0170435 |
| Popis: | GLP-1 receptors are ideal targets for preoperative imaging of benign insulinoma and for quantifying the beta cell mass. The existing clinical tracers targeting GLP-1R are all agonists with low specific activity and very high kidney uptake. In order to solve those issues we evaluated GLP-1R agonist Ex-4 and antagonist Ex(9-39) radioiodinated at Tyr40 side by side with [Nle14,Lys40(Ahx-DOTA-68Ga)NH2]Ex-4 (68Ga-Ex-4) used in the clinic. The Kd, Bmax, internalization and binding kinetics of [Nle14,125I-Tyr40-NH2]Ex-4 and [Nle14,125I-Tyr40-NH2]Ex (9-39) were studied in vitro using Ins-1E cells. Biodistribution and imaging studies were performed in nude mice bearing Ins-1E xenografts. In vitro evaluation demonstrated high affinity binding of the [Nle14,125I-Tyr40-NH2]Ex-4 agonist to the Ins-1E cells with fast internalization kinetics reaching a plateau after 30 min. The antagonist [Nle14,125I-Tyr40-NH2]Ex(9-39) did not internalize and had a 4-fold higher Kd value compared to the agonist. In contrast to [Nle14,125I-Tyr40-NH2]Ex(9-39), which showed low and transient tumor uptake, [Nle14,125I-Tyr40-NH2]Ex-4 demonstrated excellent in vivo binding properties with tumor uptake identical to that of 68Ga-Ex-4, but substantially lower kidney uptake resulting in a tumor-to-kidney ratio of 9.7 at 1 h compared to 0.3 with 68Ga-Ex-4. Accumulation of activity in thyroid and stomach for both peptides, which was effectively blocked by irenat, confirms that in vivodeiodination is the mechanism behind the low kidney retention of iodinated peptides. The 124I congener of [Nle14,125I-Tyr40-NH2]Ex-4 demonstrated a similar favourable biodistribution profile in the PET imaging studies in contrast to the typical biodistribution pattern of [Nle14,Lys40(Ahx-DOTA-68Ga)NH2]Ex-4. Our results demonstrate that iodinated Ex-4 is a very promising tracer for imaging of benign insulinomas. It solves the problem of high kidney uptake of the radiometal-labelled tracers by improving the tumor-to-kidney ratio measured for [Nle14,Lys40(Ahx-DOTA-68Ga)NH2]Ex-4 by 32 fold. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|