title: Radioiodinated Exendin-4 Is Superior to the Radiometal-Labelled Glucagon-Like Peptide-1 Receptor Probes Overcoming Their High Kidney Uptake.
abstract: 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 vivo deiodination 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.
authors.affiliation: Department of Nuclear Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.|Department of Nuclear Medicine, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.
authors.forename: Tilman
authors.initials: T
authors.lastname: Läppchen
authors.affiliation: Department of Nuclear Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
authors.forename: Roswitha
authors.initials: R
authors.lastname: Tönnesmann
authors.affiliation: Department of Radiology and Nuclear Medicine, VU University Medical Centre, Amsterdam, The Netherlands.
authors.forename: Jos
authors.initials: J
authors.lastname: Eersels
authors.affiliation: Department of Nuclear Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Philipp T
authors.initials: PT
authors.lastname: Meyer
authors.affiliation: Department of Nuclear Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Helmut R
authors.initials: HR
authors.lastname: Maecke
authors.affiliation: Department of Nuclear Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Svetlana N
authors.initials: SN
authors.lastname: Rylova
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D000077270:Exenatide; D005260:Female; D005710:Gallium Radioisotopes / Q000493:pharmacokinetics; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D007340:Insulinoma / Q000000981:diagnostic imaging / Q000378:metabolism*; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D007668:Kidney / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism*; D010455:Peptides / Q000493:pharmacokinetics*; D000072078:Positron Emission Tomography Computed Tomography / Q000379:methods; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014688:Venoms / Q000493:pharmacokinetics*
chemical_list: D005710:Gallium Radioisotopes; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007457:Iodine Radioisotopes; D010455:Peptides; D019275:Radiopharmaceuticals; D014688:Venoms; D000077270:Exenatide