Research Article: Radioiodinated Exendin-4 Is Superior to the Radiometal-Labelled Glucagon-Like Peptide-1 Receptor Probes Overcoming Their High Kidney Uptake

Date Published: January 19, 2017

Publisher: Public Library of Science

Author(s): Tilman Läppchen, Roswitha Tönnesmann, Jos Eersels, Philipp T. Meyer, Helmut R. Maecke, Svetlana N. Rylova, Juri G. Gelovani.


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.

Partial Text

Glucagon like peptide-1 receptors (GLP-1R) are ideal targets for the imaging of benign insulinoma due to their high density on the surface of more than 90% of these tumors [1]. Physiological expression of GLP-1 receptors on the pancreatic beta cells is also being exploited preclinically and potentially clinically for imaging of the pancreatic beta cell mass to quantify the loss of islets in type 1 diabetes [2,3]. Since islet transplantation may be a promising treatment option for patients with diabetes, the GLP-1 targeted imaging is being explored for visualization of transplanted islets and monitoring their survival [4,5].

GLP-1 receptor targeting peptides are important imaging tools for preoperative localization of benign insulinoma. Currently available tracers show a high and persistent renal uptake and low specific activity, resulting in side effects such as hypoglycaemia due to insulin secretion after activation of the GLP-1 receptor. We attempted to solve these issues by using radioiodinated analogues of the agonist Ex-4 and the antagonist Ex(9–39).

Even though the antagonist [Nle14,125I-Tyr40NH2]Ex(9–39) recognized more binding sites on GLP-1R, it had a lower affinity than the agonist and it may not be suitable for clinical translation. The [Nle14,125I-Tyr40NH2]Ex-4 agonist, in contrast, showed excellent tumor uptake and at the same time exhibited pharmacokinetics superior to all other GLP-1R tracers presently available, with particularly high tumor-to-kidney ratio and good contrast to normal organs. Preclinical PET imaging data strongly suggest that Ex-4 radioiodinated with 124I may be a promising alternative to the radio-metal labelled derivatives for imaging of GLP-1 receptor positive insulinoma. It can further improve the sensitivity of the preoperative localization of benign insulinoma.




0 0 vote
Article Rating
Notify of
Inline Feedbacks
View all comments