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[Lys⁴⁰(Ahx-DTPA-¹¹¹In)NH₂]Exendin-4, a Very Promising Ligand for Glucagon-like Peptide-1 (GLP-1) Receptor Targeting

¹ Clinic and Institute of Nuclear Medicine, University Hospital Basel, Basel, Switzerland; ² Department of Nuclear Medicine, Hospital of the Philipps-University, Marburg, Germany; ³ Institute of Biochemistry and Genetics, Center for Biomedicine, University of Basel, Basel, Switzerland; ⁴ Division of Radiological Chemistry, University Hospital Basel, Basel, Switzerland; ⁵ Institute of Pathology, University of Bern, Bern, Switzerland; and ⁶ Department of Radiology, Hospital of the Philipps-University, Marburg, Germany

Correspondence: For correspondence or reprints contact: Helmut R. Mäcke, PhD, Division of Radiological Chemistry, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland. E-mail: hmaecke{at}uhbs.ch

High levels of glucagon-like peptide-1 (GLP-1) receptor expression in human insulinomas and gastrinomas provide an attractive target for imaging, therapy, and intraoperative tumor localization, using receptor-avid radioligands. The goal of this study was to establish a tumor model for GLP-1 receptor targeting and to use a newly designed exendin-4–DTPA (DTPA is diethylenetriaminepentaacetic acid) conjugate for GLP-1 receptor targeting. Methods: Exendin-4 was modified C-terminally with Lys⁴⁰-NH₂, whereby the lysine side chain was conjugated with Ahx-DTPA (Ahx is aminohexanoic acid). The GLP-1 receptor affinity (50% inhibitory concentration [IC₅₀] value) of [Lys⁴⁰(Ahx-DTPA)NH₂]exendin-4 as well as the GLP-1 receptor density in tumors and different organs of Rip1Tag2 mice were determined. Rip1Tag2 mice are transgenic mice that develop insulinomas in a well-defined multistage tumorigenesis pathway. This animal model was used for biodistribution studies, pinhole SPECT/MRI, and SPECT/CT. Peptide stability, internalization, and efflux studies were performed in cultured ß-tumor cells established from tumors of Rip1Tag2 mice. Results: The GLP-1 receptor affinity of [Lys⁴⁰(Ahx-DTPA)NH₂]exendin-4 was found to be 2.1 ± 1.1 nmol/L (mean ± SEM). Because the GLP-1 receptor density in tumors of Rip1Tag2 mice was very high, a remarkably high tumor uptake of 287 ± 62 %IA/g (% injected activity per gram tissue) was found 4 h after injection. This resulted in excellent tumor visualization by pinhole SPECT/MRI and SPECT/CT. In accordance with in vitro data, [Lys⁴⁰(Ahx-DTPA-¹¹¹In)NH₂]exendin-4 uptake in Rip1Tag2 mice was also found in nonneoplastic tissues such as pancreas and lung. However, lung and pancreas uptake was distinctly lower compared with that of tumors, resulting in a tumor-to-pancreas ratio of 13.6 and in a tumor-to-lung ratio of 4.4 at 4 h after injection. Furthermore, in vitro studies in cultured ß-tumor cells demonstrated a specific internalization of [Lys⁴⁰(Ahx-DTPA-¹¹¹In)NH₂]exendin-4, whereas peptide stability studies indicated a high metabolic stability of the radiopeptide in ß-tumor cells and human blood serum. Conclusion: The high density of GLP-1 receptors in insulinomas as well as the high specific uptake of [Lys⁴⁰(Ahx-DTPA-¹¹¹In)NH₂]exendin-4 in the tumor of Rip1Tag2 mice indicate that targeting of GLP-1 receptors in insulinomas may become a useful imaging method to localize insulinomas in patients, either preoperatively or intraoperatively. In addition, Rip1Tag2 transgenic mice represent a suitable animal tumor model for GLP-1 receptor targeting.

Key Words: glucagon-like peptide-1 receptor • insulinoma • exendin-4 • transgenic mouse model • ¹¹¹In

COPYRIGHT © 2006 by the Society of Nuclear Medicine, Inc.

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