PT - JOURNAL ARTICLE AU - Damian Wild AU - Martin Béhé AU - Andreas Wicki AU - Daniel Storch AU - Beatrice Waser AU - Martin Gotthardt AU - Boris Keil AU - Gerhard Christofori AU - Jean Claude Reubi AU - Helmut R. Mäcke TI - [Lys<sup>40</sup>(Ahx-DTPA-<sup>111</sup>In)NH<sub>2</sub>]Exendin-4, a Very Promising Ligand for Glucagon-like Peptide-1 (GLP-1) Receptor Targeting DP - 2006 Dec 01 TA - Journal of Nuclear Medicine PG - 2025--2033 VI - 47 IP - 12 4099 - http://jnm.snmjournals.org/content/47/12/2025.short 4100 - http://jnm.snmjournals.org/content/47/12/2025.full SO - J Nucl Med2006 Dec 01; 47 AB - 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 β-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 β-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 β-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.