RT Journal Article
SR Electronic
T1 [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
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 2025
OP 2033
VO 47
IS 12
A1 Damian Wild
A1 Martin Béhé
A1 Andreas Wicki
A1 Daniel Storch
A1 Beatrice Waser
A1 Martin Gotthardt
A1 Boris Keil
A1 Gerhard Christofori
A1 Jean Claude Reubi
A1 Helmut R. Mäcke
YR 2006
UL http://jnm.snmjournals.org/content/47/12/2025.abstract
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.