Are radiolabeled GLP-1 receptor antagonists useful for scintigraphy?

Objectives We have recently introduced the receptor agonist Exendin-4 as a radiopeptide for the glucagon-like peptide-1 receptor (GLP-1-R). Preclinical data have indicated that for imaging the SSTRs radiolabeled antagonists are preferable to agonists. Therefore, the aim of this study was to compare the In-111 labeled GLP-1-R agonist Exendin-4 with the GLP-1-R antagonist Exendin-4 (9-39) for imaging of GLP-1-R positive tumors.

Methods Peptides were labeled with ¹¹¹In via DTPA coupled to -amine of ⁴⁰Lys. The labeled peptides were examined on GLP-1 R transfected CHL cells for internalization and receptor affinity. Biodistribution experiments were performed in immunodeficient nude mice bearing wild-type and GLP-1-R positive CHL tumors.

Results The agonist showed a fast receptor specific internalization rate (>70%/15min) than the antagonist. The affinities (K_D) of the agonist and antagonist were 8.8 nM and 28.4 nM, respectively. In-vivo the the agonist showed a high uptake in receptor positive organs and the GLP-1-R positive tumors (tumor: 23.28 % i.A./g; pancreas: 8.85% i.A./g). The antagonist demonstrated a 3-times lower specific uptake in the GLP-1-R positive tumors, but uptake in the pancreas was 20-times lower.

Conclusions As reported for SSTR antagonists, GLP-1 receptor antagonist showed a lower uptake in receptor positive normal tissues than the corresponding agonists. However, the specific uptake in tumor of the GLP-1-R antagonist was lower than that of the agonist. This is likely related to its about 4-fold lower affinity. The results suggest that GLP-1-R antagonists may play a role for imaging if affinity is increased.