Approaches to Improve the Pharmacokinetics of Radiolabeled Glucagon-Like Peptide-1 Receptor Ligands Using Antagonistic Tracers

Abstract

The glucagon-like peptide-1 (GLP-1) receptors are important biomarkers for imaging pancreatic β-cell mass and detection of benign insulinomas. Using GLP-1 receptor antagonists, we aimed to eliminate the insulin-related side effects reported for all GLP-1 receptor agonists. Additionally, using a nonresidualizing tracer, 125 I-BoltonHunter-Exendin(9-39)NH 2 ( 125 I-BH-Ex(9-39)NH 2 ), we aimed to reduce the high kidney uptake, enabling a better detection of insulinomas in the tail and head of the pancreas. Methods: The affinity and biodistribution of Ex (9- ) uptake in Ins-1E tumor, 12.5 ± 2.2 %IA/g in the pancreas, and 235.8 ± 17.0 %IA/g in the kidney, with tumor-to-blood and tumor-to-kidney ratios of 100.52 and 0.17, respectively. Biodistribution of [Lys 40 (NODAGA-68 Ga)NH 2 ]Ex(9-39) showed only 2.2 ± 0.2 %IA/g uptake in Ins-1E tumor, 1.0 ± 0.1 %IA/g in the pancreas, and 78.4 ± 8.5 %IA/g in the kidney at 1 h after injection, with tumor-to-blood and tumor-to-kidney ratios of 7.33 and 0.03, respectively. In contrast, 125 I-BH-Ex(9-39)NH 2 showed tumor uptake (42.5 ± 8.1 %IA/g) comparable to the agonist and 28.8 ± 5.1 %IA/g in the pancreas at 1 h after injection. As we hypothesized, the kidney uptake of 125 I-BH-Ex(9-39)NH 2 was low, only 12.1 ± 1.4 %IA/g at 1 h after injection. The tumor-to-kidney ratio of 125 I-BH-Ex(9-39)NH 2 was improved 20-fold. Conclusion: Our results suggest that iodinated Ex(9-39)NH 2 may be a promising tracer for imaging GLP-1 receptor expression in vivo. Because of the 20-fold improved tumorto-kidney ratio 125 I-BH-Ex(9-39)NH 2 may offer higher sensitivity in the detection of insulinomas and imaging of β-cell mass in diabetic patients. Further studies with 124 I-BH-Ex(9-39)NH 2 are warranted.Key Words: GLP-1 receptor; insulinoma; β-cell mass; antagonist The glucagon-like peptide (GLP-1) receptors are important targets because they are overexpressed on more than 90% of benign insulinomas, some malignant insulinomas, most gastrinomas, and most phaeochromocytomas (1). Physiologically they are also expressed in the endocrine pancreas. Preoperative imaging of insulinomas is critical, because it helps to precisely localize these often very small lesions in the pancreas. Therefore, imaging probes for optical (2), bimodal (3), SPECT (4-7), and PET (8-13) imaging as well as MRI (14) were developed to localize GLP-1 receptors preoperatively and in addition to determine b-cell mass in diabetic animal models and potentially in patients. In particular, SPECT (4,5,7) and PET (8,13,15) agents were successfully translated into the clinic, and several promising clinical studies were reported. Still, there are a few shortcomings with the available tracers. The tracers accumulate highly in the kidneys when residualizing radiometals are used for labeling, possibly leading to not only unnecessary high radiation doses but also problems in localizing tumors in the tail and head of the pancreas (5,8,13). The usually low specific activity of the imaging tracers, exclusively agonists, and the concomitant relative...

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

“…But most importantly the kidney uptake was very low resulting in the high tumor-to-kidney ratio of 9.7. This ratio was even better than the ratio of 3.5, which we reported for the antagonist 125 I-BH-Ex(9–39) [29], and was the highest among the published GLP-1R tracers. The tumor-to-pancreas ratios were also very similar for [Nle 14 , 125 I-Tyr 40 -NH 2 ]Ex-4 and 68 Ga-Ex-4, which would translate into similar imaging contrast for insulinomas against the normal pancreas.…”

“…Our recent data also demonstrate that in contrast to Ex-4-based tracers, which tolerated various modifications at the C-terminal very well, the Ex(9–39) antagonist was very sensitive to conjugation of the 68 Ga-DOTA or 68 Ga-NODAGA complexes at the positions Lys 27 or Lys 40 [29]. The resulting probes had low affinity and were not suitable for GLP-1 R imaging [29].…”

“…The resulting probes had low affinity and were not suitable for GLP-1 R imaging [29]. However, Ex(9–39) radioiodinated with 125 I at Lys 27 using the Bolton Hunter (BH) method showed the same binding properties for the human GLP-1 receptor-expressing tissues in vitro as endogenous GLP-1 [30].…”

“…We demonstrated that in vivo 125 I-BH-Ex(9–39) accumulated in the Ins-1E xenografts with an uptake similar to that of 68 Ga-Ex-4, the GLP-1R tracer currently used in the clinic [22]. Most importantly, however radioiodination resulted in a significant reduction of the radioligand’s kidney uptake [29]. In comparison to 68 Ga-Ex-4, the tumor-to-kidney ratio of 125 I-BH-Ex-(9–39) improved 20-fold.…”

Citius, Altius, Fortius: An Olympian Dream for Theranostics

“…Antagonists have been described for imaging other cellular targets including glucagonlike peptide-1 (20,21), neurotensin (22), and gastrin-releasing peptide (23,24). As yet these agents remain primarily the focus of preclinical studies, but some are entering early clinical trials.…”