The glucose-dependent insulinotropic polypeptide receptor: a novel target for neuroendocrine tumor imaging—first
Eleni Gourni1, Beatrice Waser2, Pascal Clerc3
1German Cancer Consortium (DKTK), Heidelberg, Germany Department of Nuclear Medicine, University Hospital Freiburg, Freiburg, Germany German Cancer Research Center (DKFZ), Heidelberg, Germany.
Unlabelled:
A new family of peptide receptors, the incretin receptor family, overexpressed on many neuroendocrine tumors (NETs) is of great importance because it may enable the in vivo peptide-based receptor targeting of a category of NETs that does not express the somatostatin receptor. Impressive in vivo diagnostic data were published for glucagonlike peptide 1 receptor-targeting radiopeptides. Recently, promising in vitro data have appeared for the second member of the incretin family, the glucose-dependent insulinotropic polypeptide (GIP) receptor. This prompted us to develop and evaluate a new class of radioligands with the potential to be used for the in vivo targeting of GIP receptor-positive tumors.
Methods:
GIP(1-42) was modified C-terminally, and the truncated peptides [Lys(30)(aminohexanoic acid [Ahx]-DOTA)]GIP(1-30)NH2 (EG1), [Lys(16)(Ahx-DOTA)]GIP(1-30)NH2 (EG2), and [Nle(14), Lys(30)(Ahx-DOTA)]GIP(1-30)NH2 (EG4) were conjugated with Ahx-DOTA via the Lys(16) and Lys(30) side chains. Their inhibitory concentration of 50% (IC50) was determined using [(125)I-Tyr(10)]GIP(1-30) as radioligand and GIP(1-30) as control peptide. The DOTA conjugates were labeled with (111)In and (68)Ga. In vitro evaluation included saturation and internalization studies using the pancreatic endocrine cell line INR1G9 transfected with the human GIP receptor (INR1G9-hGIPr). The in vivo evaluation consisted of biodistribution and PET imaging studies on nude mice bearing INR1G9-hGIPr tumors.
Results:
Binding studies (IC50 and saturation studies) showed high affinity toward GIP receptor for the GIP conjugates. Specific in vitro internalization was found, and almost the entire cell-associated activity was internalized (>90% of the cell-bound activity), supporting the agonist potency of the (111)In-vectors. (111)In-EG4 and (68)Ga-EG4 were shown to specifically target INR1G9-hGIPr xenografts, with tumor uptake of 10.4% ± 2.2% and 17.0% ± 4.4% injected activity/g, 1 h after injection, respectively. Kidneys showed the highest uptake, which could be reduced by approximately 40%-50% with a modified-fluid-gelatin plasma substitute or an inhibitor of the serine protease dipeptidyl peptidase 4. The PET images clearly visualized the tumor.
Conclusion:
The evaluation of EG4 as a proof-of-principle radioligand indicated the feasibility of imaging GIP receptor-positive tumors. These results prompt us to continue the development of this family of radioligands for imaging of a broad spectrum of NETs.
Insights
New radioligands targeting the glucose-dependent insulinotropic polypeptide (GIP) receptor show promise for imaging neuroendocrine tumors (NETs). These GIP receptor-targeting agents enable visualization of NETs that do not express somatostatin receptors.
Area of Science:
- Nuclear Medicine
- Oncology
- Radiopharmaceutical Chemistry
Background:
- Incretin receptors, including the GIP receptor, are overexpressed on certain neuroendocrine tumors (NETs).
- Targeting GIP receptors offers a potential strategy for diagnosing NETs that lack somatostatin receptors.
- Previous studies demonstrated success with GLP-1 receptor-targeting radiopeptides.
Purpose of the Study:
- To develop and evaluate novel radioligands for targeting GIP receptor-positive tumors.
- To assess the in vitro and in vivo performance of new GIP receptor-targeting agents.
Main Methods:
- Modified GIP(1-42) peptides (EG1, EG2, EG4) were synthesized and conjugated with DOTA.
- Radioligands were labeled with Indium-111 ((111)In) and Gallium-68 ((68)Ga).
- In vitro studies included binding affinity, internalization, and cell-based assays. In vivo studies involved biodistribution and PET imaging in tumor-bearing mice.
Main Results:
- GIP conjugates demonstrated high affinity for the GIP receptor.
- (111)In-labeled peptides showed specific internalization into GIP receptor-expressing cells.
- (111)In-EG4 and (68)Ga-EG4 specifically targeted GIP receptor-positive xenografts, with clear visualization on PET imaging.
Conclusions:
- EG4 serves as a proof-of-principle radioligand for imaging GIP receptor-positive tumors.
- These findings support the continued development of GIP receptor-targeting radioligands for NET imaging.
- This approach may expand diagnostic capabilities for a wider range of NETs.
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