The Glucose-Dependent Insulinotropic Polypeptide Receptor: A Novel Target for Neuroendocrine Tumor Imaging—First Preclinical Studies

Abstract

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 showed high affinity toward GIP receptor for the GIP conjugates. Specific in vitro internalization was found, and almost the entire cellassociated activity was internalized (.90% of the cell-bound activity), supporting the agonist potency of the 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-ofprinciple radioligand indicated the feasibility of imaging GIP receptorpositive tumors. These results prompt us to continue the development of this family of radioligands for imaging of a broad spectrum of NETs.

Prognostic Impact of Novel Molecular Subtypes of Small Intestinal Neuroendocrine Tumor

“…In particular, aberrant methylation of GIPR is proposed as a mechanism of upregulation of this gene. GIPR overexpression in SINETs has been reported previously, and radiolabeled ligands are in development as novel diagnostic agents for NETs particularly those not expressing somatostatin receptors (26); however, this is the first description of aberrant methylation being associated with GIPR upregulation in NETs. The success of novel radioligands suggests that therapeutic agents targeted to the GIPR receptor could be developed and may increase the range of molecularly targeted therapeutics available for use in NET patients.…”

Targeting Neuropeptide Receptors for Cancer Imaging and Therapy: Perspectives with Bombesin, Neurotensin, and Neuropeptide-Y Receptors

“…2) (5). Another member of this family, the receptor for glucosedependent insulinotropic polypeptide, has recently been found to be expressed in most pancreatic, ileal, and bronchial NETs, including those that are somatostatin receptor-negative (6), as well as in medullary thyroid cancer (7), and radiolabeled glucose-dependent insulinotropic polypeptide analogs are promising (8). Other targets in NETs are the cholecystokinin B receptor and the recently described neuropeptide S receptor 1 (9).…”

Approaches to Multireceptor Targeting: Hybrid Radioligands, Radioligand Cocktails, and Sequential Radioligand Applications

“…Within the incretin family, another receptor was recently shown to be overexpressed in most gastrointestinal and pancreatic NETs: the glucose-dependent insulinotropic polypeptide (GIP) receptor (10). Preclinical evidence has shown that 68 Ga-DOTA-GIP can label GIP receptor-positive cancers in animals, although this method is not yet used in clinics (11). In addition, cholecystokinin (CCK) receptors (CCK1 and CCK2 subtypes) are overexpressed in GEP NETs (7,12), with CCK2 being overexpressed more frequently than CCK1.…”

“…RGD-based peptides have been coupled via a Glu spacer to the GRP receptor-targeting peptide bombesin (7)(8)(9)(10)(11)(12)(13)(14). The glutamic acid spacer allows also coupling of a chelator such as DOTA or NOTA for radiometal labeling or a prosthetic group for 18 F labeling.…”

“…With the use of (radio)chemical strategies developed before for agents targeting GLP-1 (9,49) and GIP (11) receptors, a series of radioligands may be developed as imaging (and possibly radiotherapeutic) agents targeting tumors expressing these receptors simultaneously (11). Receptor families with different receptor subtypes such as the somatostatin receptors may also benefit from a similar approach.…”