Abstract
Somatostatin receptor targeting is considered the standard nuclear medicine technique for visualization of neuroendocrine tumors (NET). Since not all NETs over-express somatostatin receptors, the search for novel targets, visualizing these NETs, is ongoing. Many NETs, expressing low somatostatin receptor levels, express glucose-dependent insulinotropic polypeptide (GIP) receptors (GIPR). Here, we evaluated the performance of [Lys37(DTPA)]N-acetyl-GIP1-42, a newly synthesized GIP analogue to investigate whether NET imaging via GIPR targeting is feasible. Therefore, [Lys37(DTPA)]N-acetyl-GIP1-42 was radiolabeled with 111In with specific activity up to 1.2 TBq/µmol and both in vitro and in vivo receptor targeting properties were examined. In vitro, [Lys37(111In-DTPA)]N-acetyl-GIP1-42 showed receptor-mediated binding to BHK-GIPR positive cells, NES2Y cells and isolated islets. In vivo, both NES2Y and GIPR-transfected BHK tumors were visualized on SPECT/CT. Furthermore, co-administration of an excess unlabeled GIP1-42 lowered tracer uptake from 0.7 ± 0.2%ID/g to 0.6 ± 0.01%ID/g (p = 0.78) in NES2Y tumors and significantly lowered tracer uptake from 3.3 ± 0.8 to 0.8 ± 0.2%ID/g (p = 0.0001) in GIPR-transfected BHK tumors. In conclusion, [Lys37(111In-DTPA)]N-acetyl-GIP1-42 shows receptor-mediated binding in various models. Furthermore, both GIPR-transfected BHK tumors and NES2Y tumors were visible on SPECT/CT using this tracer. Therefore, [Lys37(111In-DTPA)]N-acetyl-GIP1-42 SPECT seems promising for visualization of somatostatin receptor negative NETs.
Highlights
A variety of alternative peptide receptors, such as cholecystokinin (CCK) receptors[12], vasoactive intestinal peptide (VIP) receptors[13] and glucagon-like peptide 1 (GLP-1) receptors (GLP-1R)[14] are expressed on neuroendocrine tumors (NET)
Since it was described that GIP1-30 exhibits reduced receptor binding affinity when compared to the full length peptide GIP1-4226,27, we have investigated the potential of a newly synthesized GIP1-42 analogue, [Lys37(111In-DTPA)]N-acetyl-GIP1-42 (Fig. 1) as a radiotracer for NET imaging, starting from the initial hypothesis that a full-length peptide-based tracer might show improved characteristics for in vivo NET imaging when compared to GIP1-30
Subcutaneous BHK-GIPR and NES2Y tumors were visualized by SPECT after injection of [Lys37(111In-DTPA)]N-acetyl-GIP1-42
Summary
A variety of alternative peptide receptors, such as cholecystokinin (CCK) receptors[12], vasoactive intestinal peptide (VIP) receptors[13] and glucagon-like peptide 1 (GLP-1) receptors (GLP-1R)[14] are expressed on NET. GIP is secreted from the intestinal K cells after nutrient ingestion[19] and together with GLP-1, it enhances glucose-induced insulin secretion upon receptor binding on pancreatic beta cells, the so-called incretin effect[20,21]. Since malignant insulinomas display differential GLP-1R and somatostatin receptor expression patterns[25], detection rates of these tumors remain limited to 50% by scintigraphy. GLP-1R negative malignant insulinomas and a majority of somatostatin negative NETs express enhanced GIPR levels[16], rendering this receptor an interesting target for NET and insulinoma imaging. We have explored the tracers binding characteristics to NES2Y cells (a human beta cell-derived cell line, representing a more realistic model in terms of receptor expression)[28] and isolated islets of Langerhans. Subcutaneous BHK-GIPR and NES2Y tumors were visualized by SPECT after injection of [Lys37(111In-DTPA)]N-acetyl-GIP1-42
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