PET imaging of insulinoma using a ⁶⁸Ga-labeled GLP-1 analog

Objectives Surgical removal of insulinomas based on conventional radiological imaging has met difficulties. Radiotargeting offers the potential for intraoperative localization. Glucagon-like peptide 1 receptor (GLP-1R) is abundant in insulinomas which makes it an attractive target for probe development. Studies have shown success using GLP-1R agonist, exendin-4, in the detection of benign insulinoma. The objective of the study was to test the ⁶⁸Ga-labeled GLP-1 analog, ⁶⁸Ga-NOTA-EM2198, in localizing insulinomas on PET.

Methods Metabolic stability to enzymatic degradation of EM2198 was checked with HPLC after incubating it with peptidases. Binding affinity of EM2198 to GLP-1R was evaluated in a in vitro competitive receptor binding assay. In vivo targeting was evaluated in 10 male SCID mice bearing β-TC6 insulinomas by PET imaging with ⁶⁸Ga-NOTA-EM2198. Non-GLP1-R expressing PC-3 cells were used as a control. Blood glucose level was measured as an indicator of the insulinoma growth and progression.

Results All mice bearing β-TC6 tumor developed hypoglycemia after 30-50 days of implantation and showed lethargy whereas PC-3 tumor-bearing mice remained normoglycemia throughout the study. The accumulation of ⁶⁸Ga-NOTA-EM2198 in the tumor under normoglycemic condition (112 mg/dl at 28 days post-implantation (p.i.)) was 1.6 ± 0.2%ID/g at 1 h post injection. Remarkably, under hypoglycemic conditions (38 mg/dl 48 days p.i.) in the same mice, the tumor uptake increased 2.1 ± 0.3%ID/g. Uptake blockade studies with cold EM2198 at day 49 showed a significant reduction of the tumor uptake (1.2± 0.1%ID/g)(p<0.0001). No tumor accumulation was observed in PC-3 tumors.

Conclusions Our results suggest that ⁶⁸Ga-NOTA-EM2198 is a promising PET probe with potential for early detection of GLP-1R expressing insulinomas, intraoperative localization, and noninvasive monitoring of their therapies.