Context: The surgical removal of insulinomas is hampered by difficulties to localize it using conventional radiological procedures. Recently these tumors were shown to exhibit a very high density of glucagon-like peptide-1 receptors (GLP-1R) in vitro that may be used as specific targets for in vivo receptor radiolabeling. Objective: The objective of the study was to test the 111In-labeled GLP-1R agonist 111In-DOTA-exendin-4 in localizing insulinomas using single photon emission computed tomography in combination with computed tomography images. Design: This was a prospective open-label investigation. Setting: The study was conducted at three tertiary referral centers in Switzerland. Patients: Patients included six consecutive patients with proven clinical and biochemical endogenous hyperinsulinemic hypoglycemia. Intervention:¹¹¹In-DOTA-exendin-4 was administered iv at a dose of about 90 MBq (30 μg peptide) over 5 min. Whole-body planar images of the abdomen were performed at 20 min, 4 h, 23 h, 96 h, and up to 168 h after injection. After surgical removal of the insulinomas, GLP-1R expression was assessed in the tumor tissue in vitro by GLP-1R autoradiography. Main Outcome Measure: The detection rate of insulinomas was measured. Results: In all six cases, the GLP-1R scans successfully detected the insulinomas identified using conventional methods in four cases. By using a γ-probe intraoperatively, GLP-1R detection permitted a successful surgical removal of the tumors in all patients, diagnosed histopathologically as five pancreatic and one extrapancreatic insulinomas. In vitro GLP-1R autoradiography showed a high density of GLP-1R in all tested insulinomas. Conclusion:In vivo GLP-1R imaging is an innovative, noninvasive diagnostic approach that successfully localizes small insulinomas pre- and intraoperatively and that may in the future affect the strategy of insulinoma localization. In vivo GLP-1R imaging is an innovative, non-invasive diagnostic approach that successfully localizes small insulinomas pre- and intraoperatively, and that may in the future affect the strategy of insulinoma localization.

The precise localization of some insulinomas (islet-cell adenomas that secrete insulin) with the use of conventional imaging techniques, such as computed tomography (CT), magnetic resonance imaging (MRI), endosonography,¹ and indium-111 (¹¹¹In)–labeled pentetreotide scintigraphy (OctreoScan),² is a challenging clinical problem. In vitro studies have demonstrated that receptors for glucagon-like peptide 1 (GLP-1) are highly overexpressed in almost all insulinomas.^3,4 Therefore, GLP-1-like radioligands retaining high binding affinity to GLP-1 receptors have been developed. One such radioligand, [Lys⁴⁰(Ahx-DTPA-¹¹¹In)NH₂]exendin-4, successfully targeted insulinomas in the Rip1-Tag2 mouse.⁵ We evaluated the diagnostic value of GLP-1–receptor scintigraphy in two patients with insulinomas that either were not localized (Patient 1) or were unsatisfactorily localized (Patient 2) with the use of conventional imaging methods.

Small benign insulinomas are hard to localise, leading to difficulties in planning of surgical interventions. We aimed to prospectively assess the insulinoma detection rate of single-photon emission CT in combination with CT (SPECT/CT) with a glucagon-like peptide-1 receptor avid radiotracer, and compare detection rates with conventional CT/MRI techniques. In our prospective imaging study, we enrolled adults aged 25-81 years at centres in Germany, Switzerland, and the UK. Eligible patients had proven clinical and biochemical endogenous hyperinsulinaemic hypoglycaemia and no evidence for metastatic disease on conventional imaging. CT/MRI imaging was done at referring centres according to standard protocols. At three tertiary nuclear medicine centres, we used whole body planar images and SPECT/CT of the abdomen up to 168 h after injection of (111)In-[Lys40(Ahx-DTPA-(111)In)NH2]-exendin-4 ((111)In-DTPA-exendin-4) to identify insulinomas. Consenting patients underwent surgery and imaging findings were confirmed histologically. Between Oct 1, 2008, and Dec 31, 2011, we recruited 30 patients. All patients underwent (111)In-DTPA-exendin-4 imaging, 25 patients underwent surgery (with histological analysis), and 27 patients were assessed with CT/MRI. (111)In-DTPA-exendin-4 SPECT/CT correctly detected 19 insulinomas and four additional positive lesions (two islet-cell hyperplasia and two uncharacterised lesions) resulting in a positive predictive value of 83% (95% CI 62-94). One true negative (islet-cell hyperplasia) and one false negative (malignant insulinoma) result was identified in separate patients by (111)In-DTPA-exendin-4 SPECT/CT. Seven patients (23%) were referred to surgery on the basis of (111)In-DTPA-exendin-4 imaging alone. For 23 assessable patients, (111)In-DTPA-exendin-4 SPECT/CT had a higher sensitivity (95% [95% CI 74-100]) than did CT/MRI (47% [27-68]; p=0.011). (111)In-DTPA-exendin-4 SPECT/CT could provide a good second-line imaging strategy for patients with negative results on initial imaging with CT/MRI. Oncosuisse, the Swiss National Science Foundation, and UK Department of Health.

Glucagon-like peptide-1 (GLP-1) receptor imaging is superior to somatostatin receptor subtype 2 (sst₂) imaging in localizing benign insulinomas. Here, the role of GLP-1 and sst₂ receptor imaging in the management of malignant insulinoma patients was investigated. Methods: Eleven patients with malignant insulinoma were prospectively included. ¹¹¹In-[Lys⁴⁰(Ahx-diethylenetriaminepentaacetic acid [DTPA])NH₂]-exendin-4 SPECT/CT, ⁶⁸Ga- DOTATATE PET/CT, and in vitro receptor autoradiography were performed to assess the receptor status and to evaluate the detection rate. Results: GLP-1 receptor targeting was positive in 4 of 11 patients, and sst₂ receptor expression was positive in 8 of 11. In only 1 patient were both receptors expressed. In 1 patient, GLP-1 receptor imaging was the only method that successfully localized the primary tumor in the pancreas. In 3 patients with sst₂-expressing tumors, DOTATATE radiotherapy was effectively applied. Conclusion: As opposed to benign insulinomas, malignant insulinomas often lack GLP-1 receptors. Conversely, malignant insulinomas often express sst₂, which can be targeted therapeutically.

¹¹¹In-DOTA-exendin-4 SPECT/CT has been shown to be highly efficient in the detection of insulinomas. We aimed at determining whether novel PET/CT imaging with [Nle¹⁴, Lys⁴⁰(Ahx-DOTA-⁶⁸Ga)NH₂]exendin-4 (⁶⁸Ga-DOTA-exendin-4) is feasible and sensitive in detecting benign insulinomas. Methods: ⁶⁸Ga-DOTA-exendin-4 PET/CT and ¹¹¹In-DOTA-exendin-4 SPECT/CT were performed in a randomized cross-over order in 5 patients with endogenous hyperinsulinemic hypoglycemia. Gold standard for comparison was the histological diagnosis after surgery. Results: In 4 patients histological diagnosis confirmed a benign insuIinoma, whereas one patient refused surgery despite a positive ⁶⁸Ga-DOTA-exendin-4 PET/CT scan. In 4 out of 5 patients previously performed conventional imaging (CT/MRI) was not able to localize the insulinoma. ⁶⁸Ga-DOTA-exendin-4 PET/CT correctly identified the insulinoma in 4/4 patients whereas ¹¹¹In-DOTA-exendin-4 SPECT/CT correctly identified the insulinoma in 2/4 patients. Conclusion: These preliminary data suggest that ⁶⁸Ga-DOTA-exendin-4 PET/CT is feasible in detecting hidden insulinomas.