Pancreatic neuroendocrine tumors (PNET) are rare and are classified as nonfunctional or functional as discussed in detail by Batcher et al. (1). Nonfunctional PNETs usually grow in size and eventually cause a mass effect in the organ, whereas functional tumors secrete one (or more) active hormones and are subclassified on the basis of the hormone secreted by the cells constituting the tumor (e.g., insulinomas (secrete insulin), glucagonomas (secrete glucagon), somatostatinomas (secrete somatostatin), etc.). Insulinomas are the most common PNETs observed in the clinic, and biochemical tests of these patients show that the individuals have fasting hypoglycemia along with hyperinsulinoma (elevated levels of insulin) (1). Complete surgical resection of the tumor is considered to be the most suitable treatment and cure for the patient (2). Most insulinomas are small and benign, and they exist as single lesions. Imaging techniques such as computed tomography (CT), magnetic resonance imaging (MRI), and endoscopic ultrasound (EUS) are often used to detect and determine the location of these tumors on the pancreas (3). However, the preoperative detection of these lesion with noninvasive imaging is difficult because the techniques are either unable to distinguish the tumor from the normal parenchymal tissue in the pancreas (e.g., CT), are expensive (e.g., MRI), or are invasive and operator-dependent (e.g., EUS) (3, 4).
Investigators have shown that insulinomas characteristically express high levels of glucagon-like peptide 1 (GLP-1) receptors (GLP-1R), and radiolabeled GLP-1–like ligands have been developed and evaluated for the detection of these PNETs (5). Although GLP-1 is the natural ligand for the GLP-1R, a major drawback of using this peptide to detect the lesions is that it is rapidly inactivated (half-life, ~2 min) by proteolytic enzymes while in circulation. As a consequence, investigators identified 111In-labeled exendin-4 or its analogs (exendin is a peptide of 39 amino acids that has a 54% homology with GLP-1, acts as an agonist of the GLP-1R, and is not inactivated by proteolytic enzymes) for the detection of insulinomas in Rip1Tag2 mice that have spontaneous insulinoma (6) and in humans (4). In another study, EM3106B, an analog of GLP-1 that contains lactam bridges, was labeled with 18F by coupling it with N-2-(4-[18F]-fluorobenzamido)ethylmaleimide ([18F]-FBEM), and the labeled compound was successfully used with positron emission tomography (PET) to detect subcutaneous insulinomas in nude mice (7). As an extension of the earlier work, structural analogs of exendin-4 were conjugated with [18F]FBEM for labeling with 18F, and the biodistribution of [18F]FBEM-[Cys0]-exendin-4 and [18F]FBEM-[Cys40]-exendin-4 was studied in mice bearing INS-1 cell xenograft tumors (for structural details of the compounds, see the Synthesis section below) (5). The radiolabeled compounds were also evaluated with PET to detect tumors that overexpressed GLP-1R in these mice.