18F-radiolabeled analogs of exendin-4 for PET imaging of GLP-1 in insulinoma

Abstract

Purpose Glucagon-like peptide type 1 (GLP-1) is an incretin peptide that augments glucose-stimulated insulin release following oral consumption of nutrients. Its message is transmitted via a G protein-coupled receptor called GLP-1R, which is colocalized with pancreatic β-cells. The GLP-1 system is responsible for enhancing insulin release, inhibiting glucagon production, inhibiting hepatic gluconeogenesis, inhibiting gastric mobility, and suppression of appetite. The abundance of GLP-1R in pancreatic β-cells in insulinoma, a cancer of the pancreas, and the activity of GLP-1 in the cardiovascular system have made GLP-1R a target for molecular imaging. Methods We prepared 18F radioligands for GLP-1R by the reaction of [18F]FBEM, a maleimide prosthetic group, with [Cys0] and [Cys40] analogs of exendin-4. The binding affinity, cellular uptake and internalization, in vitro stability, and uptake and specificity of uptake of the resulting compounds were determined in an INS-1 xenograft model in nude mice. Results The [18F]FBEM-[Cysx]-exendin-4 analogs were obtained in good yield (34.3±3.4%, n=11), based on the starting compound [18F]FBEM), and had a specific activity of 45.51±16.28 GBq/μmol (1.23±0.44 Ci/μmol, n=7) at the end of synthesis. The C-terminal isomer, [18F]FBEM-[Cys40]-exendin-4, had higher affinity for INS-1 tumor cells (IC50 1.11±0.057 nM) and higher tumor uptake (25.25±3.39 %ID/g at 1 h) than the N-terminal isomer, [18F]FBEM-[Cys0]-exendin-4 (IC50 2.99±0.06 nM, uptake 7.20±1.26 %ID/g at 1 h). Uptake of both isomers into INS-1 tumor, pancreas, stomach, and lung could be blocked by preinjection of nonradiolabeled [Cysx]-exendin-4 (p<0.05). Conclusion [18F]FBEM-[Cys40]-exendin-4 and [18F]FBEM-[Cys0]-exendin-4 have high affinity for GLP-1R and display similar in vitro cell internalization. The higher uptake into INS-1 xenograft tumors exhibited by [18F]FBEM-[Cys40]-exendin-4 suggests that this compound would be the better tracer for imaging GLP-1R.

Approaches to Improve the Pharmacokinetics of Radiolabeled Glucagon-Like Peptide-1 Receptor Ligands Using Antagonistic Tracers

“…Among published GLP-1 receptor tracers, the fluorinated agonist [ 18 F]FBEM-[Cys 40 ]-exendin-4 showed a comparable tumor-tokidney ratio (4.94 at 2 h after injection) and in addition it had a better tumor-to-liver ratio than the iodinated tracer (12). This might suggest that fluorinated GLP-1 receptor antagonists could be worthwhile to study.…”

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

“…A new and promising family of G-proteincoupled receptors is the incretin receptor family (8,10,11). The imaging of tumors overexpressing the glucagonlike peptide 1 (GLP-1) receptor was proven to be successful in insulinoma preclinically (12)(13)(14)(15)(16)(17) and clinically (18,19). Recently, it was found that the second member of the incretin receptor family, the glucose-dependent insulinotropic polypeptide (GIP) receptor, is overexpressed in specific NETs.…”

PET of Glucagonlike Peptide Receptor Upregulation After Myocardial Ischemia or Reperfusion Injury

“…Exendin-4 shows a 53% amino acid homology with GLP-1 but is resistant to dipeptidyl-peptidase-IV attack and, consequently, has a much longer plasma half-life (19). Recently, we developed 2 novel PET probes, 18 F-FBEM-EM3106B and 18 F-FBEM-Cys 40 -exendin-4, for GLP-1R-targeted PET (20,21). In an INS-1 rat insulinoma xenograft model, both tracers showed high and receptorspecific tumor accumulation.…”