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

Kiesewetter, Dale; Gao, Haokao; Ma, Ying; Niu, Gang; Quan, Qimeng; Guo, Ning; Chen, Xiaoyuan
March 2012
European Journal of Nuclear Medicine & Molecular Imaging;Mar2012, Vol. 39 Issue 3, p463
Academic Journal
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 F radioligands for GLP-1R by the reaction of [F]FBEM, a maleimide prosthetic group, with [Cys] and [Cys] 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 [F]FBEM-[Cys]-exendin-4 analogs were obtained in good yield (34.3 ± 3.4%, n = 11), based on the starting compound [F]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, [F]FBEM-[Cys]-exendin-4, had higher affinity for INS-1 tumor cells (IC 1.11 ± 0.057 nM) and higher tumor uptake (25.25 ± 3.39 %ID/g at 1 h) than the N-terminal isomer, [F]FBEM-[Cys]-exendin-4 (IC 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 [Cys]-exendin-4 ( p < 0.05). Conclusion: [F]FBEM-[Cys]-exendin-4 and [F]FBEM-[Cys]-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 [F]FBEM-[Cys]-exendin-4 suggests that this compound would be the better tracer for imaging GLP-1R.


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