18F 标记的 exendin-4 类似物用于胰岛素瘤中 GLP-1 的 PET 成像。

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

机构信息

Laboratory of Molecular Imaging and Nanomedicine (LOMIN), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), Bethesda, MD 20892, USA.

出版信息

Eur J Nucl Med Mol Imaging. 2012 Mar;39(3):463-73. doi: 10.1007/s00259-011-1980-0. Epub 2011 Dec 15.

DOI:10.1007/s00259-011-1980-0

PMID:22170321

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3617488/

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 (18)F radioligands for GLP-1R by the reaction of [(18)F]FBEM, a maleimide prosthetic group, with [Cys(0)] and [Cys(40)] 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 [(18)F]FBEM-[Cys(x)]-exendin-4 analogs were obtained in good yield (34.3 ± 3.4%, n = 11), based on the starting compound [(18)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, [(18)F]FBEM-[Cys(40)]-exendin-4, had higher affinity for INS-1 tumor cells (IC(50) 1.11 ± 0.057 nM) and higher tumor uptake (25.25 ± 3.39 %ID/g at 1 h) than the N-terminal isomer, [(18)F]FBEM-[Cys(0)]-exendin-4 (IC(50) 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(x)]-exendin-4 (p < 0.05).

CONCLUSION

[(18)F]FBEM-[Cys(40)]-exendin-4 and [(18)F]FBEM-[Cys(0)]-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 [(18)F]FBEM-[Cys(40)]-exendin-4 suggests that this compound would be the better tracer for imaging GLP-1R.

摘要

目的

胰高血糖素样肽 1（GLP-1）是一种肠促胰岛素肽，可在口服营养物质后增强葡萄糖刺激的胰岛素释放。其信息通过一种称为 GLP-1R 的 G 蛋白偶联受体传递，该受体与胰腺β细胞共存。GLP-1 系统负责增强胰岛素释放、抑制胰高血糖素产生、抑制肝糖异生、抑制胃动力和抑制食欲。胰岛素瘤中 GLP-1R 的丰富度和 GLP-1 在心血管系统中的活性使 GLP-1R 成为分子成像的目标。

方法

我们通过 [(18)F]FBEM，一种马来酰亚胺前体基团，与 exendin-4 的 [Cys(0)]和 [Cys(40)]类似物反应，制备了用于 GLP-1R 的 (18)F 放射性配体。在裸鼠的 INS-1 异种移植模型中，测定了所得化合物的结合亲和力、细胞摄取和内化、体外稳定性以及摄取和摄取特异性。

结果

基于起始化合物 [(18)F]FBEM)，[(18)F]FBEM-[Cys(x)]-exendin-4 类似物以良好的收率（34.3±3.4%，n=11）获得，并且在合成结束时具有 45.51±16.28GBq/μmol（1.23±0.44Ci/μmol，n=7）的特定放射性活度。C 末端异构体，[(18)F]FBEM-[Cys(40)]-exendin-4，对 INS-1 肿瘤细胞具有更高的亲和力（IC50 为 1.11±0.057nM）和更高的肿瘤摄取率（1 小时时为 25.25±3.39%ID/g）比 N 末端异构体，[(18)F]FBEM-[Cys(0)]-exendin-4（IC50 为 2.99±0.06nM，摄取率为 1 小时时为 7.20±1.26%ID/g）。两种异构体进入 INS-1 肿瘤、胰腺、胃和肺的摄取均可通过预注射非放射性 [Cys(x)]-exendin-4 阻断（p<0.05）。

结论

[(18)F]FBEM-[Cys(40)]-exendin-4 和 [(18)F]FBEM-[Cys(0)]-exendin-4 对 GLP-1R 具有高亲和力，并显示出相似的体外细胞内化。[(18)F]FBEM-[Cys(40)]-exendin-4 在 INS-1 异种移植肿瘤中摄取率更高，表明该化合物将是用于 GLP-1R 成像的更好示踪剂。