基于 exendin-4 的放射性药物用于胰高血糖素样肽-1 受体 PET/CT 和 SPECT/CT。

Exendin-4-based radiopharmaceuticals for glucagonlike peptide-1 receptor PET/CT and SPECT/CT.

机构信息

Clinic and Institute of Nuclear Medicine, University Hospital Basel, Basel, Switzerland.

出版信息

J Nucl Med. 2010 Jul;51(7):1059-67. doi: 10.2967/jnumed.110.074914.

DOI:10.2967/jnumed.110.074914

PMID:20595511

Abstract

UNLABELLED

Strong overexpression of glucagonlike peptide-1 (GLP-1) receptors in human insulinoma provides an attractive target for imaging. The first clinical trials demonstrated that GLP-1 receptor SPECT/CT using [Lys(40)(Ahx [6-aminohexanoic acid]-DOTA-(111)In)NH(2)]-exendin-4 can localize hardly detectable insulinomas. However, [Lys(40)(Ahx-DOTA-(111)In)NH(2)]-exendin-4 imaging has drawbacks related to the use of (111)In in that it is costly and carries a relatively high radiation burden for the patient. The aim of this study was the preclinical evaluation of [Lys(40)(Ahx-DOTA-(68)Ga)NH(2)]-exendin-4 for PET/CT and [Lys(40)(Ahx-hydrazinonicotinamide [HYNIC]-(99m)Tc)NH(2)]-exendin-4 for SPECT/CT.

METHODS

Internalization, biodistribution, dosimetry, and imaging studies were performed in the Rip1Tag2 mouse model of pancreatic beta-cell carcinogenesis and compared with our gold standard [Lys(40)(Ahx-DOTA-(111)In)NH(2)]-exendin-4. Poly-glutamic acid and Gelofusine, a gelatin-based plasma expander, were used for renal uptake reduction studies.

RESULTS

The tumor uptake of [Lys(40)(Ahx-DOTA-(68)Ga)NH(2)]-exendin-4 was 205 +/- 59 percentage injected activity per gram of tissue at 4 h. Other GLP-1 receptor-positive organs showed more than 4.8 times lower radioactivity uptake. [Lys(40)(Ahx-HYNIC-(99m)Tc/ethylenediaminediacetic acid [EDDA])NH(2)]-exendin-4, compared with its (111)In- and (68)Ga-labeled sister compounds, showed significantly less tumor and organ uptake. The significantly lower tumor and organ uptake of [Lys(40)(Ahx-HYNIC-(99m)Tc/EDDA)NH(2)]-exendin-4 did not result in inferior tumor-to-organ ratios or reduced image quality. All radiopeptides tested showed a high tumor-to-background ratio, resulting in the visualization of small tumors (maximum diameter between 1.0 and 3.2 mm) by SPECT and PET. The only exception was the kidneys, which also showed high uptake. This uptake could be reduced by 49%-78% using poly-glutamic acid, Gelofusine, or a combination of the 2. The estimated effective radiation dose was 3.7 muSv/MBq for [Lys(40)(Ahx-HYNIC-(99m)Tc/EDDA)NH(2)]-exendin-4, which was 8 times less than that for [Lys(40)(Ahx-DOTA-(68)Ga)NH(2)]-exendin-4 and 43 times less than that for [Lys(40)(Ahx-DOTA-(111)In)NH(2)]-exendin-4.

CONCLUSION

These promising pharmacokinetic and imaging data show that [Lys(40)(Ahx-DOTA-(68)Ga)NH(2)]-exendin-4 and [Lys(40)(Ahx-HYNIC-(99m)Tc/EDDA)NH(2)]-exendin-4 are suitable candidates for clinical GLP-1 receptor imaging studies.

摘要

目的

在 Rip1Tag2 胰岛细胞瘤发生的小鼠模型中进行内化、生物分布、剂量测定和成像研究，并与我们的金标准 [Lys(40)(Ahx-DOTA-(111)In)NH(2)]-exendin-4 进行比较。聚谷氨酸和基于明胶的血浆扩张剂 Gelofusine 用于肾脏摄取减少研究。

结果

[Lys(40)(Ahx-DOTA-(68)Ga)NH(2)]-exendin-4 的肿瘤摄取率在 4 小时时为每克组织 205 +/- 59% 注射活性。其他 GLP-1 受体阳性器官的放射性摄取率高出 4.8 倍以上。与 [Lys(40)(Ahx-HYNIC-(99m)Tc/EDDA)NH(2)]-exendin-4 的 (111)In 和 (68)Ga 标记的姊妹化合物相比，[Lys(40)(Ahx-HYNIC-(99m)Tc/EDDA)NH(2)]-exendin-4 的肿瘤和器官摄取明显减少。[Lys(40)(Ahx-HYNIC-(99m)Tc/EDDA)NH(2)]-exendin-4 的肿瘤和器官摄取显著降低并未导致肿瘤与器官比值降低或图像质量降低。所有测试的放射性肽都显示出很高的肿瘤与背景比，从而通过 SPECT 和 PET 可视化小肿瘤（最大直径为 1.0 至 3.2 毫米）。唯一的例外是肾脏，其摄取也很高。使用聚谷氨酸、Gelofusine 或两者的组合，可将摄取量减少 49%-78%。估计 [Lys(40)(Ahx-HYNIC-(99m)Tc/EDDA)NH(2)]-exendin-4 的有效辐射剂量为 3.7 μSv/MBq，是 [Lys(40)(Ahx-HYNIC-(99m)Tc/EDDA)NH(2)]-exendin-4 的 8 倍，是 [Lys(40)(Ahx-DOTA-(68)Ga)NH(2)]-exendin-4 的 43 倍，是 [Lys(40)(Ahx-DOTA-(111)In)NH(2)]-exendin-4 的 135 倍。