Approaches to Improve the Pharmacokinetics of Radiolabeled Glucagon-Like Peptide-1 Receptor Ligands Using Antagonistic Tracers
Approaches to Improve the Pharmacokinetics of Radiolabeled Glucagon-Like Peptide-1 Receptor Ligands Using Antagonistic Tracers
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DOI：
10.2967/jnumed.115.168948
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发表时间：
2016-08-01
影响因子：
9.3
通讯作者：
Maecke, Helmut R.
中科院分区：
文献类型：
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作者：
Rylova, Svetlana N.;Waser, Beatrice;Maecke, Helmut R.
胰高血糖素样肽-1（GLP-1）受体是胰腺β细胞团成像和良性胰岛素瘤检测的重要生物标志物。使用GLP-1受体拮抗剂，我们旨在消除所有GLP-1受体激动剂报告的胰岛素相关副作用。此外，使用非残留示踪剂I-125-Bolton-Hunter-Exendin（9-39）NH 2（I-125-BH-Ex（9-39）NH 2），我们旨在降低肾脏的高摄取，从而能够更好地检测胰腺尾部和头部的胰岛素瘤。研究方法：将在位置Lys（27）和Lys（40）处用DOTA或NODAGA螯合剂修饰并用Ga-68和I-125-BH-Ex（9 - 39）NH 2标记的基于Ex（9 - 39）NH 2的拮抗剂的亲和力和生物分布与参考GLP-1受体激动剂[Nle（14），Lys（40）（Ahx-DOTA-Ga-68）NH 2]Ex-4进行比较。采用放射自显影法，以I-125-GLP-1（7-36）NH 2作为放射性配体，在人体组织上测定50%抑制浓度（IC 50）值。在荷大鼠Ins-1 E肿瘤的裸鼠中研究药物动力学和PET成像。结果如下：DOTA和NODAGA螯合剂在Ex（9-39）NH 2的位置Lys（27）和Lys（40）处的缀合导致体外对GLP-1受体的亲和力的明显损失。在研究的拮抗剂中，[Lys（40）（NODAGA-natGa）NH 2] Ex（9-39）显示出最低的IC 50值（46.7 +/- 16.3 nM）。参比激动剂[Nle（14），Lys（40）（Ahx-DOTA）NH 2]Ex-4表现出最高的亲和力（IC 50 = 0.9 +/- 0.3 nM）。[Nle（14），Lys（40）]的生物分布注射后1小时，[（Ahx-DOTA- Ga-68）NH 2] Ex-4在Ins-1 E肿瘤中显示出40.2 +/-8.2%注射活性/克（%IA/g）摄取，在胰腺中显示出12.5 +/-2.2%IA/g，在肾脏中显示出235.8 +/-17.0%IA/g，肿瘤与血液和肿瘤与肾脏的比率分别为100.52和0.17。注射后1小时，[Lys（40）（NODAGA-68 Ga）NH 2] Ex（9-39）的生物分布显示Ins-1 E肿瘤中仅2.2 +/-0.2% IA/g摄取，胰腺中为1.0 +/-0.1% IA/g，肾脏中为78.4 +/-8.5% IA/g，肿瘤与血液和肿瘤与肾脏的比率分别为7.33和0.03。相比之下，I-125-BH-Ex（9-39）NH 2显示与激动剂相当的肿瘤摄取（42.5 +/-8.1%IA/g），并且在注射后1小时在胰腺中显示28.8 +/-5.1%IA/g。正如我们假设的那样，I-125-BH-Ex（9-39）NH 2的肾脏摄取较低，注射后1小时仅为12.1 +/-1.4% IA/g。I-125-BH-Ex（9-39）NH 2的肿瘤-肾脏比提高了20倍。结论：碘化Ex（9-39）NH 2可能是GLP-1受体在体表达显像的一种有前景的示踪剂。由于I-125-BH-Ex（9-39）NH 2的肿瘤-肾脏比提高了20倍，因此在糖尿病患者的胰岛素瘤检测和β细胞团成像中可提供更高的灵敏度。需要对I-124-BH-Ex（9-39）NH 2进行进一步研究。
The glucagon-like peptide-1 (GLP-1) receptors are important biomarkers for imaging pancreatic beta-cell mass and detection of benign insulinomas. Using GLP-1 receptor antagonists, we aimed to eliminate the insulin-related side effects reported for all GLP-1 receptor agonists. Additionally, using a nonresidualizing tracer, I-125-Bolton-Hunter-Exendin(9-39) NH2 (I-125-BH-Ex(9-39) NH2), we aimed to reduce the high kidney uptake, enabling a better detection of insulinomas in the tail and head of the pancreas. Methods: The affinity and biodistribution of Ex(9-39) NH2-based antagonists, modified with DOTA or NODAGA chelators at positions Lys(27) and Lys(40) and labeled with Ga-68 and I-125-BH-Ex(9-39) NH2, were compared with the reference GLP-1 receptor agonist [Nle(14), Lys(40)(Ahx-DOTA-Ga-68) NH2]Ex-4. The inhibitory concentration of 50% (IC50) values were determined using autoradiography on human tissues with I-125-GLP-1(7-36)NH2 as a radioligand. Pharmacokinetics and PET imaging were studied in nude mice bearing rat Ins-1E tumors. Results: Conjugation of DOTA and NODAGA chelators at positions Lys(27) and Lys(40) of Ex(9-39)NH2 resulted in a distinct loss of affinity toward GLP-1 receptor in vitro. Among the studied antagonists, [Lys(40)(NODAGA-natGa)NH2] Ex(9-39) showed the lowest IC50 value (46.7 +/- 16.3 nM). The reference agonist [Nle(14), Lys(40)(Ahx-DOTA)NH2]Ex-4 demonstrated the highest affinity (IC50 = 0.9 +/- 0.3 nM). Biodistribution of [Nle(14), Lys(40)(Ahx-DOTA- Ga-68)NH2] Ex-4 at 1 h after injection demonstrated 40.2 +/- 8.2 percentage injected activity per gram (%IA/g) uptake in Ins-1E tumor, 12.5 +/- 2.2 % IA/g in the pancreas, and 235.8 +/- 17.0 % IA/g in the kidney, with tumor-to-blood and tumor-to-kidney ratios of 100.52 and 0.17, respectively. Biodistribution of [Lys(40)(NODAGA-68Ga)NH2] Ex(9-39) showed only 2.2 +/- 0.2 %IA/g uptake in Ins-1E tumor, 1.0 +/- 0.1 % IA/g in the pancreas, and 78.4 +/- 8.5 % IA/g in the kidney at 1 h after injection, with tumor-to-blood and tumor-to-kidney ratios of 7.33 and 0.03, respectively. In contrast, I-125-BH-Ex(9-39)NH2 showed tumor uptake (42.5 +/- 8.1 % IA/g) comparable to the agonist and 28.8 +/- 5.1 % IA/g in the pancreas at 1 h after injection. As we hypothesized, the kidney uptake of I-125-BH-Ex(9-39)NH2 was low, only 12.1 +/- 1.4 % IA/g at 1 h after injection. The tumor-to-kidney ratio of I-125-BH-Ex(9-39)NH2 was improved 20-fold. Conclusion: Our results suggest that iodinated Ex(9-39)NH2 may be a promising tracer for imaging GLP-1 receptor expression in vivo. Because of the 20-fold improved tumorto- kidney ratio I-125-BH-Ex(9-39)NH2 may offer higher sensitivity in the detection of insulinomas and imaging of beta-cell mass in diabetic patients. Further studies with I-124-BH-Ex(9-39)NH2 are warranted.