Radioiodinated Exendin-4 Is Superior to the Radiometal-Labelled Glucagon-Like Peptide-1 Receptor Probes Overcoming Their High Kidney Uptake.
Radioiodinated Exendin-4 Is Superior to the Radiometal-Labelled Glucagon-Like Peptide-1 Receptor Probes Overcoming Their High Kidney Uptake.
复制标题
放射性固化的Exendin-4优于辐射标记的胰高血糖素样肽-1受体探针，探针克服了高肾脏的摄取。
DOI：
10.1371/journal.pone.0170435
复制
发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Rylova SN
中科院分区：
文献类型：
--
作者：
Läppchen T;Tönnesmann R;Eersels J;Meyer PT;Maecke HR;Rylova SN
GLP-1受体是良性胰岛素瘤术前成像和β细胞质量定量的理想靶点。现有的靶向GLP-1 R的临床示踪剂都是具有低比活性和非常高的肾脏摄取的激动剂。为了解决这些问题，我们评估了在临床中使用的在Tyr 40处放射性碘化的GLP-1 R激动剂Ex-4和拮抗剂Ex（9-39）与[Nle 14，Lys 40（Ahx-DOTA-68 Ga）NH 2]Ex-4（68 Ga-Ex-4）并排。用Ins-1 E细胞体外研究了[Nle 14，125 I-Tyr 40-NH 2]Ex-4和[Nle 14，125 I-Tyr 40-NH 2]Ex（9-39）的Kd、Bmax、内化和结合动力学。在携带Ins-1 E异种移植物的裸鼠中进行生物分布和成像研究。体外评价表明，[Nle 14，125 I-Tyr 40-NH 2]Ex-4激动剂与Ins-1 E细胞具有高亲和力结合，快速内化动力学在30 min后达到平台期。拮抗剂[Nle 14，125 I-Tyr 40-NH 2]Ex（9-39）未内化，且Kd值是激动剂的4倍。与[Nle 14，125 I-Tyr 40-NH 2]Ex（9-39）（其显示低的和瞬时的肿瘤摄取）相反，[Nle 14，125 I-Tyr 40-NH 2]Ex-4表现出优异的体内结合特性，肿瘤摄取与68 Ga-Ex-4的相同，但实质上较低的肾摄取，导致在1小时时肿瘤与肾的比率为9.7，而68 Ga-Ex-4为0.3。这两种肽在甲状腺和胃中的活性积累被irenat有效阻断，证实了体内脱碘是碘化肽的低肾脏保留背后的机制。与[Nle 14，Lys 40（Ahx-DOTA-68 Ga）NH 2] Ex-4的典型生物分布模式相比，[Nle 14，125 I-Tyr 40-NH 2] Ex-4的124 I同系物在PET成像研究中显示出相似的有利生物分布特征。我们的研究结果表明，碘化Ex-4是一个非常有前途的示踪剂良性胰岛素瘤的成像。它通过将[Nle 14，Lys 40（Ahx-DOTA-68 Ga）NH 2]Ex-4测量的肿瘤-肾脏比提高32倍来解决放射性同位素标记的示踪剂的高肾脏摄取的问题。
GLP-1 receptors are ideal targets for preoperative imaging of benign insulinoma and for quantifying the beta cell mass. The existing clinical tracers targeting GLP-1R are all agonists with low specific activity and very high kidney uptake. In order to solve those issues we evaluated GLP-1R agonist Ex-4 and antagonist Ex(9–39) radioiodinated at Tyr40 side by side with [Nle14,Lys40(Ahx-DOTA-68Ga)NH2]Ex-4 (68Ga-Ex-4) used in the clinic. The Kd, Bmax, internalization and binding kinetics of [Nle14,125I-Tyr40-NH2]Ex-4 and [Nle14,125I-Tyr40-NH2]Ex(9–39) were studied in vitro using Ins-1E cells. Biodistribution and imaging studies were performed in nude mice bearing Ins-1E xenografts. In vitro evaluation demonstrated high affinity binding of the [Nle14,125I-Tyr40-NH2]Ex-4 agonist to the Ins-1E cells with fast internalization kinetics reaching a plateau after 30 min. The antagonist [Nle14,125I-Tyr40-NH2]Ex(9–39) did not internalize and had a 4–fold higher Kd value compared to the agonist. In contrast to [Nle14,125I-Tyr40-NH2]Ex(9–39), which showed low and transient tumor uptake, [Nle14,125I-Tyr40-NH2]Ex-4 demonstrated excellent in vivo binding properties with tumor uptake identical to that of 68Ga-Ex-4, but substantially lower kidney uptake resulting in a tumor-to-kidney ratio of 9.7 at 1 h compared to 0.3 with 68Ga-Ex-4. Accumulation of activity in thyroid and stomach for both peptides, which was effectively blocked by irenat, confirms that in vivo deiodination is the mechanism behind the low kidney retention of iodinated peptides. The 124I congener of [Nle14,125I-Tyr40-NH2]Ex-4 demonstrated a similar favourable biodistribution profile in the PET imaging studies in contrast to the typical biodistribution pattern of [Nle14,Lys40(Ahx-DOTA-68Ga)NH2]Ex-4. Our results demonstrate that iodinated Ex-4 is a very promising tracer for imaging of benign insulinomas. It solves the problem of high kidney uptake of the radiometal-labelled tracers by improving the tumor-to-kidney ratio measured for [Nle14,Lys40(Ahx-DOTA-68Ga)NH2]Ex-4 by 32 fold.