Enhanced Specific Activity by Multichelation of Exendin-3 Leads To Improved Image Quality and In Vivo Beta Cell Imaging.
Enhanced Specific Activity by Multichelation of Exendin-3 Leads To Improved Image Quality and In Vivo Beta Cell Imaging.
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Exendin-3 多螯合增强的比活性可改善图像质量和体内 Beta 细胞成像。
DOI：
10.1021/acs.molpharmaceut.7b00853
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发表时间：
2018
影响因子：
4.9
通讯作者：
Gotthardt,Martin
中科院分区：
文献类型：
--
作者：
Joosten,Lieke;Brom,Maarten;Peeters,Hanneke;Heskamp,Sandra;Béhé,Martin;Boerman,Otto;Gotthardt,Martin
使用放射性标记的毒蜥外泌肽靶向胰高血糖素样肽 1 受体 (GLP-1R) 是一种有前途的非侵入性可视化和确定 β 细胞质量 (BCM) 的方法，这可能有助于揭示糖尿病的病理生理学。然而，低肽剂量时，β 细胞上的 GLP-1R 就会饱和，因为生理条件下表达的受体数量很少。因此，需要具有高比活性的示踪剂来灵敏地成像 BCM 的微小变化。在这里，我们描述了一种具有多种螯合剂的新型基于 exendin-3 的放射性示踪剂，并确定了其体内 beta 细胞成像的潜力。 Exendin-3 通过添加 C 端与 1、2 或 6 个 DTPA 部分缀合的 6 个赖氨酸残基进行修饰。所有化合物均用 111 In 标记，并使用 GLP-1R 表达细胞在体外测定其 GLP-1R 亲和力。在具有皮下表达GLP-1R的肿瘤(INS-1)的BALB/c裸鼠中检查111 In标记的示踪剂的体内行为。挪威棕色大鼠用于胰腺 BCM 的 SPECT 可视化。添加六个赖氨酸和六个 DTPA 残基（hexendin(40–45)）导致比活性增加 7 倍（从 0.73 GBq/nmol 到 5.54 GBq/nmol）。 IC50 值在 5.2 至 69.5 nM 之间变化。所有具有两个或六个赖氨酸和 DTPA 残基的化合物的受体亲和力均显着低于 [Lys40(DTPA)]exendin-3 (4.4 nM，p< 0.05)。小鼠体内的生物分布表明，添加六种赖氨酸和 DTPA 分子后，胰腺的摄取没有显着减少。与 [Lys40(DTPA)]exendin-3 相比，Hexendin(40–45) 在 Brown挪威大鼠胰腺中的绝对 111In 摄取增加了 6 倍（182.7 ± 42.3 kBq 与 28.8 ± 6.0 kBq，p< 0.001）。由于在相同肽剂量下实现了更高的计数率，使用 hexendin(40-45) 可以改善 SPECT 上胰腺的可视化。总之，hexendin(40-45) 通过 SPECT 显示出改善的胰腺可视化效果。该示踪剂有望灵敏且特异性地检测 BCM 的微小变化。
Glucagon-like peptide-1 receptor (GLP-1R) targeting using radiolabeled exendin is a promising approach to noninvasively visualize and determine beta cell mass (BCM), which could help to unravel the pathophysiology of diabetes. However, saturation of the GLP-1R on beta cells occurs at low peptide doses, since the number of receptors expressed under physiological conditions is low. Therefore, tracers with high specific activities are required to sensitively image small variations in BCM. Here, we describe a novel exendin-3-based radiotracer with multiple chelators and determine its potential forin vivobeta cell imaging. Exendin-3 was modified by adding six lysine residues C-terminally conjugated with one, two, or six DTPA moieties. All compounds were labeled with111In and their GLP-1R affinity was determinedin vitrousing GLP-1R expressing cells. Thein vivobehavior of the111In-labeled tracers was examined in BALB/c nude mice with a subcutaneous GLP-1R expressing tumor (INS-1). Brown Norway rats were used for SPECT visualization of the pancreatic BCM. Addition of six lysine and six DTPA residues (hexendin(40–45)) resulted in a 7-fold increase in specific activity (from 0.73 GBq/nmol to 5.54 GBq/nmol). IC50values varied between 5.2 and 69.5 nM. All compounds with two or six lysine and DTPA residues had a significantly lower receptor affinity than [Lys40(DTPA)]exendin-3 (4.4 nM,p< 0.05). The biodistribution in mice revealed no significant decrease in pancreatic uptake after addition of six lysine and DTPA molecules. Hexendin(40–45) showed a 6-fold increase in absolute111In uptake in the pancreas of Brown Norway rats compared to [Lys40(DTPA)]exendin-3 (182.7 ± 42.3 kBq vs 28.8 ± 6.0 kBq,p< 0.001). Visualization of the pancreas on SPECT was improved using hexendin(40–45), due to the higher count rate, achieved at the same peptide dose. In conclusion, hexendin(40–45) showed an improved visualization of the pancreas with SPECT. This tracer holds promise to sensitively and specifically detect small variations in BCM.