68Ga-labelled-exendin-4: New GLP1R targeting agents for imaging pancreatic β-cell and insulinoma,Nuclear Medicine and Biology

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68Ga-labelled-exendin-4: New GLP1R targeting agents for imaging pancreatic β-cell and insulinoma
Nuclear Medicine and Biology ( IF 3.6 ) Pub Date : 2021-10-09 , DOI: 10.1016/j.nucmedbio.2021.10.001
Linlin Li ₁ , Ruiyue Zhao ₁ , Haiyan Hong ₁ , Guangwen Li ₂ , Yan Zhang ₂ , Yang Luo ₁ , Zhihao Zha ₃ , Jinxia Zhu ₂ , Jinping Qiao ₁ , Lin Zhu ₁ , Hank F Kung ₃

Affiliation

Objective

Glucagon-like peptide-1 receptor (GLP1R) specifically expressed on the surface of pancreatic β-cells and insulinoma, is a potential biomarker for imaging β-cell mass (BCM). In this study, two new ⁶⁸Ga-labelled GLP1R targeting agents were prepared and their biological properties for imaging BCM and insulinoma were evaluated.

Methods

[⁶⁸Ga]Ga-HBED-CC-MAL-Cys³⁹-exendin-4 ([⁶⁸Ga]Ga-4) and its dimer ([⁶⁸Ga]Ga-5) were synthesized from corresponding precursors. Cell uptake studies were evaluated in INS-1 cells. Biodistribution and microPET studies were performed in male normal Sprague-Dawley rats, diabetic rats and insulinoma xenograft NOD/SCID mice.

Results

[⁶⁸Ga]Ga-4 and [⁶⁸Ga]Ga-5 were efficiently radiolabelled by a simple one-step reaction without purification leading to high radiochemical yields and radiochemical purities (both >95%, decay corrected, n = 6, molar activity 15 GBq/μmol). They both showed excellent stability (~95%) in phosphate-buffered saline, pH 7.4, and in rat serum (~90%) for 2 h. Biodistribution studies and small animal PET/CT imaging showed that [⁶⁸Ga]Ga-4 displayed specific uptake in rat pancreas and mouse insulinoma, and a reduced uptake in the pancreas of diabetic rat was observed (~62% reduction). Notably, it exhibited a rapid time-to-peak pancreatic uptake (0.96 ± 0.19%ID/g in 15 min) and fast clearance from the kidney (42% clearance in 30 min). Results suggested a favorable in vivo kinetics for human imaging studies.

Conclusions

[⁶⁸Ga]Ga-4 targeting GLP1R of pancreatic β-cells may be a potentially useful PET agent and a suitable candidate for further structural modification studies. This agent has demonstrated several advantages, rapid time-to-peak pancreatic uptake and faster clearance from the kidney, factors may enhance diagnosis of diabetes and insulinoma.

中文翻译：

68Ga 标记的 exendin-4：用于胰腺 β 细胞和胰岛素瘤成像的新型 GLP1R 靶向剂

客观的

胰高血糖素样肽 1 受体 (GLP1R) 特异性表达于胰腺 β 细胞和胰岛素瘤表面，是 β 细胞团 (BCM) 成像的潜在生物标志物。在本研究中，制备了两种新型⁶⁸ Ga 标记的 GLP1R 靶向剂，并评估了它们对 BCM 和胰岛素瘤成像的生物学特性。

方法

[ ⁶⁸ Ga]Ga-HBED-CC-MAL-Cys ³⁹ -exendin-4 ([ ⁶⁸ Ga]Ga- 4 ) 及其二聚体([ ⁶⁸ Ga]Ga- 5 ) 由相应的前体合成。在 INS-1 细胞中评估细胞摄取研究。在雄性正常 Sprague-Dawley 大鼠、糖尿病大鼠和胰岛素瘤异种移植 NOD/SCID 小鼠中进行了生物分布和 microPET 研究。

结果

[ ⁶⁸ Ga]Ga- 4和 [ ⁶⁸ Ga]Ga- 5通过简单的一步反应进行有效放射性标记，无需纯化，从而实现高放射化学产率和放射化学纯度（均为 >95%，衰减校正， n = 6，摩尔活度） 15GBq/μmol）。它们在 pH 7.4 的磷酸盐缓冲盐水和大鼠血清中 (~90%) 2 小时均表现出优异的稳定性 (~95%)。生物分布研究和小动物PET/CT成像表明，[ ⁶⁸ Ga]Ga- 4在大鼠胰腺和小鼠胰岛素瘤中显示出特异性摄取，并且在糖尿病大鼠的胰腺中观察到摄取减少（减少约62%）。值得注意的是，它表现出快速的胰腺摄取峰值时间（15 分钟内 0.96 ± 0.19%ID/g）和快速从肾脏清除（30 分钟内清除 42%）。结果表明，其体内动力学有利于人体成像研究。