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Synthesis and biological evaluation of an 111In-labeled exendin-4 derivative as a single-photon emission computed tomography probe for imaging pancreatic β-cells
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2017-09-07 , DOI: 10.1016/j.bmc.2017.09.005
Hiroyuki Kimura , Naotaka Fujita , Kaori Kanbe , Hirokazu Matsuda , Hiroyuki Watanabe , Kenji Arimitsu , Hiroyuki Fujimoto , Keita Hamamatsu , Yusuke Yagi , Masahiro Ono , Nobuya Inagaki , Hideo Saji

A non-invasive method of pancreatic β-cell mass measurement is needed to enhance our understanding of the pathogenesis of diabetes, facilitate the early diagnosis of this disease, and promote the development of novel therapeutics. Here, we described the synthesis of a novel indium-111 (111In) exendin-4 derivative, [Lys12(In-BnDTPA-Ahx)]exendin-4, through a process involving isothiocyanate-benzyl-DTPA (BnDTPA) and 6-aminohexanoic acid (Ahx) attached to an ɛ-amino group at the lysine-12 residue. We further evaluated the potential use of this derivative as a SPECT probe for pancreatic β-cell imaging. An in vitro binding assay revealed that [Lys12(natIn-BnDTPA-Ahx)]exendin-4 has a high affinity for GLP-1 receptors (IC50 = 0.43 nM). In biodistribution experiments involving normal mice, high [Lys12(111In-BnDTPA-Ahx)]exendin-4 uptake was observed in the pancreas (21.8 ± 4.0 %ID/g) and was maintained for 2 h after injection. Pre-injection of excess exendin(9−39) markedly reduced the pancreatic uptake of [Lys12(111In-BnDTPA-Ahx)]exendin-4 (95.2%), indicating that the uptake of this tracer is specific and mediated by GLP-1 receptors. Ex vivo autoradiography experiments involving pancreatic sections from MIP-GFP mice confirmed the accumulation of [Lys12(111In-BnDTPA-Ahx)]exendin-4 in pancreatic β-cells. Finally, in mice, [Lys12(111In-BnDTPA-Ahx)]exendin-4 SPECT/CT yielded clear images of the pancreas at 30 min post-injection. In conclusion, SPECT with [Lys12(111In-BnDTPA-Ahx)]exendin-4 enables to visualize β-cells in vivo non-invasively.



中文翻译:

111 In标记的exendin-4衍生物的合成和生物学评估,作为单光子发射计算机断层摄影探头,用于胰腺β细胞成像

需要一种非侵入性的胰腺β细胞质量测量方法,以增强我们对糖尿病发病机制的了解,促进这种疾病的早期诊断并促进新型疗法的发展。在这里,我们描述了通过涉及异硫氰酸酯-苄基-DTPA(BnDTPA)和6的过程合成新型铟111(111 In)exendin-4衍生物[Lys 12(In-BnDTPA-Ahx)] exendin-4的方法。 -在赖氨酸-12残基的α-氨基上连接的-氨基己酸(Ahx)。我们进一步评估了该衍生物作为SPECT探针用于胰腺β细胞成像的潜在用途。的体外结合测定显示,[赖氨酸12NATIn-BnDTPA-Ahx)exendin-4对GLP-1受体具有很高的亲和力(IC 50  = 0.43 nM)。在涉及正常小鼠的生物分布实验中,在胰腺中观察到了高[Lys 12111 In-BnDTPA-Ahx)] exendin-4摄取(21.8±4.0%ID / g),并在注射后维持2 h。预注射过量的exendin(9-39)显着降低了[Lys 12111 In-BnDTPA-Ahx)] exendin-4(95.2%)的胰腺摄取,表明该示踪剂的摄取是特异性的,并由GLP介导-1受体。涉及MIP-GFP小鼠胰腺切片的离放射自显影实验证实了[Lys 12111In-BnDTPA-Ahx)] exendin-4在胰腺β细胞中。最后,在小鼠中,[Lys 12111 In-BnDTPA-Ahx)] exendin-4 SPECT / CT在注射后30分钟时产生了清晰的胰腺图像。总之,具有[Lys 12111 In-BnDTPA-Ahx)] exendin-4的SPECT能够非侵入性地可视化体内的β细胞。

更新日期:2017-09-07
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