Synthesis and in vivo behaviour of an exendin-4-based MRI probe capable of ß-cell-dependent contrast enhancement in the pancreas.
Synthesis and in vivo behaviour of an exendin-4-based MRI probe capable of ß-cell-dependent contrast enhancement in the pancreas.
复制标题
基于 exendin-4 的 MRI 探针的合成和体内行为，能够在胰腺中实现细胞依赖性对比度增强。
DOI：
10.1039/d0dt00332h
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Clough TJ
中科院分区：
文献类型：
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作者：
Clough TJ
全球糖尿病发病率正在上升，全球范围内对糖尿病的治疗消耗了越来越多的医疗保健支出。负责胰岛素分泌的胰腺β细胞在1型糖尿病中数量减少，在2型糖尿病中数量减少的程度更有限。然而，这两种疾病的损失程度和速度在患者之间是不同的，因此需要开发新的诊断工具，这些工具可以定量评估β细胞质量随时间的变化，并可能导致早期诊断和改进治疗。Exendin-4是胰高血糖素样肽1 （GLP-1）的有效类似物，与受体GLP-1R结合，其表达在β细胞中丰富。因此，GLP-1R在过去被用作各种内分泌胰腺成像方式的靶向探针的手段。然而，专为MRI造影剂设计的exendin-4偶联物是一个未开发的领域。在本研究中，我们报道了一种exendin-4-dota(ga)-Gd（III）复合物GdEx的合成和表征，以及它在健康和β-细胞缺失的C57BL/6J小鼠体内的行为。与无处不在的探针[Gd(dota)]−相比，GdEx被胰腺选择性摄取，在通过删除microRNA加工酶DICER引起的β-细胞丢失后，GdEx的积累明显减少。这些结果为基于类似化学方法的其他靶向MRI造影剂的开发开辟了途径。
Global rates of diabetes mellitus are increasing, and treatment of the disease consumes a growing proportion of healthcare spending across the world. Pancreatic β-cells, responsible for insulin production, decline in mass in type 1 and, to a more limited degree, in type 2 diabetes. However, the extent and rate of loss in both diseases differs between patients resulting in the need for the development of novel diagnostic tools, which could quantitatively assess changes in mass of β-cells over time and potentially lead to earlier diagnosis and improved treatments. Exendin-4, a potent analogue of glucagon-like-peptide 1 (GLP-1), binds to the receptor GLP-1R, whose expression is enriched in β-cells. GLP-1R has thus been used in the past as a means of targeting probes for a wide variety of imaging modalities to the endocrine pancreas. However, exendin-4 conjugates designed specifically for MRI contrast agents are an under-explored area. In the present work, the synthesis and characterization of an exendin-4-dota(ga)-Gd(III) complex, GdEx, is reported, along with its in vivo behaviour in healthy and in β-cell-depleted C57BL/6J mice. Compared to the ubiquitous probe, [Gd(dota)]−, GdEx shows selective uptake by the pancreas with a marked decrease in accumulation observed after the loss of β-cells elicited by deleting the microRNA processing enzyme, DICER. These results open up pathways towards the development of other targeted MRI contrast agents based on similar chemistry methodology.