Quantitative Impact of Plasma Clearance and Down-regulation on GLP-1 Receptor Molecular Imaging.
Quantitative Impact of Plasma Clearance and Down-regulation on GLP-1 Receptor Molecular Imaging.
复制标题
血浆清除率和下调对 GLP-1 受体分子成像的定量影响。
DOI：
10.1007/s11307-015-0880-2
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发表时间：
2016-02
影响因子：
3.1
通讯作者：
Thurber GM
中科院分区：
文献类型：
--
作者：
Zhang L;Thurber GM
β细胞群（β细胞团）的定量分子成像将使1型糖尿病的早期检测和治疗监测成为可能。胰高血糖素样肽-I（GLP-1）受体由于其β细胞特异性和细胞表面位置而成为有吸引力的靶标。我们定量研究了血浆清除率和受体内化对健康B6小鼠靶向效率的影响。合成了四种基于艾塞那肽的探针，其分子量、结合亲和力和血浆清除率各不相同。定量GLP-1受体内化率和体内受体表达。受体内化（体内54，000个受体/细胞）在几分钟内显著降低，降低了较慢清除剂的益处。多聚体和白蛋白结合探针分别具有较高的肾脏和肝脏摄取。缓慢的血浆清除对于GLP-1受体肽治疗剂是有益的。然而，对于基于exendin的胰岛成像，GLP-1受体的下调和非特异性背景摄取导致快速清除剂的TBR更高。
Quantitative molecular imaging of beta cell mass (BCM) would enable early detection and treatment monitoring of type-1 diabetes. The glucagon like peptide-1 (GLP-1) receptor is an attractive target due to its beta cell specificity and cell surface location. We quantitatively investigated the impact of plasma clearance and receptor internalization on targeting efficiency in healthy B6 mice. Four exenatide-based probes were synthesized that varied in molecular weight, binding affinity, and plasma clearance. The GLP-1 receptor internalization rate and in vivo receptor expression were quantified. Receptor internalization (54,000 receptors/cell in vivo) decreased significantly within minutes, reducing the benefit of a slower clearing agent. The multimers and albumin binding probes had higher kidney and liver uptake, respectively. Slow plasma clearance is beneficial for GLP-1 receptor peptide therapeutics. However, for exendin-based imaging of islets, downregulation of the GLP-1 receptor and non-specific background uptake result in a higher TBR for fast-clearing agents.