Zhang Liang, Thurber Greg M
Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA.
Department of Biomedical Engineering, University of Michigan, 2800 Plymouth Rd., Ann Arbor, MI, 48109, USA.
Mol Imaging Biol. 2016 Feb;18(1):79-89. doi: 10.1007/s11307-015-0880-2.
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, down-regulation of the GLP-1 receptor and non-specific background uptake result in a higher target-to-background ratio for fast-clearing agents.
对β细胞量（BCM）进行定量分子成像将有助于1型糖尿病的早期检测和治疗监测。胰高血糖素样肽-1（GLP-1）受体因其对β细胞的特异性和细胞表面定位而成为一个有吸引力的靶点。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，它们在分子量、结合亲和力和血浆清除率方面有所不同。对GLP-1受体内化率和体内受体表达进行了定量。
受体内化（体内每细胞54,000个受体）在几分钟内显著下降，降低了清除较慢药物的益处。多聚体和白蛋白结合探针分别有较高的肾脏和肝脏摄取。
缓慢的血浆清除率对GLP-1受体肽疗法有益。然而，对于基于艾塞那肽的胰岛成像，GLP-1受体的下调和非特异性背景摄取导致清除较快的药物具有更高的靶本比。
