Optimization of a Collagen-Targeted PET Probe for Molecular Imaging of Pulmonary Fibrosis
Optimization of a Collagen-Targeted PET Probe for Molecular Imaging of Pulmonary Fibrosis
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DOI：
10.2967/jnumed.117.193532
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发表时间：
2017-12-01
影响因子：
9.3
通讯作者：
Caravan, Peter
中科院分区：
文献类型：
--
作者：
Desogere, Pauline;Tapias, Luis F.;Caravan, Peter
对于一种简单、准确、无创、定量和高分辨率的成像模式，在早期阶段检测肺纤维化并监测疾病进展，存在很大的未满足的需求。胶原蛋白的过度表达是器官纤维化的标志。在这里，我们描述了优化的胶原靶向PET探针分期肺纤维化。方法：合成六种肽，与铜螯合剂缀合，并用Cu-64进行放射性标记。在基于板的测定中测量每种探针的胶原亲和力。在健康大鼠体内研究了探针的药代动力学和代谢稳定性。在博来霉素诱导的纤维化的小鼠模型中使用PET成像评估这些探针检测和分期体内肺纤维化的能力。结果：所有探针均表现出低微摩尔范围内的亲和力（1.6 μ M，Kd，14.6 μ M），并具有快速的血液清除。这些探针在博来霉素治疗小鼠的肺中的摄取比假治疗小鼠高2至8倍，而在博来霉素治疗小鼠和假治疗小鼠之间的其他器官中的分布相似。探针Cu-64-CBP 7显示纤维化肺中的最高摄取和最高靶与背景比。与其他探针相比，Cu-64-CBP 7的优越性可追溯到更高的代谢稳定性。通过与非结合异构体的比较，证实了Cu-64-CBP 7对胶原蛋白的特异性。结论：Cu-64-CBP 7是一种有希望的肺纤维化体内成像候选物。
There is a large unmet need for a simple, accurate, noninvasive, quantitative, and high-resolution imaging modality to detect lung fibrosis at early stage and to monitor disease progression. Overexpression of collagen is a hallmark of organ fibrosis. Here, we describe the optimization of a collagen-targeted PET probe for staging pulmonary fibrosis. Methods: Six peptides were synthesized, conjugated to a copper chelator, and radiolabeled with Cu-64. The collagen affinity of each probe was measured in a plate-based assay. The pharmacokinetics and metabolic stability of the probes were studied in healthy rats. The capacity of these probes to detect and stage pulmonary fibrosis in vivo was assessed in a mouse model of bleomycin-induced fibrosis using PET imaging. Results: All probes exhibited affinities in the low micromolar range (1.6 mu M, Kd, 14.6 mu M) and had rapid blood clearance. The probes showed 2-to 8-fold-greater uptake in the lungs of bleomycin-treated mice than sham-treated mice, whereas the distribution in other organs was similar between bleomycin-treated and sham mice. The probe Cu-64-CBP7 showed the highest uptake in fibrotic lungs and the highest target-to-background ratios. The superiority of Cu-64-CBP7 was traced to a much higher metabolic stability compared with the other probes. The specificity of Cu-64-CBP7 for collagen was confirmed by comparison with a nonbinding isomer. Conclusion: Cu-64-CBP7 is a promising candidate for in vivo imaging of pulmonary fibrosis.