Ay Ilknur, Blasi Francesco, Rietz Tyson A, Rotile Nicholas J, Kura Sreekanth, Brownell Anna Liisa, Day Helen, Oliveira Bruno L, Looby Richard J, Caravan Peter
From the Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA.
Circ Cardiovasc Imaging. 2014 Jul;7(4):697-705. doi: 10.1161/CIRCIMAGING.113.001806. Epub 2014 Apr 28.
Fibrin is a major component of arterial and venous thrombi and represents an ideal candidate for molecular imaging of thrombosis. Here, we describe imaging properties and target uptake of a new fibrin-specific positron emission tomographic probe for thrombus detection and therapy monitoring in 2 rat thrombosis models.
The fibrin-binding probe FBP7 was synthesized by conjugation of a known short cyclic peptide to a cross-bridged chelator (CB-TE2A), followed by labeling with copper-64. Adult male Wistar rats (n=26) underwent either carotid crush injury (mural thrombosis model) or embolic stroke (occlusive thrombosis model) followed by recombinant tissue-type plasminogen activator treatment (10 mg/kg, IV). FBP7 detected thrombus location in both animal models with a high positron emission tomographic target-to-background ratio that increased over time (>5-fold at 30-90 minutes, >15-fold at 240-285 minutes). In the carotid crush injury animals, biodistribution analysis confirmed high probe uptake in the thrombotic artery (≈0.5%ID/g; >5-fold greater than blood and other tissues of the head and thorax). Similar results were obtained from ex vivo autoradiography of the ipsilateral versus contralateral carotid arteries. In embolic stroke animals, positron emission tomographic-computed tomographic imaging localized the clot in the internal carotid/middle cerebral artery segment of all rats. Time-dependent reduction of activity at the level of the thrombus was detected in recombinant tissue-type plasminogen activator-treated rats but not in vehicle-injected animals. Brain autoradiography confirmed clot dissolution in recombinant tissue-type plasminogen activator-treated animals, but enduring high thrombus activity in control rats.
We demonstrated that FBP7 is suitable for molecular imaging of thrombosis and thrombolysis in vivo and represents a promising candidate for bench-to-bedside translation.
纤维蛋白是动脉和静脉血栓的主要成分，是血栓分子成像的理想靶点。在此，我们描述了一种新型纤维蛋白特异性正电子发射断层扫描探针在两种大鼠血栓形成模型中用于血栓检测和治疗监测的成像特性及靶点摄取情况。
通过将一种已知的短环肽与一种交联螯合剂（CB-TE2A）偶联，随后用铜-64标记，合成了纤维蛋白结合探针FBP7。成年雄性Wistar大鼠（n = 26）接受颈动脉挤压损伤（壁血栓形成模型）或栓塞性中风（闭塞性血栓形成模型），随后给予重组组织型纤溶酶原激活剂治疗（10 mg/kg，静脉注射）。FBP7在两种动物模型中均能检测到血栓位置，正电子发射断层扫描的靶本底比值较高，且随时间增加（30 - 90分钟时>5倍，240 - 285分钟时>15倍）。在颈动脉挤压损伤的动物中，生物分布分析证实血栓形成的动脉中探针摄取量高（≈0.5%ID/g；比头部和胸部的血液及其他组织高>5倍）。同侧与对侧颈动脉的离体放射自显影也得到了类似结果。在栓塞性中风动物中，正电子发射断层扫描 - 计算机断层扫描成像将所有大鼠的血栓定位在内侧颈动脉/大脑中动脉段。在重组组织型纤溶酶原激活剂治疗的大鼠中检测到血栓部位的活性随时间降低，但在注射赋形剂的动物中未检测到。脑放射自显影证实重组组织型纤溶酶原激活剂治疗的动物中血栓溶解，但对照大鼠的血栓活性持续较高。
我们证明FBP7适用于体内血栓形成和溶栓的分子成像，是从实验室到临床转化的有前景的候选物。
