Blasi Francesco, Oliveira Bruno L, Rietz Tyson A, Rotile Nicholas J, Day Helen, Looby Richard J, Ay Ilknur, Caravan Peter
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, Massachusetts.
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, Massachusetts
J Nucl Med. 2014 Jul;55(7):1157-63. doi: 10.2967/jnumed.113.136275. Epub 2014 May 1.
Thrombus formation plays a major role in cardiovascular diseases, but noninvasive thrombus imaging is still challenging. Fibrin is a major component of both arterial and venous thrombi and represents an ideal candidate for imaging of thrombosis. Recently, we showed that (64)Cu-DOTA-labeled PET probes based on fibrin-specific peptides are suitable for thrombus imaging in vivo; however, the metabolic stability of these probes was limited. Here, we describe 4 new probes using either (64)Cu or aluminum fluoride (Al(18)F) chelated to 2 NOTA derivatives.
Probes were synthesized using a known fibrin-specific peptide conjugated to either NODAGA (FBP8, FBP10) or NOTA-monoamide (FBP9, FBP11) as chelators, followed by labeling with (64)Cu (FBP8 and FBP9) or Al(18)F (FBP10 and FBP11). PET imaging efficacy, pharmacokinetics, biodistribution, and metabolic stability were assessed in a rat model of arterial thrombosis.
All probes had similar nanomolar affinity (435-760 nM) for the soluble fibrin fragment DD(E). PET imaging allowed clear visualization of thrombus by all probes, with a 5-fold or higher thrombus-to-background ratio. Compared with the previous DOTA derivative, the new (64)Cu probes FBP8 and FBP9 showed substantially improved metabolic stability (>85% intact in blood at 4 h after injection), resulting in high uptake at the target site (0.5-0.8 percentage injected dose per gram) that persisted over 5 h, producing increasingly greater target-to-background ratios. The thrombus uptake was 5- to 20-fold higher than the uptake in the contralateral artery, blood, muscle, lungs, bone, spleen, large intestine, and heart at 2 h after injection and 10- to 40-fold higher at 5 h. The Al(18)F derivatives FBP10 and FBP11 were less stable, in particular the NODAGA conjugate (FBP10, <30% intact in blood at 4 h after injection), which showed high bone uptake and low thrombus-to-background ratios that decreased over time. The high thrombus-to-contralateral ratios for all probes were confirmed by ex vivo biodistribution and autoradiography. The uptake in the liver (<0.5 percentage injected dose per gram), kidneys, and blood were similar for all tracers, and they all showed predominant renal clearance.
FBP8, FBP9, and FBP11 showed excellent metabolic stability and high thrombus-to-background ratios and represent promising candidates for imaging of thrombosis in vivo.
血栓形成在心血管疾病中起主要作用，但无创血栓成像仍然具有挑战性。纤维蛋白是动脉和静脉血栓的主要成分，是血栓成像的理想候选物。最近，我们表明基于纤维蛋白特异性肽的（64）Cu-DOTA标记的PET探针适用于体内血栓成像；然而，这些探针的代谢稳定性有限。在此，我们描述了4种新探针，它们使用（64）Cu或氟化铝（Al（18）F）螯合到2种NOTA衍生物上。
使用与NODAGA（FBP8、FBP10）或NOTA-单酰胺（FBP9、FBP11）作为螯合剂共轭的已知纤维蛋白特异性肽合成探针，然后用（64）Cu（FBP8和FBP9）或Al（18）F（FBP10和FBP11）标记。在动脉血栓形成的大鼠模型中评估PET成像效果、药代动力学、生物分布和代谢稳定性。
所有探针对可溶性纤维蛋白片段DD（E）具有相似的纳摩尔亲和力（435-760 nM）。PET成像使所有探针都能清晰地观察到血栓，血栓与背景的比率为5倍或更高。与先前的DOTA衍生物相比，新的（64）Cu探针FBP8和FBP9显示出显著改善的代谢稳定性（注射后4小时血液中>85%完整），导致靶部位的高摄取（每克注射剂量的0.5-0.8%）持续超过5小时，产生越来越大的靶与背景比率。注射后2小时，血栓摄取比注射后对侧动脉、血液、肌肉、肺、骨、脾、大肠和心脏中的摄取高5至20倍，5小时时高10至40倍。Al（18）F衍生物FBP10和FBP11稳定性较差，特别是NODAGA共轭物（FBP10，注射后4小时血液中<30%完整），其显示出高骨摄取和低血栓与背景比率，且随时间降低。所有探针的高血栓与对侧比率通过离体生物分布和放射自显影得到证实。所有示踪剂在肝脏（每克注射剂量<0.5%）、肾脏和血液中的摄取相似，并且它们都显示出主要的肾脏清除。
FBP8、FBP9和FBP11显示出优异的代谢稳定性和高血栓与背景比率，是体内血栓成像的有前途的候选物。
