Blasi Francesco, Oliveira Bruno L, Rietz Tyson A, Rotile Nicholas J, Day Helen, Naha Pratap C, Cormode David P, Izquierdo-Garcia David, Catana Ciprian, Caravan Peter
Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and.
J Nucl Med. 2015 Jul;56(7):1088-93. doi: 10.2967/jnumed.115.157982. Epub 2015 May 14.
The diagnosis of deep venous thromboembolic disease is still challenging despite the progress of current thrombus imaging modalities and new diagnostic algorithms. We recently reported the high target uptake and thrombus imaging efficacy of the novel fibrin-specific PET probe (64)Cu-FBP8. Here, we tested the feasibility of (64)Cu-FBP8 PET to detect source thrombi and culprit emboli after deep vein thrombosis and pulmonary embolism (DVT-PE). To support clinical translation of (64)Cu-FBP8, we performed a human dosimetry estimation using time-dependent biodistribution in rats.
Sprague-Dawley rats (n = 7) underwent ferric chloride application on the femoral vein to trigger thrombosis. Pulmonary embolism was induced 30 min or 2 d after DVT by intrajugular injection of a preformed blood clot labeled with (125)I-fibrinogen. PET imaging was performed to detect the clots, and SPECT was used to confirm in vivo the location of the pulmonary emboli. Ex vivo γ counting and histopathology were used to validate the imaging findings. Detailed biodistribution was performed in healthy rats (n = 30) at different time points after (64)Cu-FBP8 administration to estimate human radiation dosimetry. Longitudinal whole-body PET/MR imaging (n = 2) was performed after (64)Cu-FBP8 administration to further assess radioactivity clearance.
(64)Cu-FBP8 PET imaging detected the location of lung emboli and venous thrombi after DVT-PE, revealing significant differences in uptake between target and background tissues (P < 0.001). In vivo SPECT imaging and ex vivo γ counting confirmed the location of the lung emboli. PET quantification of the venous thrombi revealed that probe uptake was greater in younger clots than in older ones, a result confirmed by ex vivo analyses (P < 0.001). Histopathology revealed an age-dependent reduction of thrombus fibrin content (P = 0.006), further supporting the imaging findings. Biodistribution and whole-body PET/MR imaging showed a rapid, primarily renal, body clearance of (64)Cu-FBP8. The effective dose was 0.021 mSv/MBq for males and 0.027 mSv/MBq for females, supporting the feasibility of using (64)Cu-FBP8 in human trials.
We showed that (64)Cu-FBP8 PET is a feasible approach to image DVT-PE and that radiogenic adverse health effects should not limit the clinical translation of (64)Cu-FBP8.
尽管目前血栓成像模式和新的诊断算法取得了进展，但深静脉血栓栓塞性疾病的诊断仍然具有挑战性。我们最近报道了新型纤维蛋白特异性PET探针（64）Cu-FBP8的高靶点摄取和血栓成像效果。在此，我们测试了（64）Cu-FBP8 PET检测深静脉血栓形成和肺栓塞（DVT-PE）后源血栓和罪魁祸首栓子的可行性。为支持（64）Cu-FBP8的临床转化，我们利用大鼠体内随时间变化的生物分布进行了人体剂量学估计。
对7只Sprague-Dawley大鼠的股静脉应用氯化铁以引发血栓形成。在DVT后30分钟或2天，通过颈内静脉注射用（125）I-纤维蛋白原标记的预制血凝块诱导肺栓塞。进行PET成像以检测血凝块，并使用SPECT在体内确认肺栓塞的位置。体外γ计数和组织病理学用于验证成像结果。在给予（64）Cu-FBP8后的不同时间点，对30只健康大鼠进行详细的生物分布研究，以估计人体辐射剂量学。在给予（64）Cu-FBP8后进行纵向全身PET/MR成像（n = 2），以进一步评估放射性清除情况。
（64）Cu-FBP8 PET成像检测到DVT-PE后肺栓塞和静脉血栓的位置，显示靶点和背景组织之间的摄取存在显著差异（P < 0.001）。体内SPECT成像和体外γ计数证实了肺栓塞的位置。静脉血栓的PET定量显示，年轻血栓中的探针摄取量高于年老血栓，体外分析证实了这一结果（P < 0.001）。组织病理学显示血栓纤维蛋白含量随年龄增长而降低（P = 0.006），进一步支持了成像结果。生物分布和全身PET/MR成像显示（64）Cu-FBP8在体内迅速清除，主要通过肾脏。男性的有效剂量为0.021 mSv/MBq，女性为0.027 mSv/MBq，这支持了在人体试验中使用（64）Cu-FBP8的可行性。
我们表明（64）Cu-FBP8 PET是一种可行的DVT-PE成像方法，放射性对健康的不良影响不应限制（64）Cu-FBP8的临床转化
