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Imaging of Chemotherapy-Induced Acute Cardiotoxicity with 18F-Labeled Lipophilic Cations.
The Journal of Nuclear Medicine ( IF 9.1 ) Pub Date : 2019-12-01 , DOI: 10.2967/jnumed.119.226787
Stuart P McCluskey 1, 2 , Anna Haslop 1 , Christopher Coello 2 , Roger N Gunn 2, 3 , Edward W Tate 1 , Richard Southworth 4 , Christophe Plisson 2 , Nicholas J Long 5 , Lisa A Wells 2
Affiliation  

Many chemotherapy agents are toxic to the heart, such that increasing numbers of cancer survivors are now living with the potentially lethal cardiovascular consequences of their treatment. Earlier and more sensitive detection of chemotherapy-induced cardiotoxicity may allow improved treatment strategies and increase long-term survival. Lipophilic cation PET tracers may be suitable for early detection of cardiotoxicity. This study aimed to evaluate an 18F-labeled lipophilic phosphonium cation, [1-(2-18F-fluoroethyl),1H[1,2,3]triazole-4-ethylene]triphenylphosphonium bromide (18F-MitoPhos), as a cardiac imaging agent, comparing it with leading PET and SPECT lipophilic cationic tracers before further assessing its potential for imaging cardiotoxicity in an acute doxorubicin model. Methods: Cardiac uptake and response to decreased mitochondrial membrane potential of 18F-MitoPhos and 99mTc-sestamibi were tested in isolated perfused rat hearts. Baseline pharmacokinetic profiles of 18F-MitoPhos and 18F-fluorobenzyltriphenylphosphonium and their response to acute doxorubicin-induced cardiotoxicity were assessed in rats in vivo (10, 15, or 20 mg of doxorubicin per kilogram, intravenously, 48 h beforehand). Results: Cardiac retention of 18F-MitoPhos was more than double that of 99mTc-sestamibi in isolated perfused rat hearts. A favorable biodistribution of 18F-MitoPhos in vivo was observed, with heart-to-tissue ratios of 304 ± 186, 11.2 ± 1.2, and 3.8 ± 0.6 for plasma, liver, and lung, respectively (60 min). A significant dose-dependent loss of cardiac retention of 18F-MitoPhos was observed on doxorubicin treatment, with average cardiac SUV from 30 to 60 min (mean ± SD) decreasing from 3.5 ± 0.5 (control) to 1.8 ± 0.1 (doxorubicin, 20 mg/kg). Other assessed biomarkers showed no alterations. Conclusion: 18F-MitoPhos showed pharmacokinetic parameters suitable for cardiac imaging. A significant dose response of cardiac uptake to doxorubicin treatment was observed before detectable biomarker alterations. 18F-MitoPhos is therefore a promising tracer for imaging chemotherapy-induced cardiotoxicity. To our knowledge, this is the first demonstration of radiolabeled lipophilic cations being used for the PET imaging of chemotherapy-induced cardiotoxicity and indicates the potential application of these compounds in this area.



中文翻译:

用18F标签的亲脂性阳离子对化学疗法诱导的急性心脏毒性进行成像。

许多化学治疗剂对心脏有毒,因此越来越多的癌症幸存者现在生活在其治疗中可能致命的心血管后果中。较早和更敏感地检测到化学疗法诱发的心脏毒性可能会改善治疗策略并增加长期生存率。亲脂性阳离子PET示踪剂可能适用于心脏毒性的早期检测。这项研究旨在评估18 F标记的亲脂性nium阳离子,[1-(2- 18 F-氟乙基),1 H [1,2,3]三唑-4-乙烯]三苯基溴化phosph(18F-MitoPhos),作为心脏显像剂,将其与领先的PET和SPECT亲脂性阳离子示踪剂进行比较,然后进一步评估其在急性阿霉素模型中对心脏毒性成像的潜力。方法:在离体灌流大鼠心脏中测试了18 F-MitoPhos和99m Tc-司他他比的心脏摄取和对线粒体膜电位降低的反应。在体内大鼠中评估了18 F-MitoPhos和18 F-氟苄基三苯基phosph的基线药代动力学概况及其对急性阿霉素诱导的心脏毒性的反应(静脉注射,每48小时预先给药10、15或20 mg阿霉素)。结果:心脏保留18在离体灌流的大鼠心脏中,F-MitoPhos比99m Tc-司他米比高出一倍以上。观察到体内18 F-MitoPhos的良好生物分布,血浆,肝脏和肺部(60分钟)的心组织比分别为304±186、11.2±1.2和3.8±0.6。在阿霉素治疗中观察到18 F-MitoPhos的心脏滞留有明显的剂量依赖性损失,平均心脏SUV从30分钟到60分钟(平均值±标准差)从3.5±0.5(对照)降低到1.8±0.1(阿霉素,20)毫克/公斤)。其他评估的生物标志物未显示变化。结论: 18F-MitoPhos显示出适合心脏成像的药代动力学参数。在可检测到的生物标志物改变之前,观察到心脏吸收对阿霉素治疗的显着剂量反应。因此,18 F-MitoPhos是用于对化疗引起的心脏毒性进行成像的有前途的示踪剂。据我们所知,这是放射性标记的亲脂性阳离子用于化学疗法诱导的心脏毒性的PET成像的首次证明,表明这些化合物在该领域的潜在应用。

更新日期:2019-12-02
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