Clinical Department of Nuclear Medicine, Innsbruck Medical University, Innsbruck, Austria.
Eur J Nucl Med Mol Imaging. 2012 Jul;39(7):1175-83. doi: 10.1007/s00259-012-2110-3. Epub 2012 Apr 24.
Invasive pulmonary aspergillosis is mainly caused by Aspergillus fumigatus, and is one of the major causes of morbidity and mortality in immunocompromised patients. The mortality associated with invasive pulmonary aspergillosis remains high, mainly due to the difficulties and limitations in diagnosis. We have shown that siderophores can be labelled with (68)Ga and can be used for PET imaging of A. fumigatus infection in rats. Here we report on the further evaluation of the most promising (68)Ga-siderophore candidates, triacetylfusarinine (TAFC) and ferrioxamine E (FOXE).
Siderophores were labelled with (68)Ga using acetate buffer. Log P, protein binding and stability values were determined. Uptake by A. fumigatus was studied in vitro in cultures with high and low iron loads. In vivo biodistribution was determined in normal mice and an infection model was established using neutropenic rats inoculated with A. fumigatus. Static and dynamic μPET imaging was performed and correlated with CT images, and lung infection was evaluated ex vivo.
(68)Ga-siderophores were labelled with high radiochemical purity and specific activity. (68)Ga-TAFC and (68)Ga-FOXE showed high uptake by A. fumigatus in iron-deficient cultures. In normal mice, (68)Ga-TAFC and (68)Ga-FOXE showed rapid renal excretion with high metabolic stability. In the rat infection model focal lung uptake was detected by μPET with both compounds and increased with severity of the infection, correlating with abnormal CT images.
(68)Ga-TAFC and (68)Ga-FOXE displayed excellent in vitro stability and high uptake by A. fumigatus. Both compounds showed excellent pharmacokinetics, highly selective accumulation in infected lung tissue and good correlation with severity of disease in a rat infection model, which makes them promising agents for A. fumigatus infection imaging.
侵袭性肺曲霉病主要由烟曲霉引起，是免疫功能低下患者发病率和死亡率的主要原因之一。侵袭性肺曲霉病相关死亡率仍然很高，主要是由于诊断困难和限制。我们已经表明，铁载体可以用（68）Ga 标记，并可用于大鼠烟曲霉感染的 PET 成像。在此，我们报告了进一步评估最有前途的（68）Ga-铁载体候选物三乙酰基晕菌素（TAFC）和去铁胺 E（FOXE）的情况。
用乙酸缓冲液标记铁载体。测定了 log P、蛋白结合和稳定性值。在高载铁和低载铁培养物中研究了铁载体在体外的摄取情况。在正常小鼠和用烟曲霉接种的中性粒细胞减少症大鼠建立的感染模型中进行了体内生物分布测定。进行了静态和动态μPET 成像，并与 CT 图像相关联，以及体外评估肺部感染。
（68）Ga-铁载体具有高放射化学纯度和比活度。（68）Ga-TAFC 和（68）Ga-FOXE 在缺铁培养物中对烟曲霉具有高摄取。在正常小鼠中，（68）Ga-TAFC 和（68）Ga-FOXE 表现出快速的肾脏排泄和高代谢稳定性。在大鼠感染模型中，两种化合物都通过μPET 检测到焦点性肺部摄取，并随着感染的严重程度增加，与异常 CT 图像相关联。
（68）Ga-TAFC 和（68）Ga-FOXE 在体外表现出优异的稳定性和对烟曲霉的高摄取。两种化合物均表现出优异的药代动力学特性，对感染肺部组织具有高度选择性蓄积作用，与大鼠感染模型中疾病严重程度具有良好相关性，使其成为烟曲霉感染成像的有前途的药物。
