Bedaquiline is a promising drug against tuberculosis (TB), but limited data are available on its intralesional pharmacokinetics. Moreover, current techniques rely on invasive tissue resection, which is difficult in humans and generally limited even in animals. In this study, we developed a novel radiosynthesis for 76Br-bedaquiline and performed noninvasive, longitudinal whole-body positron emission tomography (PET) in live, Mycobacterium tuberculosis-infected mice over 48 h. After the intravenous injection, 76Br-bedaquiline distributed to all organs and selectively localized to adipose tissue and liver, with excellent penetration into infected lung lesions (86%) and measurable penetration into the brain parenchyma (15%). Ex vivo high resolution, two-dimensional autoradiography, and same section hematoxylin/eosin and immunofluorescence provided detailed intralesional drug biodistribution. PET bioimaging and high-resolution autoradiography are novel techniques that can provide detailed, multicompartment, and intralesional pharmacokinetics of new and existing TB drugs. These technologies can significantly advance efforts to optimize drug dosing.

中文翻译：

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结核病小鼠模型中76Br-苯达喹啉的放射合成和PET生物成像。

贝达喹啉是一种有前景的抗结核药物，但有关病灶内药代动力学的数据有限。此外，当前的技术依赖于侵入性组织切除术，这在人类中是困难的，并且甚至在动物中也通常受到限制。在这项研究中，我们为76Br-贝达喹啉开发了一种新型的放射合成方法，并在感染结核分枝杆菌的活小鼠中进行了48小时的无创纵向全身正电子发射断层扫描（PET）。静脉注射后，76Br-bedaquiline分布到所有器官，并选择性地定位于脂肪组织和肝脏，对被感染的肺部病变具有极好的渗透性（86％），而对脑实质的渗透性则可测量（15％）。离体高分辨率二维放射自显影，同一节苏木/曙红和免疫荧光分析提供了病灶内药物的详细生物分布。PET生物成像和高分辨率放射自显影技术是新颖的技术，可以提供新的和现有的TB药物的详细，多室和病灶内药代动力学。这些技术可以极大地推动优化药物剂量的工作。