Radiopharmaceuticals Division, Bhabha Atomic Research Centre (BARC), Mumbai, India.
Homi Bhabha National Institute, Mumbai, India.
Drug Dev Res. 2023 Nov;84(7):1513-1521. doi: 10.1002/ddr.22103. Epub 2023 Aug 11.
Noninvasive imaging techniques for the early detection of infections are in high demand. In this study, we present the development of an infection imaging agent consisting of the antimicrobial peptide fragment UBI (31-38) conjugated to the chelator 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA), which allows for labeling with the positron emitter Ga-68. The preclinical evaluation of [ Ga]Ga-NODAGA-UBI (31-38) was conducted to investigate its potential for imaging bacterial infections caused by Staphylococcus aureus. The octapeptide derived from ubiquicidin, UBI (31-38), was synthesized and conjugated with the chelator NODAGA. The conjugate was then radiolabeled with Ga-68. The radiolabeling process and the stability of the radio formulation were confirmed through chromatography. The study included both in vitro evaluations using S. aureus and in vivo evaluations in an animal model of infection and inflammation. Positron emission tomography (PET) and Cherenkov luminescence imaging (CLI) were performed to visualize the targeted localization of the radio formulation at the site of infection. Ex vivo biodistribution studies were carried out to quantify the uptake of the radio formulation in different organs and tissues. Additionally, the uptake of [ F]Fluorodeoxyglucose ([ F] FDG) in the animal model was also studied for comparison. The [ Ga]Ga-NODAGA-UBI (31-38) complex consistently exhibited high radiochemical purity (>90%) after formulation. The complex demonstrated stability in saline, phosphate-buffered saline, and human serum for up to 3 h. Notably, the complex displayed significantly higher uptake in S. aureus, which was inhibited in the presence of unconjugated UBI (29-41) peptide, confirming the specificity of the formulation for bacterial membranes. Bacterial imaging capability was also observed in PET and CLI images. Biodistribution results indicated a substantial target-to-nontarget ratio of approximately 4 at 1 h postinjection of the radio formulation. Conversely, the uptake of [ F]FDG in the animal model did not allow for the discrimination of infected and inflamed sites. Our studies have demonstrated that [ Ga]Ga-NODAGA-UBI (31-38) holds promise as a radiotracer for imaging bacterial infections caused by S. aureus.
非侵入性成像技术在早期感染检测方面的需求很高。在这项研究中，我们开发了一种感染成像剂，该成像剂由抗菌肽片段 UBI（31-38）与螯合剂 1,4,7-三氮杂环壬烷-1- 戊二酸-4,7-乙酸（NODAGA）偶联而成，允许用正电子发射体 Ga-68 进行标记。研究了[Ga]Ga-NODAGA-UBI（31-38）的临床前评估，以研究其用于成像金黄色葡萄球菌引起的细菌感染的潜力。源自泛菌防御素的八肽 UBI（31-38）被合成并与螯合剂 NODAGA 偶联。然后用 Ga-68 对该偶联物进行放射性标记。通过色谱法确认了放射性制剂的放射性标记过程和稳定性。该研究包括使用金黄色葡萄球菌进行的体外评估以及感染和炎症动物模型中的体内评估。进行正电子发射断层扫描（PET）和切伦科夫发光成像（CLI）以可视化放射性制剂在感染部位的靶向定位。进行了离体生物分布研究以量化放射性制剂在不同器官和组织中的摄取。此外，还研究了动物模型中[ F]氟脱氧葡萄糖（[ F] FDG）的摄取情况，以便进行比较。[ Ga]Ga-NODAGA-UBI（31-38）配合物在制剂后始终表现出>90%的高放射化学纯度。该配合物在生理盐水、磷酸盐缓冲盐水和人血清中在长达 3 小时内保持稳定。值得注意的是，该配合物在金黄色葡萄球菌中的摄取明显更高，而在存在未偶联 UBI（29-41）肽的情况下则受到抑制，证实了该制剂对细菌膜的特异性。在 PET 和 CLI 图像中也观察到了细菌成像能力。生物分布结果表明，放射性制剂注射后 1 小时的靶标与非靶标比值约为 4。相比之下，动物模型中[ F]FDG 的摄取不能区分感染和炎症部位。我们的研究表明，[ Ga]Ga-NODAGA-UBI（31-38）有望成为用于成像金黄色葡萄球菌引起的细菌感染的放射性示踪剂。
