Krasulova Kristyna, Neuzilova Barbora, Dvorakova Bendova Katerina, Novy Zbynek, Popper Miroslav, Hajduch Marian, Petrik Milos
Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Hnevotinska 5, 779 00, Olomouc, Czech Republic.
Czech Advanced Technology and Research Institute, Palacky University, Krizkovskeho 511/8, 779 00, Olomouc, Czech Republic.
EJNMMI Radiopharm Chem. 2024 Mar 4;9(1):20. doi: 10.1186/s41181-024-00249-z.
Siderophores are small iron-binding molecules produced by microorganisms to facilitate iron acquisition from the environment. Radiolabelled siderophores offer a promising solution for infection imaging, as they can specifically target the pathophysiological mechanisms of pathogens. Gallium-68 can replace the iron in siderophores, enabling molecular imaging with positron emission tomography (PET). Stereospecific interactions play a crucial role in the recognition of receptors, transporters, and iron utilisation. Furthermore, these interactions have an impact on the host environment, affecting pharmacokinetics and biodistribution. This study examines the influence of siderophore stereoisomerism on imaging properties, with a focus on ferrirubin (FR) and ferrirhodin (FRH), two cis-trans isomeric siderophores of the ferrichrome type.
Tested siderophores were labelled with gallium-68 with high radiochemical purity. The resulting complexes differed in their in vitro characteristics. [Ga]Ga-FRH showed less hydrophilic properties and higher protein binding values than [Ga]Ga-FR. The stability studies confirmed the high radiochemical stability of both [Ga]Ga-siderophores in all examined media. Both siderophores were found to be taken up by S. aureus, K. pneumoniae and P. aeruginosa with similar efficacy. The biodistribution tested in normal mice showed rapid renal clearance with low blood pool retention and fast clearance from examined organs for [Ga]Ga-FR, whereas [Ga]Ga-FRH showed moderate retention in blood, resulting in slower pharmacokinetics. PET/CT imaging of mice injected with [Ga]Ga-FR and [Ga]Ga-FRH confirmed findings from ex vivo biodistribution studies. In a mouse model of S. aureus myositis, both radiolabeled siderophores showed radiotracer accumulation at the site of infection.
The Ga-complexes of stereoisomers ferrirubin and ferrirhodin revealed different pharmacokinetic profiles. In vitro uptake was not affected by isomerism. Both compounds had uptake with the same bacterial culture with similar efficacy. PET/CT imaging showed that the [Ga]Ga-complexes accumulate at the site of S. aureus infection, highlighting the potential of [Ga]Ga-FR as a promising tool for infection imaging. In contrast, retention of the radioactivity in the blood was observed for [Ga]Ga-FRH. In conclusion, the stereoisomerism of potential radiotracers should be considered, as even minor structural differences can influence their pharmacokinetics and, consequently, the results of PET imaging.
铁载体是微生物产生的小分子铁结合分子，用于促进从环境中获取铁。放射性标记的铁载体为感染成像提供了一种有前景的解决方案，因为它们可以特异性地靶向病原体的病理生理机制。镓-68可以取代铁载体中的铁，从而实现正电子发射断层扫描（PET）分子成像。立体特异性相互作用在受体、转运体的识别以及铁的利用中起着关键作用。此外，这些相互作用会影响宿主环境，进而影响药代动力学和生物分布。本研究考察铁载体立体异构对成像特性的影响，重点关注铁红素（FR）和铁紫红素（FRH），这两种高铁色素类型的顺反异构铁载体。
测试的铁载体用镓-68标记，放射化学纯度高。所得复合物的体外特性有所不同。[Ga]Ga-FRH比[Ga]Ga-FR表现出更低的亲水性和更高的蛋白结合值。稳定性研究证实了两种[Ga]Ga-铁载体在所有检测介质中的高放射化学稳定性。发现两种铁载体对金黄色葡萄球菌、肺炎克雷伯菌和铜绿假单胞菌的摄取效果相似。在正常小鼠中进行的生物分布测试显示，[Ga]Ga-FR经肾脏快速清除，血池滞留率低，且从检测器官快速清除，而[Ga]Ga-FRH在血液中滞留适中，导致药代动力学较慢。对注射了[Ga]Ga-FR和[Ga]Ga-FRH的小鼠进行PET/CT成像，证实了体外生物分布研究的结果。在金黄色葡萄球菌肌炎小鼠模型中，两种放射性标记的铁载体均在感染部位显示出放射性示踪剂聚集。
铁红素和铁紫红素立体异构体的镓复合物显示出不同的药代动力学特征。体外摄取不受异构现象影响。两种化合物对相同细菌培养物的摄取效果相似。PET/CT成像显示，[Ga]Ga-复合物在金黄色葡萄球菌感染部位聚集，突出了[Ga]Ga-FR作为一种有前景的感染成像工具的潜力。相比之下，观察到[Ga]Ga-FRH的放射性在血液中滞留。总之，应考虑潜在放射性示踪剂的立体异构现象，因为即使是微小的结构差异也可能影响其药代动力学，从而影响PET成像结果。
