Shuvaev Sergey, Knipe Rachel S, Drummond Matt, Rotile Nicholas J, Ay Ilknur, Weigand-Whittier Jonah P, Ma Hua, Zhou Iris Yuwen, Roberts Jesse D, Black Katherine, Hariri Lida P, Ning Yingying, Caravan Peter
Institute for Innovation in Imaging (i3), Boston, USA.
Athinoula A. Martinos Center for Biomedical Imaging, Boston, USA.
Mol Imaging Biol. 2023 Oct;25(5):944-953. doi: 10.1007/s11307-023-01845-2. Epub 2023 Aug 23.
Idiopathic pulmonary fibrosis (IPF) is a destructive lung disease with a poor prognosis, an unpredictable clinical course, and inadequate therapies. There are currently no measures of disease activity to guide clinicians making treatment decisions. The aim of this study was to develop a PET probe to identify lung fibrogenesis using a pre-clinical model of pulmonary fibrosis, with potential for translation into clinical use to predict disease progression and inform treatment decisions.
Eight novel allysine-targeting chelators, PIF-1, PIF-2, …, PIF-8, with different aldehyde-reactive moieties were designed, synthesized, and radiolabeled with gallium-68 or copper-64. PET probe performance was assessed in C57BL/6J male mice 2 weeks after intratracheal bleomycin challenge and in naïve mice by dynamic PET/MR imaging and with biodistribution at 90 min post injection. Lung hydroxyproline and allysine were quantified ex vivo and histological staining for fibrosis and aldehyde was performed.
In vivo screening of probes identified GaPIF-3 and GaPIF-7 as probes with high uptake in injured lung, high uptake in injured lung versus normal lung, and high uptake in injured lung versus adjacent liver and heart tissue. A crossover, intra-animal PET/MR imaging study of GaPIF-3 and GaPIF-7 confirmed GaPIF-7 as the superior probe. Specificity for fibrogenesis was confirmed in a crossover, intra-animal PET/MR imaging study with GaPIF-7 and a non-binding control compound, GaPIF-Ctrl. Substituting copper-64 for gallium-68 did not affect lung uptake or specificity indicating that either isotope could be used.
A series of allysine-reactive PET probes with variations in the aldehyde-reactive moiety were evaluated in a pre-clinical model of lung fibrosis. The hydrazine-bearing probe, GaPIF-7, exhibited the highest uptake in fibrogenic lung, low uptake in surrounding liver or heart tissue, and low lung uptake in healthy mice and should be considered for further clinical translation.
特发性肺纤维化（IPF）是一种具有破坏性的肺部疾病，预后较差，临床病程不可预测，且治疗方法有限。目前尚无疾病活动度指标来指导临床医生做出治疗决策。本研究的目的是开发一种PET探针，利用肺纤维化的临床前模型来识别肺纤维化，具有转化为临床应用以预测疾病进展并为治疗决策提供依据的潜力。
设计、合成了八种具有不同醛反应性基团的新型靶向赖氨酸螯合剂PIF-1、PIF-2、…、PIF-8，并用镓-68或铜-64进行放射性标记。通过动态PET/MR成像以及注射后90分钟的生物分布，在气管内注射博来霉素攻击2周后的C57BL/6J雄性小鼠和未处理小鼠中评估PET探针性能。对肺组织中的羟脯氨酸和赖氨酸进行离体定量，并进行纤维化和醛的组织学染色。
探针的体内筛选确定GaPIF-3和GaPIF-7为在损伤肺中摄取高、损伤肺与正常肺摄取比高、损伤肺与相邻肝脏和心脏组织摄取比高的探针。一项关于GaPIF-3和GaPIF-7的交叉、动物体内PET/MR成像研究证实GaPIF-7是更优的探针。在一项关于GaPIF-7和非结合对照化合物GaPIF-Ctrl的交叉、动物体内PET/MR成像研究中证实了对纤维化的特异性。用铜-64替代镓-68不影响肺摄取或特异性，表明两种同位素均可使用。
在肺纤维化的临床前模型中评估了一系列醛反应性基团不同的靶向赖氨酸PET探针。含肼探针GaPIF-7在纤维化肺中的摄取最高，在周围肝脏或心脏组织中的摄取低，在健康小鼠肺中的摄取也低，应考虑进一步向临床转化。
