Petroni Debora, Bartoli Antonietta, Rapposelli Simona, Digiacomo Maria, Burchielli Silvia, Nesi Giulia, Lapucci Annalina, Pardini Silvia, Fucci Sabrina, Macchia Marco, Salvadori Piero A, Menichetti Luca
Institute of Clinical Physiology, Consiglio Nazionale delle Ricerche (CNR), Via Moruzzi, 1, I-56124, Pisa, Italy.
Molecular Imaging Centre, University of Turin, Via Nizza, 52, I-10125, Ivrea, Italy.
Mol Imaging Biol. 2016 Dec;18(6):916-923. doi: 10.1007/s11307-016-0965-6.
The plasma membrane P-glycoprotein (Pgp) is an efflux transporter involved in multidrug resistance and in the onset of neurodegenerative disease. Its function and most mechanisms of action are still under investigation. We developed a C-11-labeled 2-arylethylphenylamine-([C]AEPH) derivative for positron emission tomography (PET), as a novel probe to better understand the activity and the function of Pgp in vivo.
The synthetic procedure and the quality control of the selected lead compound, [C]AEPH-1, were set up and optimized. The biodistribution and the dynamic extraction in target organs of [C]AEPH-1 were studied in vivo by PET in healthy rats at baseline and after pre-treatment with a Pgp inhibitor (tariquidar).
In vivo dynamic imaging was consistent with the results of ex vivo extraction on explanted organs. An adequate stability for in vivo studies, as well as a high activity of [C]AEPH-1 in intestine and barrier tissues, has been demonstrated. Results of the blockade study showed a decrease of uptake after the pre-treatment, indicating a behavior attributable to a Pgp ligand.
The suitable pharmacokinetics and the specificity tested in the pre-treated animals have indicated the potentiality of this AEPH derivative to act as Pgp ligand, providing new opportunities for further studies on expression and function of this important efflux transporter in the fields of neurology and oncology.
质膜P - 糖蛋白（Pgp）是一种外排转运蛋白，与多药耐药性和神经退行性疾病的发生有关。其功能及大多数作用机制仍在研究中。我们开发了一种用于正电子发射断层扫描（PET）的C - 11标记的2 - 芳基乙苯胺 - （[C]AEPH）衍生物，作为一种新型探针，以更好地了解Pgp在体内的活性和功能。
建立并优化了所选先导化合物[C]AEPH - 1的合成程序和质量控制。通过PET在健康大鼠基线时以及用Pgp抑制剂（他林洛尔）预处理后，研究了[C]AEPH - 1在体内的生物分布和在靶器官中的动态摄取。
体内动态成像与离体器官的体外摄取结果一致。已证明[C]AEPH - 1在体内研究中有足够的稳定性，并且在肠道和屏障组织中有高活性。阻断研究结果显示预处理后摄取减少，表明其行为归因于Pgp配体。
在预处理动物中测试的合适药代动力学和特异性表明这种AEPH衍生物有作为Pgp配体的潜力，为在神经学和肿瘤学领域进一步研究这种重要外排转运蛋白的表达和功能提供了新机会。
