Thakur Riptee, Kumar Manoj, Kumar Aishwarya, Joshi Raman Kumar, Maheshwari Divya, Km Afsal Mohammed, Venkataswamy Manjunatha, Mohanty Bhabani, Chaudhari Pradip, Mohan Hosahalli K, Kumar Pardeep
Department of Neuroimaging & Interventional Radiology, National Institute of Mental Health & Neurosciences (NIMHANS), Bengaluru, India.
Avaant Imaging, Lexington, Massachusetts, USA.
Cancer Biother Radiopharm. 2025 Mar;40(2):96-103. doi: 10.1089/cbr.2024.0114. Epub 2024 Sep 12.
Many studies have reported the role of P-glycoprotein (Pgp) in chemoresistance in various pathological conditions such as cancer and neurodegenerative diseases, such as Alzheimer's. In this study, we are reporting the high-performance liquid chromatography (HPLC)-based purification of fluorine-18 [F]AVT-011 and its preclinical evaluation. AVT-011 was labeled with F using the nucleophilic substitution method by heating the reaction mixture at 110°C for 10 min, followed by purification using preparative HPLC and C18ec cartridge. The cell uptake study was carried out in U87 cells with and without an inhibitor. The preclinical toxicity was carried out in CD1 mice in three groups, including control, AVT-011 treated, and [F]AVT-011 treated. The biodistribution study was done in CD1 mice ( = 12) after intravenous injection of 4-6 MBq [F]AVT-011, and mice were sacrificed at various time intervals. A dose of 3.7 ± 0.7 MBq of [F]AVT-011 was injected intravenously in the healthy Swiss albino mice, and the whole-body micro-positron emission tomography was acquired at 0-, 30-, 60-, and 120-min postinjection. The radiochemical purity of [F]AVT-011 was 97 ± 1.5% as evaluated by radio-HPLC with a yield of 14 ± 2% and was stable up to 95% under conditions in blood and conditions up to 4 h. The cell uptake study showed a significant difference in control (27.4 ± 2.1%) and blocked U987 cells (73.2 ± 3.2%) after incubation of 120 min. The tissue distribution in mice showed the highest uptake in the liver (17.3 ± 2.4%), kidneys (16.6 ± 3.1%), lungs (10.4 ± 2.9%), and spleen (5.6 ± 0.8%) at 15 min, and the activity was washed out with time. The radioactivity cleared through the hepatorenal pathway. The animal imaging study also demonstrates a similar biodistribution pattern. [F]AVT-011 showed higher specific activity than the cartridge-based method but showed similar biological activity.
许多研究报告了P-糖蛋白（Pgp）在各种病理状况（如癌症和神经退行性疾病，如阿尔茨海默病）的化疗耐药性中的作用。在本研究中，我们报告了基于高效液相色谱（HPLC）的氟-18[F]AVT-011的纯化及其临床前评估。通过在110°C加热反应混合物10分钟，使用亲核取代法用F标记AVT-011，随后使用制备型HPLC和C18ec柱进行纯化。在有或没有抑制剂的U87细胞中进行细胞摄取研究。在三组CD1小鼠中进行临床前毒性研究，包括对照组、AVT-011处理组和[F]AVT-011处理组。在静脉注射4-6 MBq [F]AVT-011后，对12只CD1小鼠进行生物分布研究，并在不同时间间隔处死小鼠。向健康的瑞士白化小鼠静脉注射3.7±0.7 MBq的[F]AVT-011，并在注射后0、30、60和120分钟采集全身微型正电子发射断层扫描图像。通过放射性HPLC评估，[F]AVT-011的放射化学纯度为97±1.5%，产率为14±2%，在血液条件下和4小时内高达95%的条件下稳定。细胞摄取研究显示，在孵育120分钟后，对照组（27.4±2.1%）和阻断的U987细胞（73.2±3.2%）之间存在显著差异。小鼠的组织分布显示，在15分钟时，肝脏（17.3±2.4%）、肾脏（16.6±3.1%）、肺（10.4±2.9%）和脾脏（5.6±0.8%）摄取最高，并且活性随时间被清除。放射性通过肝肾途径清除。动物成像研究也显示了类似的生物分布模式。[F]AVT-011显示出比基于柱的方法更高的比活性，但显示出相似的生物学活性。
