PET Center, Aarhus University Hospital, Aarhus, Denmark
Department of Experimental Oncology, Aarhus University Hospital, Aarhus, Denmark; and.
J Nucl Med. 2016 Apr;57(4):615-21. doi: 10.2967/jnumed.115.169292. Epub 2016 Jan 14.
Organic cation transporters (OCTs) in the kidney proximal tubule (PT) participate in renal excretion of drugs and endogenous compounds. PT function is commonly impaired in kidney diseases, and consequently quantitative measurement of OCT function may provide an important estimate of kidney function. Metformin is a widely used drug and targets OCT type 2 located in the PT. Thus, we hypothesized that (11)C-labeled metformin would be a suitable PET tracer for quantification of renal function.
(11)C-metformin was prepared by (11)C-methylation of 1-methylbiguanide. In vitro cell uptake of (11)C-metformin was studied in LLC-PK1 cells in the presence of increasing doses of unlabeled metformin. In vivo small-animal PET studies in Sprague-Dawley rats were performed at baseline and after treatment with OCT inhibitors to evaluate renal uptake of (11)C-metformin. Kidney and liver pharmacokinetics of (11)C-metformin was investigated in vivo by dynamic (11)C-metformin PET/CT in 6 anesthetized pigs, and renal clearance of (11)C-metformin was compared with renal clearance of (51)Cr-ethylenediaminetetraacetic acid (EDTA). Formation of (11)C metabolites was investigated by analysis of blood and urine samples.
The radiochemical yield of (11)C-metformin was 15% ± 3% (n= 40, decay-corrected), and up to 1.5 GBq of tracer were produced with a radiochemical purity greater than 95% in less than 30 min. Dose-dependent uptake of (11)C-metformin in LLC-PK1 cells was rapid. Rat small-animal PET images showed (11)C-metformin uptake in the kidney and liver, the kinetics of which were changed after challenging animals with OCT inhibitors. In pigs, 80% of the injected metformin dose was rapidly present in the kidney, and a high dose of metformin caused a delayed renal uptake and clearance compared with baseline consistent with transporter-mediated competition. Renal clearance of (11)C-metformin was approximately 3 times the renal clearance of (51)Cr-EDTA.
We successfully synthesized an (11)C-metformin tracer, and PET studies in rats and pigs showed a rapid kidney uptake from the blood and excretion into the bladder similar to other radiopharmaceuticals developed for γ-camera renography.
肾脏近端小管 (PT) 中的有机阳离子转运体 (OCT) 参与药物和内源性化合物的肾脏排泄。PT 功能在肾脏疾病中通常受损，因此 OCT 功能的定量测量可能提供对肾功能的重要估计。二甲双胍是一种广泛使用的药物，靶向位于 PT 中的 OCT 类型 2。因此，我们假设 (11)C-标记的二甲双胍将是量化肾功能的合适 PET 示踪剂。
通过 1-甲基双胍的 (11)C-甲基化制备 (11)C-二甲双胍。在存在递增剂量未标记二甲双胍的情况下，在 LLC-PK1 细胞中研究 (11)C-二甲双胍的细胞摄取。在 Sprague-Dawley 大鼠中进行小动物 PET 研究，在 OCT 抑制剂治疗前后评估 (11)C-二甲双胍的肾脏摄取。通过对 6 只麻醉猪进行动态 (11)C-二甲双胍 PET/CT 研究，研究 (11)C-二甲双胍在体内的肾和肝药代动力学，并将 (11)C-二甲双胍的肾清除率与 (51)Cr-乙二胺四乙酸 (EDTA) 的肾清除率进行比较。通过分析血液和尿液样本研究 (11)C 代谢物的形成。
(11)C-二甲双胍的放射化学产率为 15%±3%（n=40，衰变校正），不到 30 分钟即可生产出放射性纯度大于 95%、达 1.5GBq 以上的示踪剂。LLC-PK1 细胞中 (11)C-二甲双胍的摄取呈剂量依赖性，快速。大鼠小动物 PET 图像显示肾脏和肝脏摄取 (11)C-二甲双胍，在挑战动物使用 OCT 抑制剂后，其动力学发生变化。在猪中，注射二甲双胍剂量的 80% 迅速存在于肾脏中，高剂量的二甲双胍导致与基线相比，肾脏摄取和清除延迟，这与转运体介导的竞争一致。(11)C-二甲双胍的肾清除率约为 (51)Cr-EDTA 的肾清除率的 3 倍。
我们成功合成了 (11)C-二甲双胍示踪剂，大鼠和猪的 PET 研究表明，其从血液中的快速肾脏摄取和排入膀胱类似于开发用于γ相机肾图的其他放射性药物。
