Department of Experimental Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
J Nucl Med. 2011 Jun;52(6):934-41. doi: 10.2967/jnumed.110.086777. Epub 2011 May 13.
We recently developed the radiotracer 4-[(3-iodophenyl)amino]-7-(2-[2-{2-(2-[2-{2-((18)F-fluoroethoxy)-ethoxy}-ethoxy]-ethoxy)-ethoxy}-ethoxy]-quinazoline-6-yl-acrylamide) ((18)F-PEG(6)-IPQA) for noninvasive detection of active mutant epidermal growth factor receptor kinase-expressing non-small cell lung cancer xenografts in rodents. In this study, we determined the pharmacokinetics, biodistribution, metabolism, and radiation dosimetry of (18)F-PEG(6)-IPQA in nonhuman primates.
Six rhesus macaques were injected intravenously with 141 ± 59.2 MBq of (18)F-PEG(6)-IPQA, and dynamic PET/CT images covering the thoracoabdominal area were acquired for 30 min, followed by whole-body static images at 60, 90, 120, and 180 min. Blood samples were obtained from each animal at several time points after radiotracer administration. Radiolabeled metabolites in blood and urine were analyzed using high-performance liquid chromatography. The (18)F-PEG(6)-IPQA pharmacokinetic and radiation dosimetry estimates were determined using volume-of-interest analysis of PET/CT image datasets and blood and urine time-activity data.
(18)F-PEG(6)-IPQA exhibited rapid redistribution and was excreted via the hepatobiliary and urinary systems. (18)F-PEG(6) was the major radioactive metabolite. The critical organ was the gallbladder, with an average radiation-absorbed dose of 0.394 mSv/MBq. The other key organs with high radiation doses were the kidneys (0.0830 mSv/MBq), upper large intestine wall (0.0267 mSv/MBq), small intestine (0.0816 mSv/MBq), and liver (0.0429 mSv/MBq). Lung tissue exhibited low uptake of (18)F-PEG(6)-IPQA due to the low affinity of this radiotracer to wild-type epidermal growth factor receptor kinase. The effective dose was 0.0165 mSv/MBq. No evidence of acute cardiotoxicity or of acute or delayed systemic toxicity was observed. On the basis of our estimates, diagnostic dosages of (18)F-PEG(6)-IPQA up to 128 MBq (3.47 mCi) per injection should be safe for administration in the initial cohort of human patients in phase I clinical PET studies.
The whole-body and individual organ radiation dosimetry characteristics and pharmacologic safety of diagnostic dosages of (18)F-PEG(6)-IPQA in nonhuman primates indicate that this radiotracer should be acceptable for PET/CT studies in human patients.
我们最近开发了放射性示踪剂 4-[(3-碘代苯)氨基]-7-(2-[2-{2-[2-[2-{2-[(18)F-氟乙氧基)乙氧基]-乙氧基]-乙氧基]-乙氧基]-喹唑啉-6-基]-丙烯酰胺）（（18）F-PEG（6）-IPQA），用于非侵入性检测啮齿动物中表达活性突变表皮生长因子受体激酶的非小细胞肺癌异种移植物。在这项研究中，我们确定了（18）F-PEG（6）-IPQA 在非人类灵长类动物中的药代动力学、生物分布、代谢和辐射剂量学。
六只恒河猴静脉注射 141±59.2MBq 的（18）F-PEG（6）-IPQA，进行 30 分钟的胸腹部动态 PET/CT 图像采集，然后在 60、90、120 和 180 分钟时进行全身静态图像采集。在放射性示踪剂给药后，从每只动物采集多个时间点的血液样本。使用高效液相色谱法分析血液和尿液中的放射性标记代谢物。使用 PET/CT 图像数据集和血液及尿液时间活性数据的感兴趣区分析来确定（18）F-PEG（6）-IPQA 的药代动力学和辐射剂量学估算值。
（18）F-PEG（6）-IPQA 表现出快速再分布，并通过肝胆和泌尿系统排泄。（18）F-PEG（6）是主要的放射性代谢物。关键器官是胆囊，平均吸收剂量为 0.394mSv/MBq。其他具有高辐射剂量的关键器官是肾脏（0.0830mSv/MBq）、大肠壁上部（0.0267mSv/MBq）、小肠（0.0816mSv/MBq）和肝脏（0.0429mSv/MBq）。由于这种放射性示踪剂与野生型表皮生长因子受体激酶的亲和力低，肺部组织对（18）F-PEG（6）-IPQA 的摄取较低。有效剂量为 0.0165mSv/MBq。未观察到急性心脏毒性或急性或迟发性全身毒性的证据。基于我们的估算，在 I 期临床 PET 研究中，每注射剂量高达 128MBq（3.47mCi）的（18）F-PEG（6）-IPQA 的诊断剂量应该是安全的。
（18）F-PEG（6）-IPQA 在非人类灵长类动物中的全身和各器官辐射剂量学特征和药理安全性表明，该放射性示踪剂应可接受用于人类患者的 PET/CT 研究。
