Platelet binding and biodistribution of [99mTc]rBitistatin in animal species and humans
Platelet binding and biodistribution of [99mTc]rBitistatin in animal species and humans
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DOI：
10.1016/j.nucmedbio.2007.03.014
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发表时间：
2007-10-01
影响因子：
3.1
通讯作者：
Maurer, Alan H.
中科院分区：
文献类型：
--
作者：
Knight, Linda C.;Romano, Jan E.;Maurer, Alan H.
简介：99（m）Tc重组比替他汀（rBitistatin）是血小板上β（11 b）β（3）（糖蛋白IIb/IIIa）受体的放射性配体，正在开发作为诊断急性血栓和栓塞体内成像的放射性药物。在对人类受试者首次给予[99（m）Tc] rBitistatin之前，在动物中评价了其生物分布和对血小板的影响。本文报道了在动物实验中的发现，并与在正常人subjects.Methods的初步结果进行了比较：[99（m）Tc]rBitistatin给药小鼠，豚鼠和狗，以评估时间依赖性的器官分布，尿排泄和血液消失率。分析血液样本以确定放射性配体与循环血小板的结合以及血浆蛋白结合的程度。测定了[99（m）Tc]rBitistatin对循环血小板计数的影响。这些因素也被确定在正常人受试者谁收到[99（m）Tc]rBitistatin作为第一阶段临床试验的一部分。结果：积累[99（m）Tc]rBitistatin的主要器官是肾脏，肝脏和脾脏在所有动物物种和人类。在人体图像上看到的主要器官是肾脏和脾脏。肝脏摄取较弱，软组织背景较低。[99（m）Tc]rBitistatin与血液中的循环血小板结合，与人相比，豚鼠和犬与血小板的结合百分比更高。血浆蛋白结合率较低，且与血小板结合率无关。主要排泄途径为尿液。[99（m）Tc]rBitistatin不影响人或狗的血小板计数。结论：[99（m）Tc]rBitistatin，当以低剂量给药用于成像时，对血小板没有不良影响，并且具有动物研究预测的定性生物分布。发现[99（m）Tc]rBitistatin与人体循环血小板结合，表明它将能够与急性血栓患者体内活化的血小板结合。(C)2007年爱思唯尔公司All rights reserved.
Introduction: 99(m)Tc recombinant bitistatin (rBitistatin) is a radioligand for beta(11b)beta(3) (glycoproteins IIb/IIIa) receptor on platelets and is being developed as a diagnostic radiopharmaceutical for in vivo imaging of acute thrombi and emboli. Prior to the first administration of [99(m)Tc] rBitistatin to human subjects, its biodistribution and effects on platelets were evaluated in animals. This paper reports findings in animal studies in comparison with initial findings in normal human subjects.Methods: [99(m)Tc]rBitistatin was administered to mice, guinea pigs and dogs to assess time-dependent organ distribution, urinary excretion and blood disappearance rates. Blood samples were analyzed to determine radioligand binding to circulating platelets and the extent of plasma protein binding. The effect of [99(m)Tc]rBitistatin on circulating platelet count was determined. These factors were also determined in normal human subjects who received [99(m)Tc]rBitistatin as part of a Phase I clinical trial.Results: The main organs that accumulated [99(m)Tc]rBitistatin were kidneys, liver and spleen in all animal species and humans. The main organs seen on human images were the kidneys and spleen. Liver uptake was fainter, and soft-tissue background was low. [99(m)Tc]rBitistatin bound to circulating platelets in blood, with a higher percentage of binding to platelets in guinea pigs and dogs compared to that in humans. Plasma protein binding was low and of little consequence in view of platelet binding. The main route of excretion was through the urine. [99(m)Tc]rBitistatin did not affect platelet counts in humans or dogs.Conclusions: [99(m)Tc]rBitistatin, when administered at low doses for imaging, has no adverse effects on platelets and has the qualitative biodistribution predicted by animal studies. [99(m)Tc]rBitistatin was found to bind to circulating platelets in humans, suggesting that it will be able to bind to activated platelets in vivo in patients with acute thrombi. (C) 2007 Elsevier Inc. All rights reserved.