VALIDATION OF A KINETIC MODEL FOR RECEPTOR IMAGING

拟议的研究将扩展三种受体的动力学模型- 结合放射性药物：[99mTc]半乳糖基-新糖白蛋白 ([99mTc]NGA)，[68Ga]去铁胺-半乳糖基-新糖白蛋白([68Ga]df-NGA)， 和high-density-[99mTc]-galactosyl-neoglycoalbumin([99mTc]HD-NGA)。每个人 试剂是针对同一受体的，即肝脏结合蛋白，但 专为特定的医疗设备设计，因此具有不同的模型结构： [99mTC]NGA，受体生物化学的平面成像和全球测量； [68Ga]DF-NGA、PET成像和受体区域测量 生物化学；和[99mTc]HD-NGA，SPECT成像和区域测量 肝脏血浆流量。 我们将扩展当前的动力学模型，以适应以下情况 结构：a)说明肝脏内的区域分布 肝血浆流量F、Ro和Ko。动态PET数据将是 使用。B)考虑肝脏血浆流量的区域分布。一个 将动态平面成像与单一SPECT图像相结合 使用。此外，我们将C)使用信号检测理论来测试 新一代软件在临床上的准确性 [99mTC]NGA动力学模型。 然后，我们将检验以下三个假设：a)动态PET模型 提供区域F、Ro和Ko的精确测量；B) SPECT模型提供了准确和精确的区域测量 肝脏血浆流动；以及C)更高的模拟速度，合适的模型 转变，更强大的优化器将提供更高的临床 准确度然后是当前的TcNGA模型。 模型测试将包括以下标准：a)拟合度，b) 动力学敏感性，c)局部可辨识性，d)似然性。这个 后者将包括每个模型参数与 独立测量值。对于区域模式(PET和SPECT)， 这些测量将包括全球和区域肝血浆流量通过 吲哚青绿提取和[~3H]D-半乳糖沉积，以及区域性 通过In测量受体密度和前向结合速率常数 组织样本的体外分析。临床准确性测试将采用 TcNGA患者影像数据的ROC分析 作为观察者的模型变换。 TcNGA放射性药物动力学系统对 受体生物化学和动力学模型符合良好的标准- 失配、局部可识别性和似是而非。因此，动态PET 使用[68Ga]DF-NGA进行成像将允许我们构建可测试的 用于区域性受体密度测量的放射性药物动力学系统 和亲和力。 通过单光子发射实现器官功能的区域性量化 计算机断层扫描(SPECT)仍然是一个难以实现的目标。校长 原因是缺乏具有物理和生物特性的放射性示踪剂。 符合旋转要求的属性 断层扫描系统。作为唯一真正的单光子发射化学物质 微球，[99mTc]HD-NGA将允许我们测试SPECT作为一种方法 肝脏局部血浆流量的绝对测量。我们的建议 整合了完成一个系统所需的所有组件 生理过程的定量成像：放射性示踪剂， 生物化学、断层摄影术和图像处理算法。未能得到治疗 SPECT作为放射性药物动力学系统中的许多组件之一将 将该仪器归类于组织大小和组织的形态测量 形状。

The proposed studies will expand the kinetic modeling of three receptor- binding radiopharmaceuticals: [99mTc]galactosyl-neoglycoalbumin ([99mTc]NGA), [68Ga]deferoxamine-galactosyl-neoglycoalbumin ([68Ga]Df-NGA), and high-density-[99mTc]-galactosyl-neoglycoalbumin ([99mTc]HD-NGA). Each agent is specific for the same receptor, hepatic binding protein, but was designed for a specific modality, and hence, different model structures: [99mTc]NGA, planar imaging and global measurement of receptor biochemistry; [68Ga]Df-NGA, PET imaging and regional measurement of receptor biochemistry; and [99mTc]HD-NGA, SPECT imaging and regional measurement of hepatic plasma flow. We will extend the current kinetic model to accommodate the following structures: A) Account for regional distribution within the liver for hepatic plasma flow F, as well as Ro and ko. Dynamic PET data will be used. B) Account for regional distribution of hepatic plasma flow. A combination of dynamic planar imaging with a single SPECT image will be used. Additionally, we will C) employ signal detection theory to test the clinical accuracy of a new generation of software for the current [99mTc]NGA kinetic model. We will then test the following three hypotheses: A) the dynamic PET model provides accurate and precise measurements of regional F, Ro, and ko; B) the SPECT model provides accurate and precise measurements of regional hepatic plasma flow; and C) higher simulation speed, an appropriate model transform, and a more robust optimizer will provide higher clinical accuracy then the current TcNGA model. Model testing will include the following criteria: a) Goodness-of-fit, b) kinetic sensitivity, c) local identifiability, and d) plausibility. The latter will include the comparison of each model parameter with independently measured values. For the regional models (PET and SPECT), these measurements will include global and regional hepatic plasma flow via indocyanine green extraction and [3H]D-galactose deposition, and regional receptor density and forward binding rate constant measurements via in vitro assay of tissue samples. Testing for clinical accuracy will employ ROC analysis of TcNGA patient imaging data using different optimizers and model transformations as observers. The TcNGA radiopharmacokinetic system displayed kinetic sensitivity to receptor biochemistry and the kinetic model met the criteria of Goodness- of-fit, local identifiability, and plausibility. Consequently, dynamic PET imaging with [68Ga]Df-NGA will permit us to construct a testable radiopharmacokinetic system for regional measurements of receptor density and affinity. Regional quantification of organ function via single photon emission computed tomography (SPECT) has remained an elusive goal. The principal reason for this is a lack of radiotracers with physical and biological properties which are compatible with the requirements of rotating tomographic systems. As the only true single photon-emitting chemical microsphere, [99mTc]HD-NGA will permit us to test SPECT as a method for the absolute measurement of regional hepatic plasma flow. Our proposal incorporates al of the components required to complete a system for quantitative imaging of physiologic process: the radiotracer, biochemistry, tomograph, and image processing algorithms. Failure to treat SPECT as one of many components within a radiopharmacokinetic system will relegate this instrument to morphologic measurements of tissue sizes and shapes.