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：[99 mTc]半乳糖基-新糖蛋白 （[99 mTc]NGA），[68 Ga]去铁胺-半乳糖基-新糖蛋白（[68 Ga]Df-NGA）， 和高密度-[99 mTc]-半乳糖基-新糖蛋白（[99 mTc]HD-NGA）。 每个 试剂对相同的受体肝结合蛋白具有特异性，但 为特定模态设计，因此，不同的模型结构： [99 mTc]NGA、平面显像和受体生物化学的整体测量; [68 Ga]Df-NGA、PET成像和受体的局部测量 [99 mTc]HD-NGA，SPECT成像和局部测量 肝血浆流量 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以及Ro和ko。 动态PET数据将 采用 B）说明肝血浆流量的区域分布。 一 动态平面成像与单个SPECT图像的组合将是 采用 此外，我们将C）采用信号检测理论来测试 新一代软件的临床准确性， [99 mTc]NGA动力学模型。 然后，我们将测试以下三个假设：A）动态PET模型 提供区域F、Ro和ko的准确和精确测量; B） SPECT模型提供了准确和精确的测量区域 肝血浆流动;和C）更高的模拟速度，合适的模型 更强大的优化器将提供更高的临床 准确性然后当前TcNGA模型。 模型检验将包括以下标准：a）拟合优度，B） 动力学灵敏度，c）局部可识别性，和d）可识别性。 的 后者将包括每个模型参数与 独立测量值。 对于区域模型（PET和SPECT）， 这些测量将包括全局和局部肝血浆流量， 吲哚菁绿色提取和[3 H] D-半乳糖沉积，以及区域 受体密度和正向结合速率常数的测量 组织样品的体外测定。 临床准确性测试将采用 使用不同的优化器对TcNGA患者成像数据进行ROC分析， 作为观察者的模型转换。 TcNGA放射性药代动力学系统显示出动力学灵敏度， 受体生物化学和动力学模型符合良好的标准- 拟合度、局部可识别性和可扩展性。 因此，动态PET [68 Ga]Df-NGA成像将允许我们构建可测试的 用于受体密度区域测量的放射性药物动力学系统 和亲和力。 通过单光子发射的器官功能的区域量化 计算机断层摄影（SPECT）仍然是一个难以实现的目标。 校长 这是因为缺乏具有物理和生物性质的放射性示踪剂。 与旋转要求相适应的性能 层析成像系统 作为唯一真正的单光子发射化学物质 微球，[99 mTc]HD-NGA将允许我们测试SPECT作为一种方法， 局部肝血浆流量的绝对测量。 我们的建议 包括完成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、断层摄影和图像处理算法。 未能治疗 SPECT作为放射性药物动力学系统内的许多组件之一， 将该仪器降级为组织尺寸的形态学测量， 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.