Logan J, Fowler J S, Volkow N D, Wolf A P, Dewey S L, Schlyer D J, MacGregor R R, Hitzemann R, Bendriem B, Gatley S J
Department of Chemistry, Brookhaven National Laboratory, Upton, NY 11973.
J Cereb Blood Flow Metab. 1990 Sep;10(5):740-7. doi: 10.1038/jcbfm.1990.127.
A graphical method of analysis applicable to ligands that bind reversibly to receptors or enzymes requiring the simultaneous measurement of plasma and tissue radioactivities for multiple times after the injection of a radiolabeled tracer is presented. It is shown that there is a time t after which a plot of integral of t0ROI(t')dt'/ROI(t) versus integral of t0Cp(t')dt'/ROI(t) (where ROI and Cp are functions of time describing the variation of tissue radioactivity and plasma radioactivity, respectively) is linear with a slope that corresponds to the steady-state space of the ligand plus the plasma volume,.Vp. For a two-compartment model, the slope is given by lambda + Vp, where lambda is the partition coefficient and the intercept is -1/[kappa 2(1 + Vp/lambda)]. For a three-compartment model, the slope is lambda(1 + Bmax/Kd) + Vp and the intercept is -[1 + Bmax/Kd)/k2 + [koff(1 + Kd/Bmax)]-1) [1 + Vp/lambda(1 + Bmax/Kd)]-1 (where Bmax represents the concentration of ligand binding sites and Kd the equilibrium dissociation constant of the ligand-binding site complex, koff (k4) the ligand-binding site dissociation constant, and k2 is the transfer constant from tissue to plasma). This graphical method provides the ratio Bmax/Kd from the slope for comparison with in vitro measures of the same parameter. It also provides an easy, rapid method for comparison of the reproducibility of repeated measures in a single subject, for longitudinal or drug intervention protocols, or for comparing experimental results between subjects. Although the linearity of this plot holds when ROI/Cp is constant, it can be shown that, for many systems, linearity is effectively reached some time before this. This analysis has been applied to data from [N-methyl-11C]-(-)-cocaine ([11C]cocaine) studies in normal human volunteers and the results are compared to the standard nonlinear least-squares analysis. The calculated value of Bmax/Kd for the high-affinity binding site for cocaine is 0.62 +/- 0.20, in agreement with literature values.
本文介绍了一种适用于与受体或酶可逆结合的配体的图形分析方法，该方法需要在注射放射性标记示踪剂后多次同时测量血浆和组织放射性。结果表明，在某个时间t之后，t0ROI(t')dt'/ROI(t)对t0Cp(t')dt'/ROI(t)的积分图（其中ROI和Cp分别是描述组织放射性和血浆放射性变化的时间函数）呈线性，其斜率对应于配体的稳态空间加上血浆体积Vp。对于双室模型，斜率由lambda + Vp给出，其中lambda是分配系数，截距为-1/[kappa 2(1 + Vp/lambda)]。对于三室模型，斜率为lambda(1 + Bmax/Kd) + Vp，截距为-[1 + Bmax/Kd)/k2 + [koff(1 + Kd/Bmax)]-1) [1 + Vp/lambda(1 + Bmax/Kd)]-1（其中Bmax代表配体结合位点的浓度，Kd是配体-结合位点复合物的平衡解离常数，koff (k4)是配体-结合位点解离常数，k2是从组织到血浆的转移常数）。这种图形方法从斜率得出Bmax/Kd的比值，以便与同一参数的体外测量值进行比较。它还提供了一种简单、快速的方法，用于比较单个受试者重复测量的可重复性、纵向或药物干预方案，或用于比较不同受试者之间的实验结果。虽然当ROI/Cp恒定时该图呈线性，但可以证明，对于许多系统，在这之前的某个时间就有效地达到了线性。该分析已应用于正常人类志愿者的[N-甲基-11C]-(-)-可卡因（[11C]可卡因）研究数据，并将结果与标准非线性最小二乘法分析进行比较。可卡因高亲和力结合位点的Bmax/Kd计算值为0.62 +/- 0.20，与文献值一致。
