Mankoff D A, Shields A F, Graham M M, Link J M, Eary J F, Krohn K A
Division of Nuclear Medicine, University of Washington, Seattle 98195, USA.
J Nucl Med. 1998 Jun;39(6):1043-55.
Carbon-11-thymidine is a PET tracer of DNA synthesis and cellular proliferation. Quantitative analysis of [11C]thymidine images is complicated by the presence of significant quantities of labeled metabolites. Estimation of the rate of thymidine incorporation into DNA using [11C]thymidine requires a kinetic model that is capable of describing the behavior of thymidine and labeled metabolites.
Based on previous studies with labeled thymidine, we constructed a five-compartment model describing the kinetic behavior of 2-[11C]thymidine and its labeled metabolites. In addition, we have performed a series of calculations and simulations to calculate the sensitivity and identifiability of model parameters to estimate the extent to which individual parameters can be estimated; to determine appropriate model constraints necessary for reproducible estimates of the constant describing flux of thymidine from the blood into DNA, i.e., thymidine flux constant; and to determine the potential accuracy of model parameter and thymidine flux constant estimates from PET imaging data.
The underlying assumptions in the thymidine compartmental model lead to a description of the thymidine flux constant for DNA incorporation in terms of model parameters. Sensitivity and identifiability analyses suggest that the model parameters pertaining to labeled metabolites will be difficult to estimate independently of the thymidine parameters. Exact evaluation of the kinetic parameters of the labeled metabolites is not the principal goal of this model. Simulations were performed that suggest that it is preferable to tightly constrain these parameters to preset values near the center of their expected ranges. Although it is difficult to estimate individual thymidine model parameters, the flux constant for incorporation into DNA can be accurately estimated (r > 0.9 for estimated versus true simulated flux constant). Flux constant estimates are not affected by modest levels of local degradation of thymidine that may occur in proliferating tissue.
By using a kinetic model for thymidine and labeled metabolites, it is possible to estimate the flux of thymidine uptake and incorporation into DNA and, thereby, noninvasively estimate regional cellular proliferation using [11C]thymidine and PET.
碳 - 11 - 胸苷是一种用于DNA合成和细胞增殖的正电子发射断层扫描（PET）示踪剂。由于存在大量标记代谢物，[11C]胸苷图像的定量分析变得复杂。使用[11C]胸苷估计胸苷掺入DNA的速率需要一个能够描述胸苷和标记代谢物行为的动力学模型。
基于先前对标记胸苷的研究，我们构建了一个五室模型来描述2 - [11C]胸苷及其标记代谢物的动力学行为。此外，我们进行了一系列计算和模拟，以计算模型参数的敏感性和可识别性，从而估计各个参数能够被估计的程度；确定对从血液进入DNA的胸苷通量常数（即胸苷通量常数）进行可重复估计所需的适当模型约束；并根据PET成像数据确定模型参数和胸苷通量常数估计的潜在准确性。
胸苷房室模型中的基本假设导致根据模型参数对DNA掺入的胸苷通量常数进行描述。敏感性和可识别性分析表明，与标记代谢物相关的模型参数很难独立于胸苷参数进行估计。对标记代谢物动力学参数的精确评估并非该模型的主要目标。进行的模拟表明，最好将这些参数严格约束在其预期范围中心附近的预设值。虽然很难估计单个胸苷模型参数，但可以准确估计掺入DNA的通量常数（估计通量常数与真实模拟通量常数的r>0.9）。通量常数估计不受增殖组织中可能发生的适度水平的胸苷局部降解的影响。
通过使用胸苷和标记代谢物的动力学模型，可以估计胸苷摄取和掺入DNA的通量，从而使用[11C]胸苷和PET无创地估计区域细胞增殖。
