Inserm, CNRS, CEA, BioMaps, Laboratoire d'Imagerie Biomédicale Multimodale Paris-Saclay, Université Paris-Saclay, CEA/SHFJ, 4 Place du Général Leclerc 91400, Orsay, France.
Inserm UMR-S1144, University of Paris Cité, 75006, Paris, France.
Mol Imaging Biol. 2023 Dec;25(6):1135-1141. doi: 10.1007/s11307-023-01864-z. Epub 2023 Oct 6.
PET imaging using [C]metoclopramide revealed the importance of P-glycoprotein (P-gp, ABCB1) in mediating the brain-to-blood efflux of substrates across the blood-brain barrier (BBB). In this work, the elimination rate constant from the brain (k), calculated from dynamic PET images without the need for arterial blood sampling, was evaluated as an outcome parameter for the interpretation of [C]metoclopramide PET data.
k parameter was obtained by linear regression of log-transformed brain time-activity curves (TACs). k values (h) obtained under baseline conditions were compared with values obtained after complete P-gp inhibition using tariquidar in rats (n = 4) and baboons (n = 4) or after partial inhibition using cyclosporine A in humans (n = 10). In baboons, the sensitivity of k to measure complete P-gp inhibition was compared with outcome parameters derived from kinetic modeling using a 1-tissue compartment model (1-TCM). Finally, k-maps were generated in each species using PMOD software.
The linear part of the log-transformed brain TACs occurred from 10 to 30 min after radiotracer injection in rats, from 15 to 60 min in baboons, and from 20 to 60 min in humans. P-gp inhibition significantly decreased k values by 39 ± 12% in rats (p < 0.01), by 32 ± 6% in baboons (p < 0.001), and by 37 ± 22% in humans (p < 0.001). In baboons, P-gp inhibition consistently decreased the brain-to-plasma efflux rate constant k (36 ± 9%, p < 0.01) leading to an increase in the total brain volume of distribution (V, 101 ± 12%, p < 0.001). In all studied species, brain k-maps displayed decreased P-gp-mediated efflux across the BBB.
k of [C]metoclopramide provides a simple outcome parameter to describe P-gp function in the living brain when arterial input function data are unavailable, although less sensitive than V. k-maps represent easy to compute parametric images reflecting the effect of P-gp on [C]metoclopramide elimination from the brain.
使用 [C] 美托洛嗪进行 PET 成像显示了 P-糖蛋白（P-gp，ABCB1）在介导血脑屏障（BBB）内底物从脑到血液的外排中的重要性。在这项工作中，从大脑中计算出的消除速率常数（k），通过不需要动脉采血的动态 PET 图像获得，被评估为解释 [C] 美托洛嗪 PET 数据的一个结果参数。
通过对对数转换的脑时间-活性曲线（TAC）进行线性回归获得 k 参数。在大鼠（n=4）和狨猴（n=4）中使用完全 P-gp 抑制剂 tariquidar 或在人类中使用部分抑制剂环孢菌素 A 获得基础条件下的 k 值（h）后，与 k 值进行比较。在狨猴中，比较了 k 测量完全 P-gp 抑制的灵敏度与使用 1 组织隔室模型（1-TCM）进行动力学建模得出的结果参数。最后，使用 PMOD 软件在每个物种中生成 k 图。
大鼠中放射性示踪剂注射后 10-30 分钟，狨猴中 15-60 分钟，人类中 20-60 分钟，log 转换的脑 TAC 的线性部分发生。P-gp 抑制使大鼠中的 k 值显著降低 39±12%（p<0.01），使狨猴中的 k 值降低 32±6%（p<0.001），使人类中的 k 值降低 37±22%（p<0.001）。在狨猴中，P-gp 抑制一致降低了脑-血浆外排速率常数 k（36±9%，p<0.01），导致总脑分布容积（V）增加 101±12%（p<0.001）。在所有研究的物种中，脑 k 图显示 P-gp 介导的 BBB 内外排减少。
当无法获得动脉输入函数数据时，[C] 美托洛嗪的 k 提供了一个简单的结果参数来描述活脑中的 P-gp 功能，尽管不如 V 敏感。k 图表示易于计算的参数图像，反映了 P-gp 对 [C] 美托洛嗪从脑消除的影响。
