Liow Jeih-San, Kreisl William, Zoghbi Sami S, Lazarova Neva, Seneca Nicholas, Gladding Robert L, Taku Andrew, Herscovitch Peter, Pike Victor W, Innis Robert B
Molecular Imaging Branch, PET Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892-2035, USA.
J Nucl Med. 2009 Jan;50(1):108-15. doi: 10.2967/jnumed.108.056226. Epub 2008 Dec 17.
11C-Loperamide is an avid substrate for P-glycoprotein (P-gp), but it is rapidly metabolized to 11C-N-desmethyl-loperamide (11C-dLop), which is also a substrate for P-gp and thereby contaminates the radioactive signal in the brain. Should further demethylation of 11C-dLop occur, radiometabolites with low entry into the brain are generated. Therefore, we evaluated the ability of 11C-dLop to quantify the function of P-gp at the blood-brain barrier in monkeys.
Six monkeys underwent 12 PET scans of the brain, 5 at baseline and 7 after pharmacologic blockade of P-gp. A subset of monkeys also underwent PET scans with 15O-water to measure cerebral blood flow. To determine whether P-gp blockade affected peripheral distribution of 11C-dLop, we measured whole-body biodistribution in 4 monkeys at baseline and after P-gp blockade.
The concentration of 11C-dLop in the brain was low under baseline conditions and increased 5-fold after P-gp blockade. This increase was primarily caused by an increased rate of entry into the brain rather than a decreased rate of removal from the brain. With P-gp blockade, uptake of radioactivity among brain regions correlated linearly with blood flow, suggesting a high single-pass extraction. After correction for cerebral blood flow, the uptake of 11C-dLop was fairly uniform among brain regions, suggesting that the function of P-gp is fairly uniformly distributed in the brain. On whole-body imaging, P-gp blockade significantly affected distribution of radioactivity only to the brain and not to other visually identified source organs. The effective dose estimated for humans was approximately 9 microSv/MBq.
PET with 11C-dLop can quantify P-gp function at the blood-brain barrier in monkeys. The single-pass extraction of 11C-dLop is high and requires correction for blood flow to accurately measure the function of this efflux transporter. The low uptake at baseline and markedly increased uptake after P-gp blockade suggest that 11C-dLop will be useful to measure a wide range of P-gp functions at the blood-brain barrier in humans.
11C-洛哌丁胺是P-糖蛋白（P-gp）的一种活性底物，但它会迅速代谢为11C-N-去甲基洛哌丁胺（11C-dLop），后者也是P-gp的底物，从而会污染脑内的放射性信号。如果11C-dLop进一步去甲基化，就会产生进入脑内较少的放射性代谢物。因此，我们评估了11C-dLop定量猴子血脑屏障处P-gp功能的能力。
6只猴子接受了12次脑部PET扫描，5次在基线状态下进行，7次在P-gp药理学阻断后进行。一部分猴子还用15O-水进行了PET扫描以测量脑血流量。为了确定P-gp阻断是否影响11C-dLop的外周分布，我们在4只猴子的基线状态和P-gp阻断后测量了全身生物分布。
在基线条件下，脑内11C-dLop的浓度较低，在P-gp阻断后增加了5倍。这种增加主要是由于进入脑内的速率增加，而不是从脑内清除的速率降低。在P-gp阻断后，脑区放射性摄取与血流量呈线性相关，表明单次通过提取率较高。校正脑血流量后，脑区内11C-dLop的摄取相当均匀，这表明P-gp的功能在脑内分布相当均匀。在全身成像中，P-gp阻断仅显著影响放射性向脑内的分布，而不影响其他视觉识别的源器官。估计对人类的有效剂量约为9微希沃特/兆贝可。
用11C-dLop进行PET检查可以定量猴子血脑屏障处的P-gp功能。11C-dLop的单次通过提取率较高，需要校正血流量以准确测量这种外排转运蛋白的功能。基线时摄取较低以及P-gp阻断后摄取明显增加表明，11C-dLop将有助于测量人类血脑屏障处广泛的P-gp功能。
