人血脑屏障的 P 糖蛋白功能可以用底物放射性示踪剂 11C-N-去甲基洛哌丁胺进行定量。
P-glycoprotein function at the blood-brain barrier in humans can be quantified with the substrate radiotracer 11C-N-desmethyl-loperamide.
机构信息
Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Maryland 20892, USA.
出版信息
J Nucl Med. 2010 Apr;51(4):559-66. doi: 10.2967/jnumed.109.070151. Epub 2010 Mar 17.
UNLABELLED
Permeability-glycoprotein (P-gp), an efflux transporter in several organs, acts at the blood-brain barrier to protect the brain from exogenous toxins. P-gp almost completely blocks brain entry of the PET radiotracer (11)C-N-desmethyl-loperamide ((11)C-dLop). We examined the ability of (11)C-dLop to quantify P-gp function in humans after increasing doses of tariquidar, an inhibitor of P-gp.
METHODS
Seventeen healthy volunteers had a total of 23 PET scans with (11)C-dLop at baseline and after increasing doses of tariquidar (2, 4, and 6 mg/kg intravenously). A subset of subjects received PET with (15)O-H(2)O to measure cerebral blood flow. Brain uptake of (11)C-dLop was quantified in 2 ways. Without blood data, uptake was measured as area under the time-activity curve in the brain from 10 to 30 min (AUC(10-30)). With arterial blood data, brain uptake was quantified with compartmental modeling to estimate the rates of entry into (K(1)) and efflux from (k(2)) the brain.
RESULTS
Brain uptake of radioactivity was negligible at baseline and increased only slightly (approximately 30%) after 2 mg of tariquidar per kilogram. In contrast, 4 and 6 mg of tariquidar per kilogram increased brain uptake 2- and 4-fold, respectively. Greater brain uptake reflected greater brain entry (K(1)), because efflux (k(2)) and cerebral blood flow did not differ between tariquidar-treated and untreated subjects. In the subjects who received the highest dose of tariquidar (and had the highest brain uptake), regional values of K(1) correlated linearly with absolute cerebral blood flow, consistent with high single-pass extraction of (11)C-dLop. AUC(10-30) correlated linearly with K(1).
CONCLUSION
P-gp function at the blood-brain barrier in humans can be quantified using PET and (11)C-dLop. A simple measure of brain uptake (AUC(10-30)) may be used as a surrogate of the fully quantified rate constant for brain entry (K(1)) and thereby avoid arterial sampling. However, to dissect the function of P-gp itself, both brain uptake and the influx rate constant must be corrected for radiotracer delivery (blood flow).
目的
研究在增加剂量的他利喹达后，11C-N-去甲基洛哌丁胺（11C-dLop）是否可用于定量人类血脑屏障中的 P-糖蛋白（P-gp）功能。
方法
17 名健康志愿者共进行了 23 次 11C-dLop PET 扫描，分别在基线时和增加剂量的他利喹达（2、4 和 6mg/kg 静脉注射）后进行。部分受试者接受 15O-H2O PET 以测量脑血流。使用 2 种方法对 11C-dLop 的脑摄取进行定量：不使用血液数据时，通过 10-30min 时脑内时间-活性曲线下面积（AUC（10-30））进行测量；使用动脉血数据时，通过房室模型对脑摄取进行定量，以估计进入（K1）和流出（k2）脑的速率。
结果
基线时放射性摄取可忽略不计，仅在每公斤 2mg 他利喹达后略有增加（约 30%）。相比之下，每公斤 4mg 和 6mg 他利喹达分别使脑摄取增加 2 倍和 4 倍。更大的脑摄取反映了更大的脑内进入（K1），因为在他利喹达治疗和未治疗的受试者之间，流出（k2）和脑血流没有差异。在接受最高剂量他利喹达的受试者中（脑摄取最高），K1 的区域值与绝对脑血流呈线性相关，这与 11C-dLop 的高单次通过提取一致。AUC（10-30）与 K1 呈线性相关。
结论
在人类中，可使用 PET 和 11C-dLop 定量血脑屏障中的 P-gp 功能。脑摄取的简单测量（AUC（10-30））可作为脑内进入的完全量化速率常数（K1）的替代物，从而避免动脉取样。然而，为了解剖 P-gp 本身的功能，必须校正放射性示踪剂输送（血流）对脑摄取和流入速率常数的影响。
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