Yasuno Fumihiko, Zoghbi Sami S, McCarron Julie A, Hong Jinsoo, Ichise Masanori, Brown Amira K, Gladding Robert L, Bacher John D, Pike Victor W, Innis Robert B
Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Maryland 20892-0135, USA.
Synapse. 2006 Dec 1;60(7):510-20. doi: 10.1002/syn.20327.
11C-(-)-RWAY ([11C]2, 3, 4, 5, 6, 7-hexahydro-1{4-[1[4-(2-methoxyphenyl)-piperazinyl]]-2-phenylbutyry}-1H-azepine) is a new radioligand for imaging brain 5-HT1A receptors with positron emission tomography. In 11C-(-)-RWAY, the direction of the amide bond is expected to reduce metabolism by hydrolysis while allowing easy 11C-labeling at the methoxy position. The purposes of this study were to evaluate different tracer kinetic models in nonhuman primates to quantify 5-HT1A receptors with 11C-(-)-RWAY and to test for the possible action of P-glycoprotein (P-gp), one of the known efflux pumps at the blood-brain barrier. The brain uptake of radioactivity from 11C-(-)-RWAY into 5-HT1A receptor-rich brain regions was severalfold greater than for its antipode (11C-(+)-RWAY) and could be displaced by receptor saturating doses of the selective 5-HT1A antagonist, WAY-100635. Pretreatment with tariquidar, a potent inhibitor of P-gp, increased brain uptake of 11C-(-)-RWAY about 1.5-fold and the plasma free fraction about 1.8-fold. Thus, the effect of tariquidar on brain uptake may have been caused by displacement of the radioligand binding to plasma proteins. Mathematical modeling showed that the estimated values of regional binding potential were correlated strongly between two-tissue compartment model and multilinear reference tissue model, and thus, supported the use of the cerebellum as a reference region.
11C-(-)-RWAY（[11C]2,3,4,5,6,7-六氢-1-{4-[1-[4-(2-甲氧基苯基)-哌嗪基]]-2-苯基丁酰}-1H-氮杂卓）是一种用于正电子发射断层显像脑5-HT1A受体的新型放射性配体。在11C-(-)-RWAY中，酰胺键的方向预计可减少水解代谢，同时便于在甲氧基位置进行11C标记。本研究的目的是评估非人类灵长类动物中不同的示踪剂动力学模型，以用11C-(-)-RWAY定量5-HT1A受体，并测试血脑屏障中已知的外排泵之一P-糖蛋白（P-gp）的可能作用。11C-(-)-RWAY的放射性在富含5-HT1A受体的脑区的脑摄取量比其对映体（11C-(+)-RWAY）高几倍，并且可被选择性5-HT1A拮抗剂WAY-100635的受体饱和剂量所取代。用P-gp的强效抑制剂他林洛尔预处理，可使11C-(-)-RWAY的脑摄取量增加约1.5倍，血浆游离分数增加约1.8倍。因此，他林洛尔对脑摄取的影响可能是由于放射性配体与血浆蛋白结合的置换所致。数学建模表明，两组织室模型和多线性参考组织模型之间区域结合潜力的估计值高度相关，因此支持将小脑用作参考区域。
