Quantification of serotonin 5-HT1A receptors in monkey brain with [11C](R)-(-)-RWAY

[11C](R)-(-)-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](R)-(-)-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](R)-(-)-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](R)-(-)-RWAY into 5-HT1A receptor-rich brain regions was severalfold greater than for its antipode ([11C](S)-(+)-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](R)-(-)-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.