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

Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Maryland 20892-0135, USA.
Synapse (Impact Factor: 2.13). 12/2006; 60(7):510-20. DOI: 10.1002/syn.20327
Source: PubMed


[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.

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Available from: Sami S Zoghbi
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    • "A number of studies have focused on the development of radioligands for imaging postsynaptic 5-HT 1A receptors, since presynaptic sites exhibit a nonlinear relationship between receptor occupancy and response (Meller et al., 1990). Although [carbonyl- 11 C]WAY- 100635, [ 18 F]FCWAY, [ 18 F]MPPF, and [carbonyl- 11 C]- Desmethyl-WAY-100635 ([ 11 C]DWAY) has been used in human studies, they have some drawbacks, such as low nonspecific uptake in the cerebellum, fast sys- temic metabolism ([carbonyl- 11 C]-WAY-100635, Yasuno et al., 2006), defluorination of the parent compound in vivo ([ 18 F]FCWAY, Carson et al., 2003), a low affinity for their targets ([ 18 F]MPPF, Shiue et al., 1997), and the low radiochemical yield ([ 11 C]DWAY , Kumar et al., 2007). Defluorination in particular is considered to be an important issue for some [ 18 F]-labeled radioligands. "
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    ABSTRACT: Introduction: [(18) F]MeFWAY has been developed for imaging the serotonin 1A receptors in the brain. The purpose of this study were to verify the metabolic stability of [(18) F]MeFWAY, to measure the degree of defluorination of [(18) F]MeFWAY in vivo, to investigate methods of inhibition of defluorination of [(18) F]MeFWAY, and to assess the efficacy of [(18) F]MeFWAY in rat brains in vivo. Methods: MicroPET experiments in rats were conducted to confirm the distribution of radioactivity in the brain. Nondisplaceable binding potential (BP(ND) ) in the hippocampus and frontal cortex were also analyzed. Miconazole and fluconazole were tested for the ability to suppress defluorination of [(18) F]MeFWAY. We conducted a blockade and displacement experiment by treating with WAY-100635. Results: In vitro stability tests showed that MeFWAY was very stable in serum for 6 h, but PET revealed that authentic [(18) F]MeFWAY underwent significant defluorination in vivo. In vitro inhibition study against decreasing parent activity in liver microsomes, miconazole and fluconazole suppressed metabolic elimination of MeFWAY. However, in the PET study, fluconazole showed more potent inhibitory activity than miconazole. In the suppression of metabolizing enzymes using fluconazole, radioactivity in skull was dramatically decreased by 81% (compared with 69% with miconazole) and it was coupled with an increase in brain uptake. Moreover, BP(ND) in hippocampus was 5.53 and 2.66 in frontal cortex. The blockade and displacement study showed the specificity of [(18) F]MeFWAY to 5-HT(1A) receptors. Conclusion: In the rat brain, [(18) F]MeFWAY microPET showed skull uptake due to defluorination in vivo. We can effectively overcome this drawback with fluconazole.
    Full-text · Article · Dec 2012 · Synapse
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    • "Epilepsia ILAE P-glycoprotein functional imaging, as further substantiated by the present investigation. In this context, it should be noted that previous studies with other PET tracers indicated that tariquidar treatment increased the plasma-free fraction of [ 11 C]-WAY, a structural homolog of [ 18 F]MPPF, an effect which might be expected to increase the magnitude of K 1 relative to the blood concentration of the tracer (Yasuno et al., 2006). However, the present study focused on the comparison between responders and nonresponders. "
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    ABSTRACT: Based on experimental findings, overexpression of P-glycoprotein at the blood-brain barrier has been suggested to be a contributor to pharmacoresistance of the epileptic brain. We test a technique for evaluation of interindividual differences of elevated transporter function, through microPET analysis of the impact of the P-glycoprotein modulator tariquidar. The preclinical study is intended for eventual translation to clinical research of patients with pharmacoresistant seizure disorders. We made a microPET evaluation of the effects of tariquidar on the brain kinetics of the P-glycoprotein substrate [(18) F]MPPF in a rat model with spontaneous recurrent seizures, in which it has previously been demonstrated that phenobarbital nonresponders exhibit higher P-glycoprotein expression than do phenobarbital responders. Mean baseline parametric maps of the [(18) F]MPPF unidirectional blood-brain clearance (K(1) ; ml/g per min) and the efflux rate constant (k(2) ; per min) did not differ between the nonresponder and responder group. Tariquidar pretreatment increased the magnitude of [(18) F]MPPF K(1) in hippocampus by a mean of 142% in the nonresponders, which significantly exceeded the 92% increase observed in the responder group. The same treatment decreased the mean magnitude of [(18) F]MPPF k(2) in hippocampus by 27% in nonresponders, without comparable effects in the responder group. These results constitute a proof-of-concept for a novel imaging approach to evaluate blood-brain barrier P-glycoprotein function in animals. By extension, [(18) F]MPPF positron emission tomography (PET) with tariquidar pretreatment may be amenable for clinical applications exploring further the relevance of P-glycoprotein overexpression, and for enabling the rational design of pharmacotherapy according to individual differences in P-glycoprotein expression.
    Full-text · Article · Sep 2010 · Epilepsia
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    • "For example, the 5-HT 1A PET tracer RWAY exists as two enantiomers. It was initially demonstrated that the (R)-(-)-RWAY entantiomer had a much higher PET signal than its antipode, (S)-(+)-RWAY (Yasuno et al., 2006). Later, it was shown that (R)-(-)- RWAY was an antagonist whereas (S)-(+)-RWAY was a partial agonist (McCarron et al., 2007). "
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    ABSTRACT: Dopaminergic signaling pathways have been extensively investigated using PET imaging, primarily with antagonist radioligands of D(2) and D(3) dopamine receptors (DARs). Recently, agonist radioligands of D(2)/D(3) DARs have begun to be developed and employed. One such agonist is (R)-2-(11)CH(3)O-N-n-propylnorapomorphine (MNPA). Here, we perform a pharmacological characterization of MNPA using recombinant D(2) and D(3) DARs expressed in HEK293 cells. MNPA was found to robustly inhibit forskolin-stimulated cAMP accumulation to the same extent as dopamine in D(2) or D(3) DAR-transfected cells, indicating that it is a full agonist at both receptors. MNPA is approximately 50-fold more potent than dopamine at the D(2) DAR, but equally potent as dopamine at the D(3) DAR. MNPA competition binding curves in membrane preparations expressing D(2) DARs revealed two binding states of high and low-affinity. In the presence of GTP, only one binding state of low affinity was observed. Direct saturation binding assays using [(3)H]MNPA revealed similar results as with the competition experiments leading to the conclusion that MNPA binds to the D(2) DAR in an agonist-specific fashion. In contrast to membrane preparations, using intact cell binding assays, only one site of low affinity was observed for MNPA and other agonists binding to the D(2) DAR. MNPA was also found to induce D(2) DAR internalization to an even greater extent than dopamine as determined using both cell surface receptor binding assays and confocal fluorescence microscopy. Taken together, our data indicate that the PET tracer, MNPA, is a full and potent agonist at both D(2) and D(3) receptors.
    Full-text · Article · Jun 2009 · Synapse
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