title: Evaluation of [C]S14506 and [F]S14506 in rat and monkey as agonist PET radioligands for brain 5-HT(1A) receptors.
abstract: In vitro and ex vivo measurements have shown that the binding of the selective high-affinity agonist, S14506 (1-[2-(4-fluorobenzoylamino)ethyl]-4-(7-methoxy-naphthyl)piperazine), to 5-HT(1A) receptors, is similar in affinity (K(d) = 0.79 nM) and extent (B(max)) to that of the antagonist, WAY 100635. We aimed to test whether S14506, labeled with a positron-emitter, might serve as a radioligand for imaging brain 5-HT(1A) receptors in vivo with positron emission tomography (PET). Here we evaluated [(11)C]S14506 and [(18)F]S14506 in rat and rhesus monkey in vivo. After intravenous administration of [(11)C]S14506 into rat, radioactivity entered brain, reaching 210% SUV at 2 min. Radioactivity uptake into brain was higher (~ 350% SUV) in rats pre-treated with the P-glycoprotein (P-gp) inhibitor, cyclosporin A. In rhesus monkey, peak brain uptake of radioactivity after administration of [(11)C]S14506 or [(18)F]S14506 was also moderate and for [(11)C]S14506 increased from ~ 170% SUV after 7 min, to 240% SUV in a monkey pre-treated with the P-gp inhibitor, tariquidar. The ratios of radioactivity in 5-HT(1A) receptor-rich regions, such as cingulate or hippocampus to that in receptor-poor cerebellum reached between 1.35 and 1.5 at 60 min for both [(11)C]S14506 and [(18)F]S14506. [(11)C]S14506 gave one major polar radiometabolite in monkey plasma, and [(18)F]S14506 gave three and two more polar radiometabolites in rat and monkey plasma, respectively. The rat radiometabolites of [(18)F]S14506 did not accumulate in brain. [(18)F]S14506 was not radiodefluorinated in monkey. Thus, despite high-affinity and lack of troublesome brain radiometabolites, both [(11)C]S14506 and [(18)F]S14506 were ineffective for imaging rat or monkey brain 5-HT(1A) receptors in vivo, even under P-gp inhibited conditions. Explanations for the failure of these radioligands are offered.
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Room B3C346, Bethesda MD 20892-1003, USA.
authors.forename: Shuiyu
authors.initials: S
authors.lastname: Lu
authors.forename: Jeih-San
authors.initials: JS
authors.lastname: Liow
authors.forename: Sami S
authors.initials: SS
authors.lastname: Zoghbi
authors.forename: Jinsoo
authors.initials: J
authors.lastname: Hong
authors.forename: Robert B
authors.initials: RB
authors.lastname: Innis
authors.forename: Victor W
authors.initials: VW
authors.lastname: Pike