(S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin: a putative 5-HT1A-receptor antagonist

Se, Hillver; Björk, Lena; Li, Yali; Svensson, Björn E.; Ross, Sherman; Andén, Nils‐Erik; Hacksell, Uli

doi:10.1021/jm00168a002

Cited by 98 publications

(47 citation statements)

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“…Spiperone,spiroxatrine,propranolol,pindolol,BMY 7378,NAN 190, and (S)-UH 301 are partial antagonists (Fozard and Kilbinger, 1985;Glennon et al, 1988;Hillver et al, 1990;Nelson and Taylor, 1986;Tricklebank et al, 1984;Yocca et al, 1987). (S)-UH-301 displays 5-HT 1A receptor antagonist properties, but has only eightfold selectivity for 5-HT 1A relative to dopamine D2 binding sites (Hillver et al, 1990). Another compound, (1,1,3-trioxo-2H-1,2-benzoisothiazol-2-yl)butyl]-1-piperazinyl6 1H-indole-2-carboxylate), has been described as a potent and selective 5-HT 1A receptor antagonist in vitro and in vivo (Schoeffter et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

p-[18F]-MPPF: A potential radioligand for PET studies of 5-HT1A receptors in humans

Shiue

Mozley

et al. 1997

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The purpose of this study was to develop a radiopharmaceutical that could be used to selectively image 5-HT1A receptors with positron emission tomography (PET). No-carrier-added 4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-[18F] fluorobenzamido]ethylpiperazine (p-[18F]-MPPF, 2) was synthesized by the nucleophilic substitution of the corresponding nitro precursor 1 with K[18F]/Kryptofix 2.2.2. in dimethyl sulfoxide (DMSO) at 140 degrees C for 20 min followed by purification with high-performance liquid chromatography (HPLC) in 10% yield in a synthesis time of 90 min from end of bombardment (EOB). Specific activity was 1-4 Ci/microM. Biodistribution studies in rats showed that the initial uptake of 2 in the brain was high (0.7% dose/g tissue at 2 min). It was then rapidly eliminated. Rates of elimination were significantly slower in brain regions with high concentrations of 5-HT1A receptors (hippocampus, cortex, and hypothalamus) than in control regions. The maximum hippocampal/cerebellar ratio was 5.6:1 at 30 min postinjection. Uptake values in serotonergic, but not in control, regions were significantly reduced by prior treatment with either (+/-)-8-OH-DPAT (2 mg/kg, i.v., 5 min prior) or WAY 100635 (1 mg/kg, i.v., 5 min prior). Radioactivity in the femur did not increase with time, suggesting that in vivo defluorination may not be the major route of metabol sm. PET studies of 2 in a monkey demonstrated selective uptake and retention of 2 in the hippocampus. The hippocampal/cerebellar ratio was 3:1 at 30 min postinjection. The ratio was reduced to 1:1 by administering (+/-)-8-OH-DPAT (2 mg/kg, i.v.) 23 min postinjection of 2. Analyses of arterial plasma by HPLC revealed that 20% of radioactivity in the plasma remained as the parent compound 2 at 30 min postinjection. The results suggest that p-[18F]-MPPF may be a useful radioligand for studying cerebral 5-HT1A receptors in humans with PET techniques.

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Section: Introductionmentioning

confidence: 99%

p-[18F]-MPPF: A potential radioligand for PET studies of 5-HT1A receptors in humans

Shiue

Mozley

et al. 1997

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“…Specifically, we have previously reported that low doses of the selective and efficacious 5-HT1A receptor agonist (R)-8-OH-DPAT increase the firing rate and burst firing of midbrain DA cells, an effect that was more pronounced in the VTA than in the zona compacta, SN, whereas high doses of (R)-8-OH-DPAT depressed the firing rate of DA neurons in both areas (Arborelius et al, 1993a). Moreover, we found that the 5-HT m receptor antagonist (S)-UH-301 (Hillver et al, 1990;Bj6rk et al, 1991;Nomikos et al, 1992;Arborelius et al, 1994) produces a decrease in DA cell activity in both the VTA and the SN, as well as a decrease in DA biosynthesis in dopaminergic terminal areas (Bj6rk et al, 1991;Arborelius et al, 1993a). Generally, an increased activity, particularly in burst firing, of DA neurons has been shown to be associated with increased release of DA in terminal regions (Gonon, 1988).…”

Section: Introductionmentioning

confidence: 63%

“…It is possible that the inhibitory effect of (S)-UH-301 on DA levels in the NAC and striatum is mediated through stimulation of DA-D2 or DA-D 3 receptors for which the drug has some affinity (Hillver et al, 1990;Hacksell personal communication) since the suppressant effect of (S)-UH-301 on midbrain DA cell activity was abolished by pretreatment with the potent DA-DJ D 3 receptor antagonist raclopride (Arborelius et al, 1993a). Also, it is well established that DA-D2 but also DA-D3 receptor agonists decrease the release of DA from nerve terminals (Zetterstr6m and Ungerstedt, 1984;Nomikos et al, 1991;Damsma et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

The 5-HT1A receptor antagonist (S)-UH-301 decreases dopamine release in the rat nucleus accumbens and striatum

Nomikos

Arborelius²,

Höök³

et al. 1996

J. Neural Transmission

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In this study we employed in vivo microdialysis to examine the effects of the selective 5-HT1A receptor antagonist (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin [(S)-UH-301] on extracellular concentrations of dopamine (DA) and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the nucleus accumbens (NAC) and dorsal striatum of awake freely moving rats. Systemic administration of (S)-UH-301 (1.25, 2.5, 5.0 mg/kg s.c.) dose-dependently decreased extracellular concentrations of DA, DOPAC and HVA in the NAC. (S)-UH-301 (2.5 mg/kg s.c.) also decreased DA, but not DOPAC and HVA, concentrations in the striatum. Infusion of low concentrations (1, 10 microM) of (S)-UH-301 into either the NAC or the striatum did not affect DA levels, while only the highest concentration (1,000 microM) significantly decreased DA levels in both areas. Similarly, infusion of the selective 5-HT1A receptor agonist (R)-8-hydroxy-2-(di-n-propylamino)tetralin [(R)-8-OH-DPAT] only in high concentrations (100, 1,000 microM) decreased DA levels in both regions. These data suggest that (S)-UH-301 decreases DA release both in the NAC and the striatum probably indirectly via its purported DA-D2/D3 receptor agonistic properties. However, the observed inhibitory effect of (S)-UH-301 on DA release in the studied brain regions may also be explained, at least partly, by a serotonergic influence on the DA systems, acting at 5-HT1A receptor sites located elsewhere in the brain.

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“…Especially, it is the 5-HT 1A receptor that may be involved in these various physiological processes. [5][6][7][8][9][10] A major task in the clinical routine is depression, because it affects an estimated 121 million people worldwide 11 while the molecular basis for depression is not fully being understood. However, deficits in the activity of serotoninmediated neurons in the brain are clearly central to the disease.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of novel WAY 100635 derivatives containing a norbornene group and radiofluorination of [¹⁸F]AH1.MZ as a serotonin 5‐HT_1A receptor antagonist for molecular imaging

Herth

Kramer

Rösch

2009

Labelled Comp Radiopharmac

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(S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin: a putative 5-HT1A-receptor antagonist

Cited by 98 publications

References 4 publications

p-[18F]-MPPF: A potential radioligand for PET studies of 5-HT1A receptors in humans

p-[18F]-MPPF: A potential radioligand for PET studies of 5-HT1A receptors in humans

The 5-HT1A receptor antagonist (S)-UH-301 decreases dopamine release in the rat nucleus accumbens and striatum

Synthesis of novel WAY 100635 derivatives containing a norbornene group and radiofluorination of [¹⁸F]AH1.MZ as a serotonin 5‐HT_1A receptor antagonist for molecular imaging

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(S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin: a putative 5-HT1A-receptor antagonist

Cited by 98 publications

References 4 publications

p-[18F]-MPPF: A potential radioligand for PET studies of 5-HT1A receptors in humans

p-[18F]-MPPF: A potential radioligand for PET studies of 5-HT1A receptors in humans

The 5-HT1A receptor antagonist (S)-UH-301 decreases dopamine release in the rat nucleus accumbens and striatum

Synthesis of novel WAY 100635 derivatives containing a norbornene group and radiofluorination of [18F]AH1.MZ as a serotonin 5‐HT1A receptor antagonist for molecular imaging

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Synthesis of novel WAY 100635 derivatives containing a norbornene group and radiofluorination of [¹⁸F]AH1.MZ as a serotonin 5‐HT_1A receptor antagonist for molecular imaging