SB-616234-A (1-[6-(cis-3,5-dimethylpiperazin-1-yl)-2,3-dihydro-5-methoxyindol-1-yl]-1-[2′methyl-4′-(5-methyl-1,2,3-oxadiazol-3-yl)biphenyl-4-yl]methanone hydrochloride): A novel, potent and selective 5-HT1B receptor antagonist

Scott, Claire M.; Langmead, Christopher J.; Clarke, Kirsten; Wyman, Paul; Smith, Paul W.; Starr, Kathryn R.; Dawson, Lee A.; Price, Gary; Hagan, James J.; Watson, Jeannette M.

doi:10.1016/j.neuropharm.2006.01.008

Cited by 6 publications

(5 citation statements)

References 33 publications

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“…A careful comparison of [ 11 C]P943 and [ 11 C]AZ10419369 will be facilitated by the publication of modeling studies for both tracers. SB-616234-A (1-[6-( cis -3,5-Dimethylpiperazin-1-yl)-2,3-dihydro-5-methoxyindol-1-yl]-1-[20-methyl-40-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methanone hydrochloride) also looks promising based on the in vitro and behavior characterization data; however, its in vivo specificity has not been evaluated yet [37, 38]. …”

Section: Discussionmentioning

confidence: 99%

High-resolution imaging of brain 5-HT1B receptors in the rhesus monkey using [11C]P943

Nabulsi¹,

Huang²,

Weinzimmer³

et al. 2010

Nuclear Medicine and Biology

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The serotonin 5-HT1B receptors regulate the release of serotonin and are involved in various disease states, including depression and schizophrenia. The goal of the study was to evaluate a high affinity and high selectivity antagonist, [11C]P943, as a PET tracer for imaging the 5-HT1B receptor. [11C]P943 was synthesized via N-methylation of the precursor with [11C]methyl iodide or [11C]methyl triflate using automated modules. The average radiochemical yield was approx. 10% with radiochemical purity of >99% and specific activity of 8.8 ± 3.6 mCi/nmol at the end-of-synthesis (n = 37). PET imaging was performed in non-human primates with a High Resolution Research Tomograph (HRRT) scanner with a bolus/infusion paradigm. Binding potential (BPND) was calculated using the equilibrium ratios of regions to cerebellum. The tracer uptake was highest in the globus pallidus and occipital cortex, moderate in basal ganglia and thalamus, and lowest in the cerebellum, which is consistent with the known brain distribution of 5-HT1B receptors. Infusion of tracer at different specific activities (by adding various amount of unlabeled P943) reduced BPND values in a dose-dependent manner, demonstrating the saturability of the tracer binding. Blocking studies with GR127935 (2 mg/kg, IV), a selective 5-HT1B/5-HT1D antagonist, resulted in reduction of BPND values by 42-95% across regions; for an example, in occipital region from 0.71 to 0.03, indicating a complete blockade. These results demonstrate the saturability and specificity of [11C]P943 for 5HT1B receptors, suggesting its suitability as a PET radiotracer for in vivo evaluations of the 5-HT1B receptor system in humans.

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Section: Discussionmentioning

confidence: 99%

High-resolution imaging of brain 5-HT1B receptors in the rhesus monkey using [11C]P943

Nabulsi¹,

Huang²,

Weinzimmer³

et al. 2010

Nuclear Medicine and Biology

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“…Two animals (B and C) were scanned with a challenge of 2 and 5 mg kg −1 of the selective 5HT 1B antagonist SB‐616234‐S (mesylate salt, 50‐fold selective for 5‐HT1B over 5‐HT1D, Scott et al, 2006), infused over 60 min starting 73 ± 8 min prior to the postchallenge scan. Three animals (A, B, and C) were scanned with a challenge of 3 mg kg −1 of the selective 5HT 1D antagonist SB‐714786 (free base, 250‐fold selective for 5‐HT1D over 5‐HT1B, Ward et al, 2005) infused over 60 min starting 65 ± 8 min prior to the postchallenge scan.…”

Section: Methodsmentioning

confidence: 99%

Characterization of in vivo pharmacological properties and sensitivity to endogenous serotonin of [¹¹C] P943: A positron emission tomography study in Papio anubis

Ridler¹,

Plisson²,

Rabiner³

et al. 2011

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[11 C] P943 is a recently developed PET radiotracer for serotonin 5-HT1B receptors. We characterized a number of its in vivo pharmacokinetic properties, including the evaluation of its two stereo-isomers, saturability of specific binding, selectivity for 5-HT1B and 5-HT1D receptors, and vulnerability to pharmacologically induced increases in endogenous 5-HT levels. Six isoflurane-anesthetized baboons were scanned with [11 C] P943 at baseline, and following various pharmacological manipulations. The interventions included the administration of pharmacological doses of P943, SB-616234-S (a 5-HT1B selective antagonist), SB-714786 (a 5-HT1D selective antagonist), as well as the administration of 5-HT releasing agents (fenfluramine, amphetamine) and 5-HT reuptake inhibitor (citalopram). [11 C] P943 was observed to bind saturably and specifically to 5-HT1B receptors and to be sensitive to all three challenges known to alter 5-HT levels in the proximity of receptors. [11 C] P943 shows promise as a tracer to image serotonin function in healthy subjects as well as subjects with psychiatric or neurologic conditions.

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“…NAS-181 [139], S-18127 [140], SB-236057 [141], SB-224289 [143], SB-616234 (138,144,145] and AR-A2 (see Fig. 7) [146][147][148].…”

Section: -Ht 1b/d Receptor Antagonism and Sert Inhibitionmentioning

confidence: 98%

5-HT1 Receptor Augmentation Strategies as Enhanced Efficacy Therapeutics for Psychiatric Disorders

Dawson

Bromidge²

2008

CTMC

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Since the initial observations linking 5-HT to psychiatric illness, evidence for a role of 5-HT and, in particular, a decreased brain serotonergic function in the pathology of a plethora of related disorders, has grown. However, it is the role of 5-HT in the pathogenesis of anxiety disorders and depression and the mechanism of action of antidepressants which has received the most attention. Thus enhanced serotonergic neurotransmission has become one of the unifying mechanisms of action of modern day antidepressants/anxiolytics such as monoamine oxidase inhibitors, tricyclic antidepressants, and serotonin reuptake inhibitors. Interestingly all of these treatments are associated with a delay to therapeutic efficacy and in some cases treatment resistance, despite immediate enhancements in serotonergic neurotransmission. The postulated reason for this is the need for temporal neuroplastic changes in the control of serotonergic neurotransmission, and more specifically changes in 5-HT(1) autoreceptor function. Thus significant research has gone into pharmacologically targeting these 5-HT(1) autoreceptors as a means of augmenting the efficacy of current therapeutic mechanisms. Here we will review the rationale behind the various augmentation strategies adopted and the progress made in identifying novel therapeutics for conditions such as depression and anxiety disorders.

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SB-616234-A (1-[6-(cis-3,5-dimethylpiperazin-1-yl)-2,3-dihydro-5-methoxyindol-1-yl]-1-[2′methyl-4′-(5-methyl-1,2,3-oxadiazol-3-yl)biphenyl-4-yl]methanone hydrochloride): A novel, potent and selective 5-HT1B receptor antagonist

Cited by 6 publications

References 33 publications

High-resolution imaging of brain 5-HT1B receptors in the rhesus monkey using [11C]P943

High-resolution imaging of brain 5-HT1B receptors in the rhesus monkey using [11C]P943

Characterization of in vivo pharmacological properties and sensitivity to endogenous serotonin of [¹¹C] P943: A positron emission tomography study in Papio anubis

5-HT1 Receptor Augmentation Strategies as Enhanced Efficacy Therapeutics for Psychiatric Disorders

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SB-616234-A (1-[6-(cis-3,5-dimethylpiperazin-1-yl)-2,3-dihydro-5-methoxyindol-1-yl]-1-[2′methyl-4′-(5-methyl-1,2,3-oxadiazol-3-yl)biphenyl-4-yl]methanone hydrochloride): A novel, potent and selective 5-HT1B receptor antagonist

Cited by 6 publications

References 33 publications

High-resolution imaging of brain 5-HT1B receptors in the rhesus monkey using [11C]P943

High-resolution imaging of brain 5-HT1B receptors in the rhesus monkey using [11C]P943

Characterization of in vivo pharmacological properties and sensitivity to endogenous serotonin of [11C] P943: A positron emission tomography study in Papio anubis

5-HT1 Receptor Augmentation Strategies as Enhanced Efficacy Therapeutics for Psychiatric Disorders

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Characterization of in vivo pharmacological properties and sensitivity to endogenous serotonin of [¹¹C] P943: A positron emission tomography study in Papio anubis