Quantifying drug-related 5-HT1A receptor occupancy with [18F]MPPF

Passchier, Jan; Waarde, Aren van; Pieterman, RM; Willemsen, Atm; Vaalburg, W

doi:10.1007/s002130100688

Cited by 16 publications

(11 citation statements)

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“…Low levels of 5-HT 1A receptor occupancy by buspirone at clinically effective doses have been reported previously in human positron emission tomography studies (Rabiner et al, 2000;Passchier et al, 2001). A single dose of 10 or 40 mg of buspirone occupies ϳ5% 5-HT 1A receptors in healthy human subjects (Rabiner et al, 2000;Passchier et al, 2001).…”

Section: Discussionmentioning

confidence: 53%

“…A single dose of 10 or 40 mg of buspirone occupies ϳ5% 5-HT 1A receptors in healthy human subjects (Rabiner et al, 2000;Passchier et al, 2001). A similar low fraction (Ͻ10%) of occupancy in humans has been observed with other selective and nonselective 5-HT 1A agonists such as tandospirone, flesinoxan, and EMD 128 130 after single or multiple clinical doses capable of activating central 5-HT 1A receptor functions (Nakayama et al, 2002;Rabiner et al, 2002;Bantick et al, 2004).…”

Section: Discussionmentioning

confidence: 59%

“…Although behavioral/clinical effects of buspirone and other 5-HT 1A agonists are believed to be mediated through occupying and acting on 5-HT 1A receptors, the level of 5-HT 1A receptor occupancy required for the effects has not been well investigated. In two human positron emission tomography studies, little or no occupancy of 5-HT 1A receptors has been observed after administration of clinically efficacious doses of buspirone (Rabiner et al, 2000;Passchier et al, 2001 …”

Section: Introductionmentioning

confidence: 99%

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6-Hydroxybuspirone Is a Major Active Metabolite of Buspirone: Assessment of Pharmacokinetics and 5-Hydroxytryptamine_1AReceptor Occupancy in Rats

Wong

Dockens²,

Pajor³

et al. 2007

Drug Metab Dispos

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ABSTRACT:The pharmacokinetics and in vivo potency of 6-hydroxybuspirone (6-OH-buspirone), a major metabolite of buspirone, were investigated. The plasma clearance (47.3 ؎ 3.5 ml/min/kg), volume of distribution (2.6 ؎ 0.3 l/kg), and half-life (1.2 ؎ 0.2 h) of 6-OHbuspirone in rats were similar to those for buspirone. Bioavailability was higher for 6-OH-buspirone (19%) compared with that for buspirone (1.4%). After intravenous infusions to steady-state levels in plasma, 6-OH-buspirone and buspirone increased 5-hydroxytryptamine (HT) 1A Buspirone ( Fig. 1) is a potent and selective 5-HT 1A receptor partial agonist that has been prescribed for the treatment of generalized anxiety disorders (Sramek et al., 2002;Blier and Ward, 2003;Goodman, 2004). Although the onset of action of buspirone is relatively slow and the efficacy is only obtained after chronic treatment, therapy with buspirone is not associated with undesirable side effects such as sedation, cognitive impairment, withdrawal symptoms, and potential abuse liability that can occur with benzodiazepine treatment (Eison and Temple, 1986;Tunnicliff, 1991;Argyropoulos and Nutt, 1999). Buspirone has also been suggested to have a role in the treatment of depressive disorders (Thase et al., 1998;Blier and Ward, 2003).Current hypotheses on the clinical mechanisms of action of buspirone focus on its agonist activities on 5-HT 1A receptors (Schreiber and De Vry, 1993;Blier and Ward, 2003). Belonging to the superfamily of G-protein-coupled receptors, 5-HT 1A receptors share a high identity (89%) of their transmembrane-spanning amino acid sequences in humans and rats (Albert et al., 1990). They are abundant as presynaptic (somatodendritic) autoreceptors on serotonergic neurons, primarily in the midbrain dorsal raphe nucleus; activation of the 5-HT 1A autoreceptors inhibits the neuronal activity and results in a reduction of 5-HT release in terminal synapses of the serotonergic neurons (Blier and Ward, 2003). 5-HT 1A receptors are also present as postsynaptic receptors in the forebrain limbic structures; activation of these receptors inhibits activities of postsynaptic neurons innervated by serotonergic axonal terminals. It has been hypothesized that prolonged activation of 5-HT 1A autoreceptors in the dorsal raphe with 5-HT 1A agonists, such as buspirone and its analogs, results in desensitization of the receptors and consequently increases releases of 5-HT in the limbic regions (Blier and Ward, 2003). The enhanced serotonergic functions are believed to be responsible for anxiolytic and antidepressant effects of these agents. Although behavioral/clinical effects of buspirone and other 5-HT 1A agonists are believed to be mediated through occupying and acting on 5-HT 1A receptors, the level of 5-HT 1A receptor occupancy required for the effects has not been well investigated. In two human positron emission tomography studies, little or no occupancy of 5-HT 1A receptors has been observed after administration of clinically efficacious doses of buspirone (Rabiner et al., 200...

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 59%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

6-Hydroxybuspirone Is a Major Active Metabolite of Buspirone: Assessment of Pharmacokinetics and 5-Hydroxytryptamine_1AReceptor Occupancy in Rats

Wong

Dockens²,

Pajor³

et al. 2007

Drug Metab Dispos

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“…It is also of note that the pharmacodynamic effects of agonists binding to receptors can be considerable, even at low levels of occupancy, because of signal amplification. Therefore, although 5-HT 1A receptor occupancy with antagonists has been readily observed in animal and human PET studies, with occupancies as high as 52-71% in man with 40 mg DU 125530 (Rabiner et al, 2002c), agonist occupancy has only been identified in animal PET studies Shiue et al, 1997), and not in human studies (using lower drug doses) despite their pharmacological effects being manifest (Passchier et al, 2001;Nakayama et al, 2002;Rabiner et al, 2002a).…”

Section: Figurementioning

confidence: 96%

A Positron Emission Tomography Study of the 5-Ht1A Receptor in Schizophrenia and during Clozapine Treatment

Bantick

Montgomery²,

Bench

et al. 2004

J Psychopharmacol

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Several post-mortem studies have identified increases of 5-HT1A receptor density in frontal cortical areas in schizophrenic patients, and one has found increases in the cerebellar vermis. Clozapine has moderate affinity at the 5-HT1A receptor, and this may be of therapeutic importance. This positron emission tomography (PET) study attempted to replicate the post-mortem findings in vivo and sought an occupancy effect of clozapine at the 5-HT1A receptor. We recruited healthy controls, and patients with schizophrenia who were divided into those receiving clozapine and those receiving neuroleptics lacking 5-HT1A receptor affinity. Each volunteer received a PET scan, using the 5-HT1A receptor radioligand [carbonyl-11C]WAY-100635, and a magnetic resonance imaging scan. The cerebellar vermis was examined by comparing time-activity data between groups. For other brain regions (the raphe and subdivisions of the cerebral cortex), binding potential images were generated to reflect receptor density, then analysed using 'region of interest' and voxel-by-voxel methods. No significant changes of 5-HT1A receptor density were found in schizophrenic patients compared to controls. Two other PET studies, containing drug naïve rather than medicated schizophrenic patients, have also reported no increase in 5-HT1A receptor density in the frontal cortex. The results obtained in vivo bring into question the importance of the receptor in the pathophysiology of the illness. Clozapine did not occupy the 5-HT1A receptor at clinical doses. This is consistent with recent related PET results: 5-HT1A agonists do not appear to measurably block the binding of antagonist radiotracers in man at doses that are pharmacologically active but which are limited by tolerability.

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“…It can be assumed that only a limited portion of [ 11 C]WAY 100635 binding might be susceptible to tandospirone. Passchier et al (2001) also failed to find a measurable occupancy by a clinical dose of buspirone, a 5-HT 1A partial agonist, using the antagonist radioligand [ 18 F]MPPF. Another possible explanation is the spare receptor or receptor reserve hypothesis, which is based on the idea that in the systems with a large "receptor reserve" (Goldenstein et al 1974), ED 50 can be expected to be much less than the dose at 50% receptor occupancy (Furchgott 1978), and the pharmacological effect is acquired at a low occupancy.…”

Section: Discussionmentioning

confidence: 86%

In vivo drug action of tandospirone at 5-HT 1A receptor examined using positron emission tomography and neuroendocrine response

Nakayama

Suhara²,

Okubo³

et al. 2002

Psychopharmacology

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Quantifying drug-related 5-HT1A receptor occupancy with [18F]MPPF

Cited by 16 publications

References 1 publication

6-Hydroxybuspirone Is a Major Active Metabolite of Buspirone: Assessment of Pharmacokinetics and 5-Hydroxytryptamine_1AReceptor Occupancy in Rats

6-Hydroxybuspirone Is a Major Active Metabolite of Buspirone: Assessment of Pharmacokinetics and 5-Hydroxytryptamine_1AReceptor Occupancy in Rats

A Positron Emission Tomography Study of the 5-Ht1A Receptor in Schizophrenia and during Clozapine Treatment

In vivo drug action of tandospirone at 5-HT 1A receptor examined using positron emission tomography and neuroendocrine response

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Quantifying drug-related 5-HT1A receptor occupancy with [18F]MPPF

Cited by 16 publications

References 1 publication

6-Hydroxybuspirone Is a Major Active Metabolite of Buspirone: Assessment of Pharmacokinetics and 5-Hydroxytryptamine1AReceptor Occupancy in Rats

6-Hydroxybuspirone Is a Major Active Metabolite of Buspirone: Assessment of Pharmacokinetics and 5-Hydroxytryptamine1AReceptor Occupancy in Rats

A Positron Emission Tomography Study of the 5-Ht1A Receptor in Schizophrenia and during Clozapine Treatment

In vivo drug action of tandospirone at 5-HT 1A receptor examined using positron emission tomography and neuroendocrine response

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6-Hydroxybuspirone Is a Major Active Metabolite of Buspirone: Assessment of Pharmacokinetics and 5-Hydroxytryptamine_1AReceptor Occupancy in Rats

6-Hydroxybuspirone Is a Major Active Metabolite of Buspirone: Assessment of Pharmacokinetics and 5-Hydroxytryptamine_1AReceptor Occupancy in Rats