Positron emission tomography study of pindolol occupancy of 5-HT1A receptors in humans: preliminary analyses

Martínez, Diana; Mawlawi, Osama; Hwang, Dah‐Ren; Kent, Justine; Simpson, Norman R.; Parsey, Ramin V.; Hashimoto, Tomoki; Slifstein, Mark; Huang, Yiyun; Heertum, Ronald Van; Abi‐Dargham, Anissa; Caltabiano, S; Malizia, Andrea L.; Cowley, Hugh; Mann, J. John; Laruelle, Marc

doi:10.1016/s0969-8051(00)00122-0

Cited by 22 publications

(14 citation statements)

References 36 publications

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“…A well known example of a compound that exhibits preferential interaction with a subpopulation of 5-HT 1A receptors is the partial agonist pindolol, which preferentially occupies somato-dendritic 5-HT 1A receptors in the raphe nucleus, as demonstrated by PET brain imaging studies (Martinez et al, 2001). However, pindolol also acts as a ␤-adrenoreceptor antagonist and therefore only possesses limited receptor selectivity.…”

Section: Anatomically Selective Targeting Of 5-ht 1a and 5-ht 2a Tranmentioning

confidence: 99%

Anatomically Selective Serotonergic Type 1A and Serotonergic Type 2A Therapies for Parkinson's Disease: An Approach to Reducing Dyskinesia without Exacerbating Parkinsonism?

Huot¹,

Fox²,

Newman‐Tancredi³

et al. 2011

J Pharmacol Exp Ther

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L-DOPA remains the most effective treatment for Parkinson's disease (PD). However, long-term administration of L-DOPA is compromised by complications, particularly dyskinesia. Serotonergic type 1A (5-HT 1A ) receptor agonists and serotonergic type 2A (5-HT 2A ) receptor antagonists were, until recently, considered to be promising therapies against dyskinesia. However, there have been some recent high-profile failures in clinical trials, notably with sarizotan, and it seems that these classes of drugs may also impair L-DOPA antiparkinsonian efficacy. A simple explanation for the loss of antiparkinsonian benefit might be lack of good selectivity of these compounds for their respective targets, particularly with respect to off-target actions on dopaminergic receptors or poor dose selection in clinical studies. However, such explanations do not hold broadly when considering the actions of all compounds studied to date, whether in animal models or clinical trials. Here, we review 5-HT 1A and 5-HT 2A receptor function in PD and provide an anatomically based rationale as to why in some instances 5-HT 1A -and 5-HT 2A -modulating drugs might worsen parkinsonism, in addition to reducing dyskinesia. We propose that, in addition to selectivity for specific receptor subtypes, to target 5-HT 1A and 5-HT 2A receptors to alleviate dyskinesia, without worsening parkinsonism, it will be necessary to develop compounds that display anatomical selectivity, targeting corticostriatal transmission, while avoiding 5-HT receptors on ascending serotonergic and dopaminergic inputs from the raphe and substantia nigra, respectively.

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Section: Anatomically Selective Targeting Of 5-ht 1a and 5-ht 2a Tranmentioning

confidence: 99%

Anatomically Selective Serotonergic Type 1A and Serotonergic Type 2A Therapies for Parkinson's Disease: An Approach to Reducing Dyskinesia without Exacerbating Parkinsonism?

Huot¹,

Fox²,

Newman‐Tancredi³

et al. 2011

J Pharmacol Exp Ther

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“…At present, the level of binding to the 5‐HT 1A receptors required for a silent 5‐HT antagonist, such as lecozotan, to produce efficacy as a symptomatic treatment for AD is not known. Pindolol, a 5‐HT 1A antagonist, has been shown to have a 5‐HT 1A RO of 20%–40% at daily doses of 7.5–30 mg 23 . Lecozotan produced a dose‐related increase in 5‐HT 1A temporal cortex RO, and the 5 mg dose demonstrated a consistent binding to that receptor.…”

Section: Discussionmentioning

confidence: 98%

A Positron Emission Tomography Study to Assess Binding of Lecozotan, a Novel 5-Hydroxytryptamine-1A Silent Antagonist, to Brain 5-HT1A Receptors in Healthy Young and Elderly Subjects, and in Patients With Alzheimer's Disease

Raje¹,

Patat

Parks³

et al. 2007

Clin Pharmacol Ther

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This positron emission tomography (PET) study was conducted to assess binding of lecozotan, a new potent and silent 5-hydroxytryptamine-1A (5-HT1A) antagonist being developed for the treatment of Alzheimer's disease (AD), to 5-HT1A receptors in the human brain using 11C-labeled WAY-100635. Lecozotan was administered as a single dose of 0.5, 1, or 5 mg to young subjects and 5 mg to elderly subjects and AD patients. PET measurements were performed at 3-4 time points over a 25-h period. Mean peak 5-HT1A receptor occupancy (RO) in young subjects (seen at 1 h) was 10%, 18%, and 44% for the three doses, respectively. Mean peak RO was slightly higher in elderly (63%) and AD patients (55%). An Emax pharmacokinetic/pharmacodynamic model adequately described the lecozotan plasma concentration-RO relationship. Steady-state peak RO is predicted to be approximately 70% for 5 mg q12 h (twice-daily). Results demonstrate that lecozotan binds to the human brain 5-HT1A receptors and has a maximum observed RO of 50-60% following a single dose of 5 mg in elderly subjects/AD patients.

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“…Administration of the 5HT 1A receptor weak partial agonist pindolol was found to hasten the improvement of depressed patients treated with an SSRI, presumably because of prevention of the activation of autoreceptors [Artigas et al, 1994]. In PET studies with healthy volunteers, Rabiner et al [2000] and Martinez et al [2001] have demonstrated a significantly higher level of occupancy of 5HT 1A receptors in the dorsal Raphe nucleus by pindolol than of those in cortical and limbic regions. This differential level of occupancy may be important in the augmentation of response to SSRIs.…”

Section: Drug Targets In Other Systemsmentioning

confidence: 98%

Positron emission tomography and its use to image the occupancy of drug binding sites

Gatley

Volkow

Fowler

et al. 2003

Drug Development Research

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The development of positron emission tomography (PET) and the ability to synthesize compounds labeled with the short-lived positron emitters 11 C and 18 F has made possible the imaging and quantification of drug binding sites in the human body. By conducting PET studies with an appropriate radioligand before and after treatment with a drug, the fraction of the total number of binding sites that is occupied by the drug (the "occupancy" of the site) can often be determined. To the extent that occupancy is a good indicator of pharmacological activity, such PET experiments can aid the development of drug dosage regimens. Some of the general issues involved in PET studies of drug occupancy are discussed. There have been many such studies involving antipsychotic drugs and dopamine D 2 receptor radioligands. Since neuroleptics have been extensively reviewed elsewhere, only the major findings are discussed here. Other binding sites (and drug classes) in the dopamine system to which this methodology has been applied include: the dopamine transporter (stimulant drugs) and monoamine oxidase A and B (antidepressant drugs). Occupancy studies are also possible for many drug targets beyond the dopamine system. Drug Dev.

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Positron emission tomography study of pindolol occupancy of 5-HT1A receptors in humans: preliminary analyses

Cited by 22 publications

References 36 publications

Anatomically Selective Serotonergic Type 1A and Serotonergic Type 2A Therapies for Parkinson's Disease: An Approach to Reducing Dyskinesia without Exacerbating Parkinsonism?

Anatomically Selective Serotonergic Type 1A and Serotonergic Type 2A Therapies for Parkinson's Disease: An Approach to Reducing Dyskinesia without Exacerbating Parkinsonism?

A Positron Emission Tomography Study to Assess Binding of Lecozotan, a Novel 5-Hydroxytryptamine-1A Silent Antagonist, to Brain 5-HT1A Receptors in Healthy Young and Elderly Subjects, and in Patients With Alzheimer's Disease

Positron emission tomography and its use to image the occupancy of drug binding sites

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