Synthesis of [11C]dapoxetine · HCl, a serotonin re-uptake inhibitor: Biodistribution in rat and preliminary PET imaging in the monkey

Livni, Eli; Satterlee, W.; Robey, Roger L.; Alt, Charles A.; Meter, E. E. Van; Babich, John W.; Wheeler, William J.; O'Bannon, Douglas D.; Thrall, James H.; Fischman, Alan J.

doi:10.1016/0969-8051(94)90034-5

Cited by 25 publications

(9 citation statements)

References 15 publications

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“…[82] Brain PET studies have demonstrated significant displaceable binding of radiolabeled dapoxetine in the cerebral cortex and subcortical grey matter. [83]…”

Section: Treatmentmentioning

confidence: 99%

Premature ejaculation

McMahon

2007

Indian J Urol

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Premature ejaculation (PE) is a common male sexual disorder. Recent normative data suggests that men with an intravaginal ejaculatory latency time (IELT) of less than 1 minute have “definite” PE, while men with IELTs between 1 and 1.5 minutes have “probable” PE. Although there is insufficient empirical evidence to identify the etiology of PE, there is limited correlational evidence to suggest that men with PE have high levels of sexual anxiety and inherited altered sensitivity of central 5-HT (5-hydroxytryptamine, serotonin) receptors. Pharmacological modulation of the ejaculatory threshold using off-label daily or on-demand selective serotonin re-uptake inhibitors is well tolerated and offers patients a high likelihood of achieving improved ejaculatory control within a few days of initiating treatment, consequential improvements in sexual desire and other sexual domains. Investigational drugs such as the ejaculo-selective serotonin transport inhibitor, dapoxetine represent a major development in sexual medicine. These drugs offer patients the convenience of on-demand dosing, significant improvements in IELT, ejaculatory control and sexual satisfaction with minimal adverse effects.

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“…[82] Brain PET studies have demonstrated significant displaceable binding of radiolabeled dapoxetine in the cerebral cortex and subcortical grey matter. [83]…”

Section: Treatmentmentioning

confidence: 99%

Premature ejaculation

McMahon

2007

Indian J Urol

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“…Equilibrium radioligand binding studies using human cells demonstrate that dapoxetine binds to 5-HT, norepinephrine (NE) and dopamine (DA) reuptake transporters and inhibits uptake in the following order of potency: NE<5-HT>>DA [Gengo et al 2005]. Brain positron emission tomography studies have demonstrated significant displaceable binding of radiolabelled dapoxetine in the cerebral cortex and subcortical grey matter [Livni et al 1994]. The recent report that dapoxetine potently blocks cloned Kv4.3 potassium voltage-gated channels, which are involved in the regulation of neurotransmitter release, gives additional insight into the mechanism underlying some of the therapeutic actions of this drug [Jeong et al 2012].…”

Section: Pharmacological Treatment Of Premature Ejaculationmentioning

confidence: 99%

Dapoxetine: a new option in the medical management of premature ejaculation

McMahon

2012

Therapeutic Advances in Urology

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Premature ejaculation (PE) is a common male sexual disorder which is associated with substantial personal and interpersonal negative psychological consequences. Pharmacotherapy of PE with off-label antidepressant selective serotonin reuptake inhibitors (SSRIs) is common, effective and safe. Development and regulatory approval of drugs specifically for the treatment of PE will reduce reliance on off-label treatments and serve to fill an unmet treatment need. The objective of this article is to review evidence supporting the efficacy and safety of dapoxetine in the treatment of PE. MEDLINE, Web of Science, PICA, EMBASE and the proceedings of major international and regional scientific meetings were searched for publications or abstracts published during the period 1993-2012 that used the word 'dapoxetine' in the title, abstract or keywords. This search was then manually cross referenced for all papers. This review encompasses studies of dapoxetine pharmacokinetics, animal studies, human phase I, II and III studies, independent postmarketing and pharmacovigilance efficacy and safety studies and drug-interaction studies. Dapoxetine is a potent SSRI which is administered on demand 1-3 h prior to planned sexual contact. It is rapidly absorbed and eliminated, resulting in minimal accumulation, and has doseproportional pharmacokinetics which are unaffected by multiple dosing. Dapoxetine 30 mg and 60 mg has been evaluated in five industry-sponsored randomized, double-blind, placebo-controlled studies in 6081 men aged at least 18 years. Outcome measures included stopwatch-measured intravaginal ejaculatory latency time (IELT), Premature Ejaculation Profile (PEP) inventory items, Clinical Global Impression of Change (CGIC) in PE, and adverse events. Mean IELT, all PEP items and CGIC improved significantly with both doses of dapoxetine versus placebo (all p <0.001). The most common treatment-related adverse effects included nausea (11.0% for 30 mg, 22.2% for 60 mg), dizziness (5.9% for 30 mg, 10.9% for 60 mg), and headache (5.6% for 30 mg, 8.8% for 60 mg), and evaluation of validated rated scales demonstrated no SSRI class-related effects with dapoxetine use. Dapoxetine, as the first drug developed for PE, is an effective and safe treatment for PE and represents a major advance in sexual medicine.

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“…High SERT density is observed at the level of the midbrain nuclei, reflecting the presence of SERT on both the 5-HT cell body (raphe nuclei) and on terminals of the dense 5-HT innervation of the adjacent structures (substantia nigra, nucleus interpeduncularis, locus ceruleus, nucleus nervi Br]5-bromo-6-nitroquipazine have been evaluated as potential PET or SPECT radiotracers and found to be unsuitable due to high lipophilicity and/or high nonspecific binding (Hashimoto et al, 1987;Lasne et al, 1989;Dannals et al, 1990;Hume et al, 1991;Nelson et al, 1991;Livni et al, 1994;Scheffel et al, 1994;Jagust et al, 1996;Bergstrom et al, 1997;Smith et al, 1997;Zea-Ponce et al, 1997;Lundkvist et al, 1999).…”

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confidence: 99%

Comparative Evaluation in Nonhuman Primates of Five PET Radiotracers for Imaging the Serotonin Transporters: [¹¹C]McN 5652, [¹¹C]ADAM, [¹¹C]DASB, [¹¹C]DAPA, and [¹¹C]AFM

Huang

Hwang

Narendran

et al. 2002

J Cereb Blood Flow Metab

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The recent introduction of a number of new radiotracers suitable for imaging the serotonin transporters (SERT) has radically changed the field of SERT imaging. Whereas, until recently, only one selective SERT radiotracer was available ([11C]McN 5652) for SERT imaging with positron emission tomography (PET), several new C-11-labeled radiotracers of the N,N-dimethyl-2-(arylthio)benzylamine class have been described as appropriate imaging agents for the SERT. The aim of this study was to conduct a comparative evaluation of four of the most promising agents in this class ([11C]ADAM, [11C]DASB, [11C]DAPA, and [11C]AFM) with the reference tracer [11C]McN 5652 under standardized experimental conditions. This evaluation included in vitro measurements of affinity and lipophilicity, and in vivo PET imaging experiments in baboons. In vitro, DASB displayed significantly lower affinity for SERT than the other four tracers. In the blood, [11C]DASB and [11C]AFM display faster clearance and higher free fractions. Brain uptake was analyzed with kinetic modeling using a one-tissue compartment model and the metabolite-corrected arterial input function. The kinetic uptake of [11C]DASB was significantly faster compared with the other compounds, and the scan duration required to derive time-independent estimates of regional distribution volumes was shorter. [11C]DAPA exhibited the slowest brain kinetic. Regional-specific-to-nonspecific equilibrium partition coefficient (V3“) was the highest for [11C]AFM, followed by [11C]DASB and [11C]DAPA, which in turn provided higher V3” values than [11C]ADAM and [11C]McN 5652. From these experiments, two ligands emerged as superior radiotracers that provide a significant improvement over [11C]McN 5652 for PET imaging of SERT: [11C]DASB, because it enables the measurement of SERT availability in a shorter scanning time, and [11C]AFM, because its higher signal-to-noise ratios provide a more reliable measurement of SERT availability in brain regions with relatively low density of SERT, such as in the limbic system.

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Synthesis of [11C]dapoxetine · HCl, a serotonin re-uptake inhibitor: Biodistribution in rat and preliminary PET imaging in the monkey

Cited by 25 publications

References 15 publications

Premature ejaculation

Premature ejaculation

Dapoxetine: a new option in the medical management of premature ejaculation

Comparative Evaluation in Nonhuman Primates of Five PET Radiotracers for Imaging the Serotonin Transporters: [¹¹C]McN 5652, [¹¹C]ADAM, [¹¹C]DASB, [¹¹C]DAPA, and [¹¹C]AFM

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Synthesis of [11C]dapoxetine · HCl, a serotonin re-uptake inhibitor: Biodistribution in rat and preliminary PET imaging in the monkey

Cited by 25 publications

References 15 publications

Premature ejaculation

Premature ejaculation

Dapoxetine: a new option in the medical management of premature ejaculation

Comparative Evaluation in Nonhuman Primates of Five PET Radiotracers for Imaging the Serotonin Transporters: [11C]McN 5652, [11C]ADAM, [11C]DASB, [11C]DAPA, and [11C]AFM

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Comparative Evaluation in Nonhuman Primates of Five PET Radiotracers for Imaging the Serotonin Transporters: [¹¹C]McN 5652, [¹¹C]ADAM, [¹¹C]DASB, [¹¹C]DAPA, and [¹¹C]AFM