Serotonin transporter occupancy by escitalopram and citalopram in the non-human primate brain: a [11C]MADAM PET study

Finnema, Sjoerd J.; Halldin, Christer; Bang‐Andersen, Benny; Bundgaard, Christoffer; Farde, Lars

doi:10.1007/s00213-015-3961-7

Cited by 9 publications

(19 citation statements)

References 44 publications

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“…There were four stages in the experiments. First, to support that the 5-HTT affinity of citalopram in rhesus monkeys is comparable to that previously reported for cynomolgus monkeys [29], one rhesus monkey (NHP1) underwent PET measurements with [ 11 C] MADAM before and after administration of 2.0 mg/kg of citalopram. Second, to determine the 5-HTT affinity of vortioxetine in rhesus monkeys, four monkeys (NHP2-NHP5) underwent PET measurements with [ 11 C]MADAM before and after administration of one dose of vortioxetine (0.1, 0.3, 1.0, or 3.0 mg/kg, respectively).…”

Section: Methodssupporting

confidence: 67%

“…Plasma drug concentrations for vortioxetine and citalopram were determined using ultra performance liquid chromatography (UPLC) followed by tandem mass spectrometry (MS/MS) detection according to procedures reported previously [29] and as described in Supplementary Materials and Methods. The mean of the plasma drug concentration at eight time points after injection of radioligand and during time of PET data acquisition was used to represent plasma drug concentration in each PET experiment.…”

Section: Determination Of Plasma Drug Concentrationsmentioning

confidence: 99%

“…where I max is the maximal inhibition (%), C P is the plasma drug concentration and ID 50 or K i corresponds to the drug dose or the plasma drug concentration at which 5-HTT occupancy is 50%, respectively [29,39]. Based on Eq.…”

Section: Relationship Between Pretreatment Drugs and 5-htt Occupancymentioning

confidence: 99%

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Effect of clinically relevant doses of vortioxetine and citalopram on serotonergic PET markers in the nonhuman primate brain

Yang

Степанов

Amini

et al. 2019

Neuropsychopharmacol.

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Vortioxetine is a multimodal antidepressant approved for treatment of major depressive disorder. Preclinical studies have demonstrated that the mechanism of action of vortioxetine might be different from selective serotonin reuptake inhibitors (SSRIs), including larger serotonin (5-HT) release and direct modulation of several 5-HT receptors. In the current positron emission tomography (PET) study, we evaluated the mechanism of action of vortioxetine by comparing its effect to the SSRI citalopram on the binding of [ 11 C]AZ10419369 to the 5-HT 1B receptor in the nonhuman primate brain. Initially, the 5-HT transporter (5-HTT) binding of vortioxetine was determined by [ 11 C]MADAM PET measurements before and after administration of vortioxetine (0.1-3.0 mg/kg) and data were used to confirm clinically relevant dosing in subsequent PET measurements with [ 11 C]AZ10419369. The 5-HT 1B receptor binding was significantly decreased after 0.3 mg/kg of citalopram in the dorsal raphe nucleus (5%), as well as after 0.3 mg/kg of vortioxetine in six brain regions (~25%) or 1.0 mg/kg of vortioxetine in all 12 examined regions (~48%). Moreover, there was no effect of 1.0 mg/kg of vortioxetine on the binding of [ 11 C]Cimbi-36 to the 5-HT 2A receptor, which has comparable sensitivity to 5-HT release as [ 11 C]AZ10419369 binding. In conclusion, at clinically relevant doses, vortioxetine induced larger reductions in [ 11 C]AZ10419369 binding than citalopram. These observations suggest that vortioxetine binds to the 5-HT 1B receptor at clinically relevant doses. Future studies are warranted to evaluate the role of the 5-HT 1B receptor in the therapeutic effects of vortioxetine and as a potential target for the development of novel antidepressant drugs.

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Section: Methodssupporting

confidence: 67%

Section: Determination Of Plasma Drug Concentrationsmentioning

confidence: 99%

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Effect of clinically relevant doses of vortioxetine and citalopram on serotonergic PET markers in the nonhuman primate brain

Yang

Степанов

Amini

et al. 2019

Neuropsychopharmacol.

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“…Plasma drug concentrations were determined using ultra performance liquid chromatography (UPLC) followed by tandem mass spectrometry (MS/MS) detection according to procedures reported previously [25]. The details of the blood sample analysis are described in Online Resource 1.…”

Section: Methodsmentioning

confidence: 99%

Characterization of [11C]Lu AE92686 as a PET radioligand for phosphodiesterase 10A in the nonhuman primate brain

Yang

Степанов

Amini

et al. 2016

Eur J Nucl Med Mol Imaging

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Purpose[11C]Lu AE92686 is a positron emission tomography (PET) radioligand that has recently been validated for examining phosphodiesterase 10A (PDE10A) in the human striatum. [11C]Lu AE92686 has high affinity for PDE10A (IC 50 = 0.39 nM) and may also be suitable for examination of the substantia nigra, a region with low density of PDE10A. Here, we report characterization of regional [11C]Lu AE92686 binding to PDE10A in the nonhuman primate (NHP) brain.MethodsA total of 11 PET measurements, seven baseline and four following pretreatment with unlabeled Lu AE92686 or the structurally unrelated PDE10A inhibitor MP-10, were performed in five NHPs using a high resolution research tomograph (HRRT). [11C]Lu AE92686 binding was quantified using a radiometabolite-corrected arterial input function and compartmental and graphical modeling approaches.ResultsRegional time-activity curves were best described with the two-tissue compartment model (2TCM). However, the distribution volume (V T) values for all regions were obtained by the Logan plot analysis, as reliable cerebellar V T values could not be derived by the 2TCM. For cerebellum, a proposed reference region, V T values increased by ∼30 % with increasing PET measurement duration from 63 to 123 min, while V T values in target regions remained stable. Both pretreatment drugs significantly decreased [11C]Lu AE92686 binding in target regions, while no significant effect on cerebellum was observed. Binding potential (BP ND) values, derived with the simplified reference tissue model (SRTM), were 13–17 in putamen and 3–5 in substantia nigra and correlated well to values from the Logan plot analysis.ConclusionsThe method proposed for quantification of [11C]Lu AE92686 binding in applied studies in NHP is based on 63 min PET data and SRTM with cerebellum as a reference region. The study supports that [11C]Lu AE92686 can be used for PET examinations of PDE10A binding also in substantia nigra.Electronic supplementary materialThe online version of this article (doi:10.1007/s00259-016-3544-9) contains supplementary material, which is available to authorized users.

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“…PET measurement in NHP can typically be performed up to three times in one experimental day [ 3 – 5 ]. Such series of measurements allows for estimation of the blocking or displacement effect of drugs, release of neurotransmitters in different conditions, or assessment of the test-retest reproducibility of a PET radioligand, in a single day.…”

Section: Introductionmentioning

confidence: 99%

Potential Effect of Prolonged Sevoflurane Anesthesia on the Kinetics of [11C]Raclopride in Non-human Primates

et al. 2017

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PurposePositron emission tomography (PET) in non-human primates (NHP) is commonly performed under anesthesia, with sevoflurane being a widely used inhaled anesthetic. PET measurement in NHP can be repeated, and a difference in radioligand kinetics has previously been observed between the first and second PET measurement on the same day using sevoflurane anesthesia. In this study, we evaluated the effect of prolonged sevoflurane anesthesia on kinetics and binding potential (BPND) of [11C]raclopride in NHP.ProceduresThree cynomolgus monkeys underwent two to three PET measurements with [11C]raclopride under continuous sevoflurane anesthesia on the same day. The concentration of sevoflurane was adjusted according to the general conditions and safety parameters of the NHP. Time to peak (TTP) radioactivity in the striatum was estimated from time-activity curves (TACs). The BPND in the striatum was calculated by the simplified reference tissue model using the cerebellum as reference region.ResultsIn each NHP, the TTP became shorter in the later PET measurements than in the first one. Across all measurements (n = 8), concentration of sevoflurane correlated with TTP (Spearman’s ρ = − 0.79, p = 0.03), but not with BPND (ρ = − 0.25, p = 0.55).ConclusionsThese data suggest that sevoflurane affects the shape of TACs but has no evident effect on BPND in consecutive PET measurements.

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Serotonin transporter occupancy by escitalopram and citalopram in the non-human primate brain: a [11C]MADAM PET study

Cited by 9 publications

References 44 publications

Effect of clinically relevant doses of vortioxetine and citalopram on serotonergic PET markers in the nonhuman primate brain

Effect of clinically relevant doses of vortioxetine and citalopram on serotonergic PET markers in the nonhuman primate brain

Characterization of [11C]Lu AE92686 as a PET radioligand for phosphodiesterase 10A in the nonhuman primate brain

Potential Effect of Prolonged Sevoflurane Anesthesia on the Kinetics of [11C]Raclopride in Non-human Primates

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