No correlation between serotonin and its metabolite 5-HIAA in the cerebrospinal fluid and [<sup>11</sup>C]AZ10419369 binding measured with PET in healthy volunteers

Tiger, Mikael; Svenningsson, Per; Nord, Magdalena; Jabre, Sandra; Halldin, Christer; Lundberg, J.

doi:10.1002/syn.21761

Cited by 5 publications

(4 citation statements)

References 20 publications

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“…Samples from this study underwent a maximum of three freeze thaw cycles which resulted in degradation of serotonin. The serotonin concentrations that were measured were lower than published values [ 41 ] and were 5—tenfold lower than concentrations measured in a larger sample of the ABC biobank study (data not shown here). The samples from the ABC biobank study were analysed after only one thaw cycle.…”

Section: Resultscontrasting

confidence: 72%

Concentration gradients of monoamines, their precursors and metabolites in serial lumbar cerebrospinal fluid of neurologically healthy patients determined with a novel LC–MS/MS technique

Tigchelaar

Muller

Atmosoerodjo

et al. 2023

Fluids Barriers CNS

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Background Potential biomarkers for neuropsychiatric disorders are cerebrospinal fluid (CSF) monoamines and their corresponding precursors and metabolites. During CSF sampling, CSF flows towards the lumbar sampling site from more cranial regions. To compare the results of studies in which different CSF volumes were acquired, it is important to know if ventricular-lumbar concentration gradients exist. This has only been addressed for a few biogenic amines, and almost exclusively in neurologically unwell patients due to the burden of a lumbar puncture (necessary to obtain CSF). The aim of our study was to determine if concentration gradients exist for routinely measured CSF constituents and biogenic amines in neurologically healthy patients. We applied a novel ultrasensitive liquid chromatography mass spectrometry (LC–MS/MS) method for the simultaneous quantification of multiple monoamines, precursors and metabolites in CSF and plasma. Methods CSF and blood samples were collected from twenty neurologically healthy patients undergoing spinal anaesthesia. Ten mL of lumbar CSF was collected in five consecutive two mL fractions. We determined leucocyte and erythrocyte counts, glucose, albumin and protein concentrations and quantified monoamines, precursors and metabolites on each of the fractions using LC–MS/MS. Results In twenty patients (60% male; median age: 46 years), dopamine, DOPAC, 3-MT, HVA, noradrenaline, normetanephrine and 5-HIAA concentrations increased from the first to the last CSF fraction (all p < 0.001). CSF adrenaline concentrations were below the detection limit, whereas serotonin measurements were regarded as unreliable. Albumin and total protein levels decreased significantly across CSF fractions. Conclusions A ventricular-lumbar CSF concentration gradient existed for most of the investigated analytes. This is a novel finding for dopamine, noradrenaline, 3-MT and normetanephrine. These results contribute to the understanding of the neurobiology and underline the importance of standardized procedures for CSF handling to allow comparisons between studies.

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Section: Resultscontrasting

confidence: 72%

Concentration gradients of monoamines, their precursors and metabolites in serial lumbar cerebrospinal fluid of neurologically healthy patients determined with a novel LC–MS/MS technique

Tigchelaar

Muller

Atmosoerodjo

et al. 2023

Fluids Barriers CNS

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“…Furthermore, pilot studies in human subjects found no correlation between 5-HT or its metabolite 5-hydroxyindole acetic acid (5-HIAA) in the CSF with [ 11 C]AZ10419369 binding in brain. This indicates that [ 11 C]AZ10419369, and perhaps intrasynaptic 5-HT levels, may not correlate with serotonin and 5-HIAA levels in CSF [83]. More recently zolmitriptan, a selective 5-HT 1B/1D R agonist has been tested in human with [ 11 C]AZ10419369 and no significant occupancy was detected with a 5 mg dose, whereas 4–5% occupancy was found for 10 mg dose [84].…”

Section: Introductionmentioning

confidence: 99%

PET Tracers for Serotonin Receptors and Their Applications

Js¹,

Mann

2015

CNSAMC

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Serotonin receptors (5-HTRs) are implicated in the pathophysiology of a variety of neuropsychiatric and neurodegenerative disorders and are also targets for drug therapy. In the CNS, most of these receptors are expressed in high abundance in specific brain regions reflecting their role in brain functions. Quantifying binding to 5-HTRs in vivo may permit assessment of physiologic and pathologic conditions, and monitoring disease progression, evaluating treatment response, and for investigating new treatment modalities. Positron emission tomography (PET) molecular imaging has the sensitivity to quantify binding of 5-HTRs in CNS disorders and to measure drug occupancy as part of a process of new drug development. Although research on PET imaging of 5-HTRs have been performed more than two decades, the successful radiotracers so far

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“…However, with a single dose of 20 mg escitalopram given to healthy human volunteers, there was no radioligand displacement. Furthermore, [ 11 C]AZ10419369 BP ND has not been shown to correlate with concentrations of serotonin and its metabolite 5-HIAA (5-hydroxyindoleacetic acid) in cerebrospinal fluid 45 . Thus, although a change in serotonin concentration cannot be ruled out, the increase in hippocampal BP ND most likely reflects increased 5-HT 1B receptor density after ketamine for MDD.…”

Section: Discussionmentioning

confidence: 99%

A randomized placebo-controlled PET study of ketamine´s effect on serotonin1B receptor binding in patients with SSRI-resistant depression

et al. 2020

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The glutamate N-methyl-d-aspartate receptor antagonist ketamine has a rapid antidepressant effect. Despite large research efforts, ketamine’s mechanism of action in major depressive disorder (MDD) has still not been determined. In rodents, the antidepressant properties of ketamine were found to be dependent on both the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and the serotonin (5-HT)1B receptor. Low 5-HT1B receptor binding in limbic brain regions is a replicated finding in MDD. In non-human primates, AMPA-dependent increase in 5-HT1B receptor binding in the ventral striatum (VST) has been demonstrated after ketamine infusion. Thirty selective serotonin reuptake inhibitor-resistant MDD patients were recruited via advertisement and randomized to double-blind monotherapy with 0.5 mg/kg ketamine or placebo infusion. The patients were examined with the 5-HT1B receptor selective radioligand [11C]AZ10419369 and positron emission tomography (PET) before and 24–72 h after treatment. 5-HT1B receptor binding did not significantly alter in patients treated with ketamine compared with placebo. An increase in 5-HT1B receptor binding with 16.7 % (p = 0.036) was found in the hippocampus after one ketamine treatment. 5-HT1B receptor binding in VST at baseline correlated with MDD symptom ratings (r = −0.426, p = 0.019) and with reduction of depressive symptoms with ketamine (r = −0.644, p = 0.002). In conclusion, reduction of depressive symptoms in MDD patients after ketamine treatment is correlated inversely with baseline 5-HT1B receptor binding in VST. Further studies examining the role of 5-HT1B receptors in the antidepressant mechanism of action of ketamine should be conducted, homing in on the 5-HT1B receptor as an MDD treatment response marker.

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No correlation between serotonin and its metabolite 5-HIAA in the cerebrospinal fluid and [¹¹C]AZ10419369 binding measured with PET in healthy volunteers

Cited by 5 publications

References 20 publications

Concentration gradients of monoamines, their precursors and metabolites in serial lumbar cerebrospinal fluid of neurologically healthy patients determined with a novel LC–MS/MS technique

Concentration gradients of monoamines, their precursors and metabolites in serial lumbar cerebrospinal fluid of neurologically healthy patients determined with a novel LC–MS/MS technique

PET Tracers for Serotonin Receptors and Their Applications

A randomized placebo-controlled PET study of ketamine´s effect on serotonin1B receptor binding in patients with SSRI-resistant depression

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No correlation between serotonin and its metabolite 5-HIAA in the cerebrospinal fluid and [11C]AZ10419369 binding measured with PET in healthy volunteers

Cited by 5 publications

References 20 publications

Concentration gradients of monoamines, their precursors and metabolites in serial lumbar cerebrospinal fluid of neurologically healthy patients determined with a novel LC–MS/MS technique

Concentration gradients of monoamines, their precursors and metabolites in serial lumbar cerebrospinal fluid of neurologically healthy patients determined with a novel LC–MS/MS technique

PET Tracers for Serotonin Receptors and Their Applications

A randomized placebo-controlled PET study of ketamine´s effect on serotonin1B receptor binding in patients with SSRI-resistant depression

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No correlation between serotonin and its metabolite 5-HIAA in the cerebrospinal fluid and [¹¹C]AZ10419369 binding measured with PET in healthy volunteers