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In vivo serotonin-sensitive binding of [11C]CUMI-101: a serotonin 1A receptor agonist positron emission tomography radiotracer.

ABSTRACT: Positron emission tomography studies of 5-hydroxytryptamine (5-HT)(1A) receptors have hitherto been limited to antagonist radiotracers. Antagonists do not distinguish high/low-affinity conformations of G protein-coupled receptors and are less likely to be sensitive to intrasynaptic serotonin levels. We developed a novel 5-HT(1A) agonist radiotracer [(11)C]CUMI-101. This study evaluates the sensitivity of [(11)C]CUMI-101 binding to increases in intrasynaptic serotonin induced by intravenous citalopram and fenfluramine. Two Papio anubis were scanned, using [(11)C]CUMI-101 intravenous bolus of 4.5 ± 1.5 mCi. Binding potential (BP(F)=B(avail)/K(D)) was measured before (n=10) and 20 minutes after elevation of intrasynaptic serotonin by intravenous citalopram (2 mg/kg, n=3; 4 mg/kg, n=3) and fenfluramine (2.5 mg/kg, n=3) using a metabolite-corrected arterial input function. Occupancy was also estimated by the Lassen graphical approach. Both citalopram and fenfluramine effects were significant for BP(F) (P=0.031, P=0.049, respectively). The Lassen approach estimated 15.0, 30.4, and 23.7% average occupancy after citalopram 2 mg/kg, 4 mg/kg, and fenfluramine 2.5 mg/kg, respectively. [(11)C]CUMI-101 binding is sensitive to a large increase in intrasynaptic serotonin in response to robust pharmacological challenges. These modest changes in BP(F) may make it unlikely that this ligand will detect changes in intrasynaptic 5-HT under physiologic conditions; future work will focus on evaluating its utility in measuring the responsiveness of the 5-HT system to pharmacological challenges.

SUBMITTER: Milak MS

PROVIDER: S-EPMC3049488 | biostudies-other | 2011 Jan

REPOSITORIES: biostudies-other

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Project description:BackgroundThe pathophysiology of bipolar disorder (BD) remains largely unknown despite it causing significant disability and suicide risk. Serotonin signaling may play a role in the pathophysiology, but direct evidence for this is lacking. Treatment of the depressed phase of the disorder is limited. Previous studies have indicated that positron emission tomography (PET) imaging of the serotonin 1A receptor (5HT1AR) may predict antidepressant response.MethodsA total of 20 participants with BD in a current major depressive episode and 16 healthy volunteers had PET imaging with [11C]CUMI-101, employing a metabolite-corrected input function for quantification of binding potential to the 5HT1AR. Bipolar participants then received an open-labeled, 6-week clinical trial with a selective serotonin reuptake inhibitor (SSRI) in addition to their mood stabilizer. Clinical ratings were obtained at baseline and during SSRI treatment.ResultsPretreatment binding potential (BPF) of [11C]CUMI-101 was associated with a number of pretreatment clinical variables within BD participants. Within the raphe nucleus, it was inversely associated with the baseline Montgomery Åsberg Rating Scale (P = .026), the Beck Depression Inventory score (P = .0023), and the Buss Durkee Hostility Index (P = .0058), a measure of lifetime aggression. A secondary analysis found [11C]CUMI-101 BPF was higher in bipolar participants compared with healthy volunteers (P = .00275). [11C]CUMI-101 BPF did not differ between SSRI responders and non-responders (P = .907) to treatment and did not predict antidepressant response (P = .580). Voxel-wise analyses confirmed the results obtained in regions of interest analyses.ConclusionsA disturbance of serotonin system function is associated with both the diagnosis of BD and its severity of depression. Pretreatment 5HT1AR binding did not predict SSRI antidepressant outcome.The study was listed on clinicaltrials.gov with identifier NCT02473250.

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In vivo serotonin-sensitive binding of [11C]CUMI-101: a serotonin 1A receptor agonist positron emission tomography radiotracer.

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