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(11)C-CUMI-101, a PET radioligand, behaves as a serotonin 1A receptor antagonist and also binds to ?(1) adrenoceptors in brain.

ABSTRACT: UNLABELLED:The PET radioligand (11)C-CUMI-101 was previously suggested as a putative agonist radioligand for the serotonin 1A (5-hydroxytryptamine 1A [5-HT1A]) receptor in recombinant cells expressing human 5-HT1A receptor. However, a recent study showed that CUMI-101 behaved as a potent 5-HT1A receptor antagonist in rat brain. CUMI-101 also has moderate affinity (Ki = 6.75 nM) for ?1 adrenoceptors measured in vitro. The current study examined the functional properties and selectivity of CUMI-101, both in vitro and in vivo. METHODS:The functional assay was performed using (35)S-GTP?S (GTP is guanosine triphosphate) in primate brains. The cross-reactivity of CUMI-101 with ?1 adrenoceptors was performed using in vitro radioligand binding studies in rat, monkey, and human brains as well as in vivo PET imaging in mouse, rat, and monkey brains. RESULTS:CUMI-101 did not stimulate (35)S-GTP?S binding in primate brain, in contrast to 8-OH-DPAT, a potent 5-HT1A receptor agonist. Instead, CUMI-101 behaved as a potent 5-HT1A receptor antagonist by dose-dependently inhibiting 8-OH-DPAT-stimulated (35)S-GTP?S binding. Both in vitro and in vivo studies showed that CUMI-101 had significant ?1 adrenoceptor cross-reactivity. On average, across all 3 species examined, cross-reactivity was highest in the thalamus (>45%) and lowest in the neocortex and cerebellum (<10%). PET imaging further confirmed that only preblocking with WAY-100635 plus prazosin decreased (11)C-CUMI-101 brain uptake to that of self-block. CONCLUSION:CUMI-101 behaves as a 5-HT1A receptor antagonist in primate brain, with significant, regional-dependent ?1 adrenoceptor cross-reactivity, limiting its potential use as a PET radioligand in humans.

SUBMITTER: Shrestha SS

PROVIDER: S-EPMC4247002 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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(11)C-CUMI-101, a PET radioligand, behaves as a serotonin 1A receptor antagonist and also binds to α(1) adrenoceptors in brain.

Shrestha Stal Saurav SS Liow Jeih-San JS Lu Shuiyu S Jenko Kimberly K Gladding Robert L RL Svenningsson Per P Morse Cheryl L CL Zoghbi Sami S SS Pike Victor W VW Innis Robert B RB

Journal of nuclear medicine : official publication, Society of Nuclear Medicine 20140101 1

<h4>Unlabelled</h4>The PET radioligand (11)C-CUMI-101 was previously suggested as a putative agonist radioligand for the serotonin 1A (5-hydroxytryptamine 1A [5-HT1A]) receptor in recombinant cells expressing human 5-HT1A receptor. However, a recent study showed that CUMI-101 behaved as a potent 5-HT1A receptor antagonist in rat brain. CUMI-101 also has moderate affinity (Ki = 6.75 nM) for α1 adrenoceptors measured in vitro. The current study examined the functional properties and selectivity of ...[more]

PMID: 24385311

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Project description:IntroductionThe purpose of this research is to evaluate the prospects for the use of 4-(trans-18F-fluoranylmethyl)-N-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-N-pyridin-2-ylcyclohexane-1-carboxamide (18F-Mefway) in comparison to 18F-trans-4-fluoro-N-2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide (18F-FCWAY) for the quantification of 5-HT1A receptors in human subjects.MethodFive healthy male controls were included for two positron emission tomography (PET) studies: 18F-FCWAY PET after the pretreatment with 500 mg of disulfiram and two months later, 18F-Mefway PET without disulfiram. Regional time-activity curves (TACs) were extracted from nine cortical and subcortical regions in dynamic PET images. Using cerebellar cortex without vermis as reference tissue, in vivo kinetics for both radioligands were compared based on the distribution volume ratio (DVR) calculated by non-invasive Logan graphical analysis and area under the curve ratio of the TACs (AUC ratio).ResultAlthough the pattern of regional uptakes in the 18F-Mefway PET was similar to that of the 18F-FCWAY PET (highest in the hippocampus and lowest in the cerebellar cortex), the amount of regional uptake in 18F-Mefway PET was almost half of that in 18F-FCWAY PET. The skull uptake in 18F-Mefway PET was only 25% of that in 18F-FCWAY PET with disulfiram pretreatment. The regional DVR values and AUC ratio values for 18F-Mefway were 17-40% lower than those of 18F-FCWAY. In contrast to a small overestimation of DVR values by AUC ratio values (< 10%) in 18F-FCWAY PET, the overestimation bias of AUC ratio values was much higher (up to 21%) in 18F-Mefway PET.ConclusionAs 18F-Mefway showed lower DVR values and greater overestimation bias of AUC ratio values, 18F-Mefway may appear less favorable than 18F-FCWAY. However, in contrast to 18F-FCWAY, the resistance to in vivo defluorination of 18F-Mefway obviates the need for the use of a defluorination inhibitor. Thus, 18F-Mefway may be a good candidate PET radioligand for 5-HT1A receptor imaging in human.

Project description:BACKGROUND:Abnormalities in the hypothalamic-pituitary-adrenal axis, serotonergic system, and stress response have been linked to the pathogenesis of major depressive disorder. State-dependent hyper-reactivity of the hypothalamic-pituitary-adrenal axis is seen in major depressive disorder, and higher binding to the serotonin 1A receptor is observed as a trait in both currently depressed and remitted untreated major depressive disorder. Here, we sought to examine whether a relationship exists between cortisol secretion in response to a stressor and serotonin 1A receptor binding throughout the brain, both in healthy controls and participants with major depressive disorder. METHODS:Research participants included 42 medication-free, depressed subjects and 31 healthy volunteers. Participants were exposed to either an acute, physical stressor (radial artery catheter insertion) or a psychological stressor (Trier Social Stress Test). Levels of serotonin 1A receptor binding on positron emission tomography with [11C]WAY-100635 were also obtained from all participants. The relationship between [11C]WAY-100635 binding and cortisol was examined using mixed linear effects models with group (major depressive disorder vs control), cortisol, brain region, and their interactions as fixed effects and subject as a random effect. RESULTS:We found a positive correlation between post-stress cortisol measures and serotonin 1A receptor ligand binding levels across multiple cortical and subcortical regions, independent of diagnosis and with both types of stress. The relationship between [11C]WAY-100635 binding and cortisol was homogenous across all a priori brain regions. In contrast, resting cortisol levels were negatively correlated with serotonin 1A receptor ligand binding levels independently of diagnosis, except in the RN. There was no significant difference in cortisol between major depressive disorder participants and healthy volunteers with either stressor. Similarly, there was no correlation between cortisol and depression severity in either stressor group. CONCLUSIONS:This study suggests that there may be a common underlying mechanism that links abnormalities in the serotonin system and hypothalamic-pituitary-adrenal axis hyper-reactivity to stress. Future studies need to determine how hypothalamic-pituitary-adrenal axis dysfunction affects mood to increase the risk of suicide in major depression.

Project description:BackgroundThe NMDA receptor (NMDAR) plays a key role in the central nervous system, e.g., for synaptic transmission. While synaptic NMDARs are thought to have protective characteristics, activation of extrasynaptic NMDARs might trigger excitotoxic processes linked to neuropsychiatric disorders. Since extrasynaptic NMDARs are typically GluN2B-enriched, the subunit is an interesting target for drug development and treatment monitoring. Recently, the novel GluN2B-specific PET radioligand (R)-[11C]Me-NB1 was investigated in rodents and for the first time successfully translated to humans. To assess whether (R)-[11C]Me-NB1 is a valuable radioligand for (repeated) clinical applications, we evaluated its safety, biodistribution and dosimetry.MethodsFour healthy subjects (two females, two males) underwent one whole-body PET/MR measurement lasting for more than 120 min. The GluN2B-specific radioligand (R)-[11C]Me-NB1 was administered simultaneously with the PET start. Subjects were measured in nine passes and six bed positions from head to mid-thigh. Regions of interest was anatomically defined for the brain, thyroid, lungs, heart wall, spleen, stomach contents, pancreas, liver, kidneys, bone marrow and urinary bladder contents, using both PET and MR images. Time-integrated activity coefficients were estimated to calculate organ equivalent dose coefficients and the effective dose coefficient. Additionally, standardized uptake values (SUV) were computed to visualize the biodistribution.ResultsAdministration of the radioligand was safe without adverse events. The organs with the highest uptake were the urinary bladder, spleen and pancreas. Organ equivalent dose coefficients were higher in female in almost all organs, except for the urinary bladder of male. The effective dose coefficient was 6.0 µSv/MBq.ConclusionThe GluN2B-specific radioligand (R)-[11C]Me-NB1 was well-tolerated without reported side effects. Effective dose was estimated to 1.8 mSv when using 300 MBq of presented radioligand. The critical organ was the urinary bladder. Due to the low effective dose coefficient of this radioligand, longitudinal studies for drug development and treatment monitoring of neuropsychiatric disorders including neurodegenerative diseases are possible. Trial registration Registered on 11th of June 2019 at https://www.basg.gv.at (EudraCT: 2018-002933-39).

Dataset Information

(11)C-CUMI-101, a PET radioligand, behaves as a serotonin 1A receptor antagonist and also binds to ?(1) adrenoceptors in brain.

Publications

(11)C-CUMI-101, a PET radioligand, behaves as a serotonin 1A receptor antagonist and also binds to α(1) adrenoceptors in brain.

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