18F-F13640 PET imaging of functional receptors in humans

Colom, Matthieu; Costes, Nicolas; Redouté, Jérôme; Dailler, Frédéric; Gobert, Florent; Bars, Didier Le; Billard, Thierry; Newman‐Tancredi, Adrian; Zimmer, Luc

doi:10.1007/s00259-019-04473-7

Cited by 17 publications

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“…On the one hand, [ 18 F]F13640 binds widely to 5-HT 1A receptors in the brain Table 1. and covers many brain regions in both animals (Vidal et al, 2018a) and, as recently shown, in humans (Colom et al, 2020).…”

Section: Discussionmentioning

confidence: 74%

[18F]F13640, a 5-HT1A Receptor Radiopharmaceutical Sensitive to Brain Serotonin Fluctuations

et al. 2021

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IntroductionSerotonin is involved in a variety of physiological functions and brain disorders. In this context, efforts have been made to investigate the in vivo fluctuations of this neurotransmitter using positron emission tomography (PET) imaging paradigms. Since serotonin is a full agonist, it binds preferentially to G-protein coupled receptors. In contrast, antagonist PET ligands additionally interact with uncoupled receptors. This could explain the lack of sensitivity to serotonin fluctuations of current 5-HT1A radiopharmaceuticals which are mainly antagonists and suggests that agonist radiotracers would be more appropriate to measure changes in neurotransmitter release. The present study evaluated the sensitivity to endogenous serotonin release of a recently developed, selective 5-HT1A receptor PET radiopharmaceutical, the agonist [18F]F13640 (a.k.a. befiradol or NLX-112).Materials and MethodsFour cats each underwent three PET scans with [18F]F13640, i.e., a control PET scan of 90 min, a PET scan preceded 30 min before by an intravenous injection 1 mg/kg of d-fenfluramine, a serotonin releaser (blocking challenge), and a PET scan comprising the intravenous injection of 1 mg/kg of d-fenfluramine 30 min after the radiotracer injection (displacement challenge). Data were analyzed with regions of interest and voxel-based approaches. A lp-ntPET model approach was implemented to determine the dynamic of serotonin release during the challenge study.ResultsD-fenfluramine pretreatment elicited a massive inhibition of [18F]F13640 labeling in regions known to express 5-HT1A receptors, e.g., raphe nuclei, hippocampus, thalamus, anterior cingulate cortex, caudate putamen, occipital, frontal and parietal cortices, and gray matter of cerebellum. Administration of d-fenfluramine during PET acquisition indicates changes in occupancy from 10% (thalamus) to 31% (gray matter of cerebellum) even though the dissociation rate of [18F]F13640 over the 90 min acquisition time was modest. The lp-ntPET simulation succeeded in differentiating the control and challenge conditions.ConclusionThe present findings demonstrate that labeling of 5-HT1A receptors with [18F]F13640 is sensitive to serotonin concentration fluctuations in vivo. Although the data underline the need to perform longer PET scan to ensure accurate measure of displacement, they support clinical development of [18F]F13640 as a tool to explore experimental paradigms involving physiological or pathological (neurological or neuropsychiatric pathologies) fluctuations of extracellular serotonin.

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Section: Discussionmentioning

confidence: 74%

[18F]F13640, a 5-HT1A Receptor Radiopharmaceutical Sensitive to Brain Serotonin Fluctuations

et al. 2021

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“…We recently developed and validated in animal the first fluorinated agonist radiotracer of 5-HT1A receptors, [ 18 F]F13640 [34], and we have transferred it to humans as a new PET radiopharmaceutical [35]. This radiotracer is a full 5-HT1AR agonist and displays a high affinity and selectivity for 5-HT1A receptors [36,37] Here, the aim was to investigate changes of 5-HT1AR coupling in the 6-OHDA-lesioned rat model of Parkinson's disease using both a 5-HT1A antagonist radiotracer, [ 18 F]MPPF, and the agonist radiotracer [ 18 ]F13640.…”

Section: Introductionmentioning

confidence: 99%

Different Alterations of Agonist and Antagonist Binding to 5-HT1A Receptor in a Rat Model of Parkinson’s Disease and Levodopa-Induced Dyskinesia: A MicroPET Study

Vidal

Levigoureux

Chaib

et al. 2021

JPD

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Background: The gold-standard treatment for Parkinson’s disease is L-DOPA, which in the long term often leads to levodopa-induced dyskinesia. Serotonergic neurons are partially responsible for this, by converting L-DOPA into dopamine before uncontrolled release as a “false neurotransmitter”. The stimulation of 5-HT1A receptors can reduce involuntary movements but this mechanism is poorly understood. Objective: This study aimed to investigate the functionality of 5-HT1A receptor using positron emission tomography in hemiparkinsonian rats with or without dyskinesia induced by 3-weeks daily treatment with L-DOPA. Imaging sessions were performed “off” L-DOPA. Methods: Each rat underwent a positron emission tomography scan with [18F]F13640, a 5-HT1AR agonist (which labels receptors in a high affinity state for agonists) or [18F]MPPF, a 5-HT1AR antagonist (which labels all the receptors). Results: There were decreases of [18F]MPPF binding in hemiparkinsonian rats in cortical areas. In dyskinetic animals, changes were slighter but also found in other regions. In hemiparkinsonian rats, [18F]F13640 uptake was decreased in the globus pallidus and thalamus. On the contralateral side, binding was increased in the insula, the hippocampus and the amygdala. In dyskinetic animals, [18F]F13640 binding was strongly increased in cortical and limbic areas, especially in the non-lesioned side. Conclusion: These data suggest that agonist and antagonist 5-HT1A receptor-binding sites are differently modified in Parkinson’s disease and levodopa-induced dyskinesia. In particular, these observations suggest an important involvement of the functional state of 5-HT1AR in levodopa-induced dyskinesia and emphasize the need to characterize this state using agonist radiotracers in physiological and pathological conditions.

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“…[ 18 F]-F13640 is therefore a promising PET tracer for in vivo imaging and quantification of functionally active 5-HT 1A receptors in the human brain, and a first-in-man study with this radiopharmaceutical is currently underway (study registration: EudraCT 2017-002722-21). The first human in vivo brain images with [ 18 F]-F13640 showed a binding pattern different from that seen with conventional antagonist 5-HT 1A radiopharmaceuticals 69 . Although the binding regions were well correlated with the density of 5-HT 1A receptors, the regions of interest were mainly cortical, indicating that these brain regions are enriched in functionally active receptors.…”

Section: [ 18 F]-f13640 a New Radiopharmaceutical Validated In Humanmentioning

confidence: 95%

Towards in vivo imaging of functionally active 5-HT1A receptors in schizophrenia: concepts and challenges

2021

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The serotonin 5-HT1A receptor has attracted wide attention as a target for treatment of psychiatric disorders. Although this receptor is important in the pharmacological mechanisms of action of new-generation antipsychotics, its characterization remains incomplete. Studies based on in vitro molecular imaging on brain tissue by autoradiography, and more recently in vivo PET imaging, have not yielded clear results, in particular due to the limitations of current 5-HT1A radiotracers, which lack specificity and/or bind to all 5-HT1A receptors, regardless of their functional status. The new concept of PET neuroimaging of functionally active G-protein-coupled receptors makes it possible to revisit PET brain exploration by enabling new research paradigms. For the 5-HT1A receptor it is now possible to use [18F]-F13640, a 5-HT1A receptor radioligand with high efficacy agonist properties, to specifically visualize and quantify functionally active receptors, and to relate this information to subjects’ pathophysiological or pharmacological state. We therefore propose imaging protocols to follow changes in the pattern of functional 5-HT1A receptors in relation to mood deficits or cognitive processes. This could allow improved discrimination of different schizophrenia phenotypes and greater understanding of the basis of therapeutic responses to antipsychotic drugs. Finally, as well as targeting functionally active receptors to gain insights into the role of 5-HT1A receptors, the concept can also be extended to the study of other receptors involved in the pathophysiology or therapy of psychiatric disorders.

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18F-F13640 PET imaging of functional receptors in humans

Cited by 17 publications

References 3 publications

[18F]F13640, a 5-HT1A Receptor Radiopharmaceutical Sensitive to Brain Serotonin Fluctuations

[18F]F13640, a 5-HT1A Receptor Radiopharmaceutical Sensitive to Brain Serotonin Fluctuations

Different Alterations of Agonist and Antagonist Binding to 5-HT1A Receptor in a Rat Model of Parkinson’s Disease and Levodopa-Induced Dyskinesia: A MicroPET Study

Towards in vivo imaging of functionally active 5-HT1A receptors in schizophrenia: concepts and challenges

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