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

Abstract

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.

First Metabolomic Signature of Blood-Brain Barrier Opening Induced by Microbubble-Assisted Ultrasound

“…As previously described with regards to tissue inflammation, our study warrants a wider use of metabolomics to explore the influence of US-and MB-related parameters on serotonergic neurotransmission. These results could be confirmed by further PET/CT studies using radiotracers dedicated to the investigation of serotonergic neurotransmission (Buchecker et al, 2020;Colom et al, 2021). In the present study, only the serotonergic neurotransmission was investigated while the striatum is also involved in GABAergic and dopaminergic neurotransmission.…”

Positron Emission Tomography (PET) Imaging Tracers for Serotonin Receptors

“…202,203 Furthermore, the uptake of [ 18 F]58 was inhibited by fenfluramine (a serotonin releaser) in a dose-dependent manner in the brain of rats and cats, suggesting its sensitivity to endogenous serotonin fluctuations. 202,204 Due to limited human data, more extensive work is needed to validate the practical usefulness of [ 18 F]58 in clinical PET imaging of 5-HT 1A receptors. As such, the development of biased agonist PET ligands has emerged as a driving force in investigating 5-HT 1A receptors in pathological conditions like neurodegenerative diseases or psychiatric disorders.…”

“…Different from 56 and 57 , 58 is not a biased agonist of 5-HT 1A receptors. PET studies with [ 18 F] 58 in different species, including rats, cats, NHPs, and even a healthy volunteer, showed that this radioligand could efficiently penetrate the brain and bind specifically to 5-HT 1A receptors but with remarkably different distribution patterns from that of antagonist radioligands. , Furthermore, the uptake of [ 18 F] 58 was inhibited by fenfluramine (a serotonin releaser) in a dose-dependent manner in the brain of rats and cats, suggesting its sensitivity to endogenous serotonin fluctuations. , Due to limited human data, more extensive work is needed to validate the practical usefulness of [ 18 F] 58 in clinical PET imaging of 5-HT 1A receptors. As such, the development of biased agonist PET ligands has emerged as a driving force in investigating 5-HT 1A receptors in pathological conditions like neurodegenerative diseases or psychiatric disorders.…”

Radiotracers for the Central Serotoninergic System

“…Indeed, in 2021, [ 18 F]F13640 was proven to be a valuable tool to explore neurological or neuropsychiatric pathologies involving fluctuations in extracellular serotonin. Indeed, Zimmer et al have shown its sensitivity to detecting in vivo 5-HT concentration fluctuations [ 68 ].…”