Perspectives on obesity imaging: [18F]2FNQ1P a specific 5-HT6 brain PET radiotracer.

BACKGROUND: Estimates suggest that approximatively 25% of the world population will be overweight in 2025. Better understanding of the pathophysiology of obesity will help to develop future therapeutics. Serotonin subtype 6 receptors (5-HT6) have been shown to be critically involved in appetite reduction and weight loss. However, it is not known if the pathological cascade triggered by obesity modifies the density of 5-HT6 receptors in the brain. METHODS: Influence of diet-induced obesity (DIO) in Wistar rats was explored using MRI (whole-body fat) and PET ([18F]2FNQ1P as a specific 5-HT6 radiotracer). The primary goal was to monitor the 5-HT6 receptor density before and after a 10-week diet (DIO group). The secondary goal was to compare 5-HT6 receptor densities between DIO group, Wistar control diet group, Zucker rats (with genetic obesity) and Zucker lean strain rats. RESULTS: Wistar rats fed with high-fat diet showed higher body fat gain than Wistar control diet rats on MRI. [18F]2FNQ1P PET analysis highlighted significant clusters of voxels (located in hippocampus, striatum, cingulate, temporal cortex and brainstem) with increased binding after high-fat diet (p < 0.05, FWE corrected). CONCLUSION: This study sheds a new light on the influence of high-fat diet on 5-HT6 receptors. This study also positions [18F]2FNQ1P PET as an innovative tool to explore neuronal consequences of obesity or eating disorder pathophysiology.

[18F]RS-127445 radiosynthesis and evaluation as a 5-HT2B receptor PET radiotracer in rat brain.

Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter involved in many physiological and pathological mechanisms through its numerous receptors. Among these, the 5-HT2B receptor is known to play a key role in multiple brain disorders but remains poorly understood. Positron emission tomography (PET) can contribute to a better understanding of pathophysiological mechanisms regulated by the 5-HT2B receptor. To develop the first PET radiotracer for the 5-HT2B receptor, RS-127445, a well-known 5-HT2B receptor antagonist, was labeled with fluorine-18. [18F]RS-127445 was synthesized in a high radiochemical purity and with a good molar activity and radiochemical yield. Preliminary PET scans in rats showed good brain penetration of [18F]RS-127445. However, competition experiments and in vitro autoradiography showed high non-specific binding, especially to brain white matter.

[18F]F13640: a selective agonist PET radiopharmaceutical for imaging functional 5-HT1A receptors in humans.

PURPOSE: F13640 (a.k.a. befiradol, NLX-112) is a highly selective 5-HT1A receptor ligand that was selected as a PET radiopharmaceutical-candidate based on animal studies. Due to its high efficacy agonist properties, [18F]F13640 binds preferentially to functional 5-HT1A receptors, which are coupled to intracellular G-proteins. Here, we characterize brain labeling of 5-HT1A receptors by [18F]F13640 in humans and describe a simplified model for its quantification. METHODS: PET/CT and PET-MRI scans were conducted in a total of 13 healthy male volunteers (29 ± 9 years old), with arterial input functions (AIF) (n = 9) and test-retest protocol (n = 8). Several kinetic models were compared (one tissue compartment model, two-tissue compartment model, and Logan); two models with reference region were also evaluated: simplified reference tissue model (SRTM) and the logan reference model (LREF). RESULTS: [18F]F13640 showed high uptake values in raphe nuclei and cortical regions. SRTM and LREF models showed a very high correlation with kinetic models using AIF. As concerns test-retest parameters and the prolonged binding kinetics of [18F]F13640, better reproducibility, and reliability were found with the LREF method. Cerebellum white matter and frontal lobe white matter stand out as suitable reference regions. CONCLUSION: The favorable brain labeling and kinetic profile of [18F]F13640, its high receptor specificity and its high efficacy agonist properties open new perspectives for studying functionally active 5-HT1A receptors, unlike previous radiopharmaceuticals that act as antagonists. [18F]F13640's kinetic properties allow injection outside of the PET scanner with delayed acquisitions, facilitating the design of innovative longitudinal protocols in neurology and psychiatry. TRIAL REGISTRATION: Trial Registration EudraCT 2017-002,722-21.

Quality control of rigid endoscopes: a comparative study between ScopeControl® and surgeons' evaluation.

BACKGROUND: In central sterile services departments (CSSD), the functionality of rigid endoscopes, which are complex and fragile reusable devices, is usually controlled visually and is considered a complex and subjective task. ScopeControl® was developed to provide an automated quality control of rigid endoscopes by measuring the value of six parameters: viewing angle (VA), field of view (FV), color correctness (CC), light transmission (LT), fibers transmission (FT), and focus (FC). The aim of the present study was to assess the ability of ScopeControl® to pre-emptively identify endoscope defects before the surgeon considers them as defective. METHODS: The same endoscope was evaluated by surgeons during surgery using a scoring scale as well as the CSSD staff using the ScopeControl® during reprocessing. The ScopeControl® categorized the endoscope into 3 groups: "passed," "in danger," and "failed." Correlations between the surgeon's evaluation and results of the ScopeControl® were calculated. RESULTS: One hundred sixty-six controls were carried out concerning 51 different endoscopes. According to the surgeon's evaluation, 78.9% and 80.7% of controls were considered as satisfactory for image and brightness quality, respectively. Results obtained using ScopeControl® found that 13.3% of controls were considered as "passed," 31.3% "in danger," and 55.4% "failed," with poor correlation with the surgeons' evaluation. LT and FT parameters represented 95.2% of the reasons for failures. The ability of the ScopeControl® to detect endoscope defects earlier than surgeons was validated by tracking the results of endoscopes used and controlled several times. CONCLUSION: The ScopeControl® achieved an objective and consistent quality control of endoscopes and showed poor correlation with the surgeon's opinion. In practice, the ScopeControl® could avoid the use of defective endoscopes in the surgery unit and thus improve the quality of the surgical procedure.

Toward Functional PET Imaging of the Spinal Cord.

At present, spinal cord imaging primarily uses magnetic resonance imaging (MRI) or computed tomography (CT), but the greater sensitivity of positron emission tomography (PET) techniques and the development of new radiotracers are paving the way for a new approach. The substantial rise in publications on PET radiotracers for spinal cord exploration indicates a growing interest in the functional and molecular imaging of this organ. The present review aimed to provide an overview of the various radiotracers used in this indication, in preclinical and clinical settings. Firstly, we outline spinal cord anatomy and associated target pathologies. Secondly, we present the state-of-the-art of spinal cord imaging techniques used in clinical practice, with their respective strengths and limitations. Thirdly, we summarize the literature on radiotracers employed in functional PET imaging of the spinal cord. In conclusion, we propose criteria for an ideal radiotracer for molecular spinal cord imaging, emphasizing the relevance of multimodal hybrid cameras, and particularly the benefits of PET-MRI integration.

Preclinical investigation of the effect of stress on the binding of [18F]F13640, a 5-HT1A radiopharmaceutical.

BACKGROUND: [18F]F13640 is a new PET radiopharmaceutical for brain molecular imaging of serotonin 5-HT1A receptors. Since we intend to use this radiopharmaceutical in psychiatric studies, it is crucial to establish possible sensitivity modification of 5-HT1A receptors availability during an acute stress exposure. In this study, we first assessed the cerebrometabolic effects of a new animal model of stress with [18F]FDG and then proceeded to test for effects of this model on the cerebral binding of [18F]F13640, a 5-HT1A receptors PET radiopharmaceutical. METHODS: Four groups of male Sprague-Dawley were used to identify the optimal model: "stressed group" (n = 10), "post-traumatic stress disorder (PTSD) group" (n = 9) and "restraint group" (n = 8), compared with a control group (n = 8). All rats performed neuroimaging [18F]FDG µPET-CT to decipher which model was the most appropriate to test effects of stress on radiotracer binding. Subsequently, a group of rats (n = 10) underwent two PET imaging acquisitions (baseline and PTSD condition) using the PET radiopharmaceutical [18F]F13640 to assess influence of stress on its binding. Voxel-based analysis was performed to assess [18F]FDG or [18F]F13640 changes. RESULTS: In [18F]FDG experiments, the PTSD group showed a pattern of cerebrometabolic activation in various brain regions previously implicated in stress (amygdala, perirhinal cortex, olfactory bulb and caudate). [18F]F13640 PET scans showed increased radiotracer binding in the PTSD condition in caudate nucleus and brainstem. CONCLUSIONS: The present study demonstrated stress-induced cerebrometabolic activation or inhibition of various brain regions involved in stress model. Applying this model to our radiotracer, [18F]F13640 showed few influence of stress on its binding. This will enable to rule out any confounding effect of stress during imaging studies.

Amino Acid Solutions for 177Lu-Oxodotreotide Premedication: A Tolerance Study.

Background: The co-infusion of amino acid solutions during peptide receptor radionuclide therapy reduces the tubular reabsorption of 177Lu-oxodotreotide, thus minimizing nephrotoxicity. In our nuclear medicine department, the patients received two different types of amino acid perfusion over time: a commercial solution (CS) containing 10% amino acids, and a 2.5% lysine−arginine (LysArg) hospital preparation, produced by a referral laboratory. The aim of the present study was to analyze the tolerance of the two amino acid solutions. Methods: The patient files were analyzed and double-checked. The study parameters comprised the gender, age, primary tumor site, type of amino acid perfusion, adverse events (AE) and WHO AE grades, antiemetic premedication, creatinine, and serum potassium level. Results: From February 2016 to February 2019, 76 patients were treated, for a total 235 cycles. AEs occurred in 71% of the CS cycles (n = 82/116), versus 18% (n = 21/119) in the LysArg group (p < 0.0001). In the CS group, the AEs were mostly WHO grade 4 (n = 24/82), and mostly grade 1 in the LysArg group (n = 13/21). Poisson regression showed a higher risk of AE overall and of grades 3 and 4 in the females and with CS. The mean creatinine clearance was identical before and after the PRRT cycles, whichever amino acid perfusion was used. Conclusions: The lysine−arginine preparation showed better tolerance than the commercial solution. The change to LysArg reduced the antiemetic premedication from four molecules to one.

Cluster headache: state of the art of pharmacological treatments and therapeutic perspectives.

Cluster headache (CH) is the most common form of trigeminal autonomic cephalalgia. Current treatments have several limitations, and new drugs are required. This article first briefly reviews present acute and preventive treatments in CH, their mechanism of action and limitations, then describes the state of the art in recent clinical drug trials since 2015, and ends with a critique of trials in the CH field. Research is limited by lack of knowledge of pathophysiology and lack of animal models. In the past 5 years, no brand-new treatment has emerged, but promising drugs, such as CGRP(R) antibodies, are under study. According to the literature and guidelines, clinicians and researchers should be aware of many limitations in study protocols: concomitant medication, patient sample size, patients' protocol compliance, and study designs that tend to restrict patient recruitment.

Preclinical validation of [18F]2FNQ1P as a specific PET radiotracer of 5-HT6 receptors in rat, pig, non-human primate and human brain tissue.

INTRODUCTION: The aim of this study was to perform in-vitro and in-vivo radiopharmacological characterizations of [18F]2FNQ1P, a new PET radiotracer of 5-HT6 receptors, in rat, pig, non-human primate and human tissues. The 5-HT6 receptor is one of the more recently identified serotonin receptors in central nervous system and, because of its role in memory and cognitive processes, is considered as a promising therapeutic target. METHODS: In-vitro autoradiography and saturation binding assays were performed in postmortem brain tissues from rat, pig, non-human primate and human caudate nucleus, completed by serum stability assessment in all species and cerebral radiometabolite and biodistribution studies in rat. RESULTS: In all species, autoradiography data revealed high binding levels of [18F]2FNQ1P in cerebral regions with high 5-HT6 receptor density. Binding was blocked by addition of SB258585 as a specific antagonist. Binding assays provided KD and Bmax values of respectively 1.34 nM and 0.03 pmol·mg-1 in rat, 0.60 nM and 0.04 pmol·mg-1 in pig, 1.38 nM and 0.07 pmol·mg-1 in non-human primate, and 1.39 nM and 0.15 pmol·mg-1 in human caudate nucleus. In rat brain, the proportion of unmetabolized [18F]2FNQ1P was >99% 5 min after iv injection and 89% at 40 min. The biodistribution studies found maximal radioactivity in lungs and kidneys (3.5 ± 1.2% ID/g and 2.0 ± 0.7% ID/g, respectively, 15 min post-injection). CONCLUSION: These radiopharmacological data confirm that [18F]2FNQ1P is a specific radiotracer for molecular imaging of 5-HT6 receptors and suggest that it could be used as a radiopharmaceutical in humans.

Change in Expression of 5-HT6 Receptor at Different Stages of Alzheimer's Disease: A Postmortem Study with the PET Radiopharmaceutical [18F]2FNQ1P.

BACKGROUND: The 5-HT6 receptor is one of the most recently identified serotonin receptors in the central nervous system. Because of its role in memory and cognitive process, this receptor might be implicated in Alzheimer's disease (AD) and associated disorders. OBJECTIVE: The aim of this study was to investigate the binding of [18F]2FNQ1P, a new specific radiotracer of 5-HT6 receptors, and to quantify 5-HT6 receptor density in caudate nucleus in a population of patients with different AD stages. METHODS: Patients were classified according to the "ABC" NIA-AA classification. In vitro binding assays were performed in postmortem brain tissue from the healthy control (HC; n = 8) and severe AD ("High"; n = 8) groups. In vitro quantitative autoradiography was performed in human brain tissue (caudate nucleus) from patients with different stages of AD: HC (n = 15), "Low" (n = 18), "Int" (n = 20), and "High" (n = 15). RESULTS: In vitro binding assays did not show significant differences for the KD and Bmax parameters between "High" and HC groups. In vitro quantitative autoradiography showed a significant difference between the "High" and HC groups (p = 0.0025). We also showed a progressive diminution in [18F]2FNQ1P specific binding, which parallels 5-HT6 receptors expression, according to increasing AD stage. Significant differences were observed between the HC group and all AD stages combined ("Low", "Intermediate", and "High") (p = 0.011). CONCLUSION: This study confirms the interest of investigating the role of 5-HT6 receptors in AD and related disorders. [18F]2FNQ1P demonstrated specific binding to 5-HT6 receptors.