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Szabolcs Lehel

Other affiliations: University of Copenhagen
Bio: Szabolcs Lehel is an academic researcher from Copenhagen University Hospital. The author has contributed to research in topics: Radioligand & Serotonin transporter. The author has an hindex of 17, co-authored 52 publications receiving 1118 citations. Previous affiliations of Szabolcs Lehel include University of Copenhagen.


Papers
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Journal ArticleDOI
TL;DR: The largest target-to-background binding ratio was found for [11C]Cimbi-36 which also had a high brain uptake compared to its analogues, and is currently the most promising candidate for investigation of 5-HT2A receptor agonist binding in the living human brain with PET.
Abstract: Positron emission tomography (PET) imaging of serotonin 2A (5-HT2A) receptors with agonist tracers holds promise for the selective labelling of 5-HT2A receptors in their high-affinity state. We have previously validated [11C]Cimbi-5 and found that it is a 5-HT2A receptor agonist PET tracer. In an attempt to further optimize the target-to-background binding ratio, we modified the chemical structure of the phenethylamine backbone and carbon-11 labelling site of [11C]Cimbi-5 in different ways. Here, we present the in vivo validation of nine novel 5-HT2A receptor agonist PET tracers in the pig brain. Each radiotracer was injected intravenously into anaesthetized Danish Landrace pigs, and the pigs were subsequently scanned for 90 min in a high-resolution research tomography scanner. To evaluate 5-HT2A receptor binding, cortical nondisplaceable binding potentials (BPND) were calculated using the simplified reference tissue model with the cerebellum as a reference region. After intravenous injection, all compounds entered the brain and distributed preferentially into the cortical areas, in accordance with the known 5-HT2A receptor distribution. The largest target-to-background binding ratio was found for [11C]Cimbi-36 which also had a high brain uptake compared to its analogues. The cortical binding of [11C]Cimbi-36 was decreased by pretreatment with ketanserin, supporting 5-HT2A receptor selectivity in vivo. [11C]Cimbi-82 and [11C]Cimbi-21 showed lower cortical BPND, while [11C]Cimbi-27, [11C]Cimbi-29, [11C]Cimbi-31 and [11C]Cimbi-88 gave rise to cortical BPND similar to that of [11C]Cimbi-5. [11C]Cimbi-36 is currently the most promising candidate for investigation of 5-HT2A receptor agonist binding in the living human brain with PET.

115 citations

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TL;DR: The findings are in line with S-carriers having an increased response in neural circuits involved in emotional processing to stressful environmental stimuli but here demonstrated as a endophenotype with dynamic changes in serotonin reuptake.

104 citations

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TL;DR: This study is the first to demonstrate an abnormally decreased cerebral SERT binding in obese individuals and whether the SERT has a direct role in the regulation of appetite and eating behaviour or whether the finding is due to a compensatory downregulation of SERT secondary to other dysfunction(s) in the serotonergic transmitter system remains to be established.

101 citations

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TL;DR: The data imply both serotonergic signaling and estradiol in the mechanisms by which sex-steroid hormone fluctuations provoke depressive symptoms and thus provide a rationale for future preventive strategies in high-risk groups.

94 citations

Journal ArticleDOI
TL;DR: Cimbi-36 is described as the first agonist PET radioligand to successfully image and quantify 5-HT2A receptors in the human brain.
Abstract: [11C]Cimbi-36 was recently developed as a selective serotonin 2A (5-HT2A) receptor agonist radioligand for positron emission tomography (PET) brain imaging. Such an agonist PET radioligand may provide a novel, and more functional, measure of the serotonergic system and agonist binding is more likely than antagonist binding to reflect 5-HT levels in vivo. Here, we show data from a first-in-human clinical trial with [11C]Cimbi-36. In 29 healthy volunteers, we found high brain uptake and distribution according to 5-HT2A receptors with [11C]Cimbi-36 PET. The two-tissue compartment model using arterial input measurements provided the most optimal quantification of cerebral [11C]Cimbi-36 binding. Reference tissue modeling was feasible as it induced a negative but predictable bias in [11C]Cimbi-36 PET outcome measures. In five subjects, pretreatment with the 5-HT2A receptor antagonist ketanserin before a second PET scan significantly decreased [11C]Cimbi-36 binding in all cortical regions with no effects in cerebellum. These results confirm that [11C]Cimbi-36 binding is selective for 5-HT2A receptors in the cerebral cortex and that cerebellum is an appropriate reference tissue for quantification of 5-HT2A receptors in the human brain. Thus, we here describe [11C]Cimbi-36 as the first agonist PET radioligand to successfully image and quantify 5-HT2A receptors in the human brain.

77 citations


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Journal ArticleDOI
TL;DR: The exceptional fast kinetics of this catalyst-free reaction, even using low concentrations of coupling partners, make it amenable for in vivo radiolabelling using pretargeting methodologies, which are discussed.
Abstract: The emerging inverse electron demand Diels–Alder (IEDDA) reaction stands out from other bioorthogonal reactions by virtue of its unmatchable kinetics, excellent orthogonality and biocompatibility. With the recent discovery of novel dienophiles and optimal tetrazine coupling partners, attention has now been turned to the use of IEDDA approaches in basic biology, imaging and therapeutics. Here we review this bioorthogonal reaction and its promising applications for live cell and animal studies. We first discuss the key factors that contribute to the fast IEDDA kinetics and describe the most recent advances in the synthesis of tetrazine and dienophile coupling partners. Both coupling partners have been incorporated into proteins for tracking and imaging by use of fluorogenic tetrazines that become strongly fluorescent upon reaction. Selected notable examples of such applications are presented. The exceptional fast kinetics of this catalyst-free reaction, even using low concentrations of coupling partners, make it amenable for in vivo radiolabelling using pretargeting methodologies, which are also discussed. Finally, IEDDA reactions have recently found use in bioorthogonal decaging to activate proteins or drugs in gain-of-function strategies. We conclude by showing applications of the IEDDA reaction in the construction of biomaterials that are used for drug delivery and multimodal imaging, among others. The use and utility of the IEDDA reaction is interdisciplinary and promises to revolutionize chemical biology, radiochemistry and materials science.

625 citations

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TL;DR: This bipartite model purports to explain how different drugs (SSRIs and psychedelics) that modulate the serotonergic system in different ways, can achieve complementary adaptive and potentially therapeutic outcomes.
Abstract: Previous attempts to identify a unified theory of brain serotonin function have largely failed to achieve consensus. In this present synthesis, we integrate previous perspectives with new and older data to create a novel bipartite model centred on the view that serotonin neurotransmission enhances two distinct adaptive responses to adversity, mediated in large part by its two most prevalent and researched brain receptors: the 5-HT1A and 5-HT2A receptors. We propose that passive coping (i.e. tolerating a source of stress) is mediated by postsynaptic 5-HT1AR signalling and characterised by stress moderation. Conversely, we argue that active coping (i.e. actively addressing a source of stress) is mediated by 5-HT2AR signalling and characterised by enhanced plasticity (defined as capacity for change). We propose that 5-HT1AR-mediated stress moderation may be the brain’s default response to adversity but that an improved ability to change one’s situation and/or relationship to it via 5-HT2AR-mediated plasticit...

378 citations

Journal ArticleDOI
TL;DR: Use of hormonal contraception, especially among adolescents, was associated with subsequent use of antidepressants and a first diagnosis of depression, suggesting depression as a potential adverse effect of hormonal contraceptive use.
Abstract: Importance Millions of women worldwide use hormonal contraception. Despite the clinical evidence of an influence of hormonal contraception on some women’s mood, associations between the use of hormonal contraception and mood disturbances remain inadequately addressed. Objective To investigate whether the use of hormonal contraception is positively associated with subsequent use of antidepressants and a diagnosis of depression at a psychiatric hospital. Design, Setting, and Participants This nationwide prospective cohort study combined data from the National Prescription Register and the Psychiatric Central Research Register in Denmark. All women and adolescents aged 15 to 34 years who were living in Denmark were followed up from January 1, 2000, to December 2013, if they had no prior depression diagnosis, redeemed prescription for antidepressants, other major psychiatric diagnosis, cancer, venous thrombosis, or infertility treatment. Data were collected from January 1, 1995, to December 31, 2013, and analyzed from January 1, 2015, through April 1, 2016. Exposures Use of different types of hormonal contraception. Main Outcomes and Measures With time-varying covariates, adjusted incidence rate ratios (RRs) were calculated for first use of an antidepressant and first diagnosis of depression at a psychiatric hospital. Results A total of 1 061 997 women (mean [SD] age, 24.4 [0.001] years; mean [SD] follow-up, 6.4 [0.004] years) were included in the analysis. Compared with nonusers, users of combined oral contraceptives had an RR of first use of an antidepressant of 1.23 (95% CI, 1.22-1.25). Users of progestogen-only pills had an RR for first use of an antidepressant of 1.34 (95% CI, 1.27-1.40); users of a patch (norgestrolmin), 2.0 (95% CI, 1.76-2.18); users of a vaginal ring (etonogestrel), 1.6 (95% CI, 1.55-1.69); and users of a levonorgestrel intrauterine system, 1.4 (95% CI, 1.31-1.42). For depression diagnoses, similar or slightly lower estimates were found. The relative risks generally decreased with increasing age. Adolescents (age range, 15-19 years) using combined oral contraceptives had an RR of a first use of an antidepressant of 1.8 (95% CI, 1.75-1.84) and those using progestin-only pills, 2.2 (95% CI, 1.99-2.52). Six months after starting use of hormonal contraceptives, the RR of antidepressant use peaked at 1.4 (95% CI, 1.34-1.46). When the reference group was changed to those who never used hormonal contraception, the RR estimates for users of combined oral contraceptives increased to 1.7 (95% CI, 1.66-1.71). Conclusions and Relevance Use of hormonal contraception, especially among adolescents, was associated with subsequent use of antidepressants and a first diagnosis of depression, suggesting depression as a potential adverse effect of hormonal contraceptive use.

362 citations

Journal ArticleDOI
TL;DR: The literature on postnatal depression in the mother and its effect on mother-infant interactions is reviewed and interventions during gestation and postpartum that may improve maternal symptoms and behavior and thus alter developmental outcome of the offspring are discussed.

327 citations

Journal ArticleDOI
TL;DR: There was not enough evidence to provide recommendations using the GRADE approach and recommendations relied on experts’ opinion, but monoclonal antibodies acting on the calcitonin gene-related peptide are new drugs which can be recommended for migraine prevention.
Abstract: Following publication of the original article [1], the authors notified us of some misreported data due to the publication of the EVOLVE-2 trial (Cephalalgia. 2018;38:1442–1454), which substantially changed the level of evidence of galcanezumab for the prevention of episodic migraine. All changes are marked in bold and with red in Figure 1 and Figure 2. Please note that the final recommendations remain unchanged.

258 citations