Szabolcs Lehel

Seasonal changes in brain serotonin transporter binding in short serotonin transporter linked polymorphic region-allele carriers but not in long-allele homozygotes.

BACKGROUND A polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) has been associated with seasonality both in patients with seasonal affective disorder and in the general population. METHOD We used in vivo molecular imaging to measure cerebral serotonin transporter (5-HTT) binding in 57 healthy Scandinavians and related the outcome to season of the year and to the 5-HTTLPR carrier status. RESULTS We found that the number of daylight minutes at the time of scanning correlated negatively with 5-HTT binding in the putamen and the caudate, with a similar tendency in the thalamus, whereas this association was not observed for the midbrain. Furthermore, in the putamen, an anatomic region with relatively dense serotonin innervation, we found a significant gene x daylight effect, such that there was a negative correlation between 5-HTT binding and daylight minutes in carriers of the short 5-HTTLPR allele but not in homozygote carriers of the long allele. CONCLUSIONS Our 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.

Cerebral serotonin transporter binding is inversely related to body mass index

Overweight and obesity is a health threat of increasing concern and understanding the neurobiology behind obesity is instrumental to the development of effective treatment regimes. Serotonergic neurotransmission is critically involved in eating behaviour; cerebral level of serotonin (5-HT) in animal models is inversely related to food intake and body weight and some effective anti-obesity agents involve blockade of the serotonin transporter (SERT). We investigated in 60 healthy volunteers body mass index (BMI) and regional cerebral SERT binding as measured with [(11)C]DASB PET. In a linear regression model with adjustment for relevant covariates, we found that cortical and subcortical SERT binding was negatively correlated to BMI (-0.003 to -0.012 BP(ND) unit per kg/m(2)). Tobacco smoking and alcohol consumption did not affect cerebral SERT binding. Several effective anti-obesity drugs encompass blockade of the SERT; yet, our study is the first to demonstrate an abnormally decreased cerebral SERT binding in obese individuals. 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, such as low baseline serotonin levels, remains to be established.

11C-NS14492 as a Novel PET Radioligand for Imaging Cerebral α7 Nicotinic Acetylcholine Receptors: In Vivo Evaluation and Drug Occupancy Measurements

Small-molecule α7 nicotinic acetylcholine receptor (α7nAChR) agonists are currently validated for use as treatment for cognitive disturbances in schizophrenia and in Alzheimer disease. A suitable radiolabeled α7nAChR PET tracer would be important for in vivo quantification of α7nAChR binding in humans and to measure α7nAChR occupancy of α7nAChR drug candidates. Here, we present the radiosynthesis and in vivo evaluation of 11C-NS14492 as a selective α7nAChR PET radioligand. Methods: The high-affinity α7nAChR-selective partial agonist NS14492 was radiolabeled by methylation of its desmethyl precursor using 11C-methyl triflate. Female Danish Landrace pigs were studied at baseline and after intravenous administration of blocking doses of either the α7nAChR partial agonist SSR180711 or the unlabeled NS14492. 11C-NS14492 was given as an intravenous bolus injection, and the pigs were scanned for 90 min both at baseline and in the blocked conditions. Arterial blood was collected during the scanning, plasma was counted, and parent compound fraction was determined with radio–high-performance liquid chromatography. PET data were quantified with a graphical analysis with arterial input; 11C-NS14492 regional distribution volumes were calculated, and α7nAChR occupancy was determined using an occupancy plot. Results: 11C-NS14492 had a high uptake in the pig brain, with the highest binding in the cerebral cortex and thalamus in accordance with α7nAChR distribution. Pretreatment with NS14492 and SSR180711 consistently decreased distribution volumes of 11C-NS14492 in all examined regions, in a dose-dependent manner, supporting the finding that the radioligand binds selectively to α7nAChR in vivo. Conclusion: We report here that 11C-NS14492 is the first, to our knowledge, PET radioligand for α7nAChR showing a dose-dependent decline in cerebral binding after receptor blockade. This compound is considered a promising PET tracer for in vivo measurements of α7nAChR binding in the human brain.

Cerebral Serotonin 4 Receptors and Amyloid-β in Early Alzheimer's Disease

The 5-HT4 receptor may play a role in memory and learning and 5-HT4 receptor activation has been suggested to modulate acetylcholine release and to reduce amyloid-β (Aβ) accumulation. The aim of this study was for the first time to investigate the in vivo cerebral 5-HT4 receptor binding in early Alzheimer disease (AD) patients in relation to cortical Aβ burden. Eleven newly diagnosed untreated AD patients (mean MMSE 24, range 19-27) and twelve age- and gender-matched healthy controls underwent a two-hour dynamic [11C]SB207145 PET scan to measure the binding potential of the 5-HT4 receptor. All AD patients and eight healthy controls additionally underwent a [11C]PIB PET scan to measure the cortical Aβ burden. When AD patients were defined on clinical criteria, no difference in cerebral 5-HT4 receptor binding between AD patients and healthy controls was found (p = 0.54). However, when individuals were reassigned to groups according to their amyloid status, the PIB-positive individuals had 13% higher 5-HT4 receptor levels than PIB-negative individuals (p = 0.02) and the importance of classification of groups is emphasized. The 5-HT4 receptor binding was a positively correlated to Aβ burden (p = 0.03) and negatively to MMSE score of the AD patients (p = 0.02). Our data suggests that cerebral 5-HT4 receptor upregulation starts at a preclinical stage of and continues while dementia is still at a mild stage, which contrasts other receptor subtypes. We speculate that this may either be a compensatory effect of decreased levels of interstitial 5-HT, an attempt to improve cognitive function, increase acetylcholine release or to counteract Aβ accumulation.

Loss of serotonin 2A receptors exceeds loss of serotonergic projections in early Alzheimer's disease: a combined [11C]DASB and [18F]altanserin-PET study.

In patients with Alzheimers disease (AD), postmortem and imaging studies have revealed early and prominent reductions in cerebral serotonin 2A (5-HT(2A)) receptors. To establish if this was due to a selective disease process of the serotonin system, we investigated the cerebral 5-HT(2A) receptor and the serotonin transporter binding, the latter as a measure of serotonergic projections and neurons. Twelve patients with AD (average Mini Mental State Examination [MMSE]: 24) and 11 healthy age-matched subjects underwent positron emission tomography (PET) scanning with [(18)F]altanserin and [(11)C]N,N-Dimethyl-2-(2-amino-4-cyanopheylthio)benzylamine ([(11)C]DASB). Overall [(18)F]altanserin binding was markedly reduced in AD by 28%-39% (p = 0.02), whereas the reductions in [(11)C]DASB binding were less prominent and mostly insignificant, except for a marked reduction of 33% in mesial temporal cortex (p = .0005). No change in [(11)C]DASB binding was found in the midbrain. We conclude that the prominent reduction in neocortical 5-HT(2A) receptor binding in early AD is not caused by a primary loss of serotonergic neurons or their projections.

Serotonin 2A receptor agonist binding in the human brain with [11C]Cimbi-36

[ 11 C]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 [ 11 C]Cimbi-36. In 29 healthy volunteers, we found high brain uptake and distribution according to 5-HT2A receptors with [ 11 C]Cimbi-36 PET. The two-tissue compartment model using arterial input measurements provided the most optimal quantification of cerebral [ 11 C]Cimbi-36 binding. Reference tissue modeling was feasible as it induced a negative but predictable bias in [ 11 C]Cimbi-36 PET outcome measures. In five subjects, pretreatment with the 5-HT2A receptor antagonist ketanserin before a second PET scan significantly decreased [ 11 C]Cimbi-36 binding in all cortical regions with no effects in cerebellum. These results confirm that [ 11 C]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 [ 11 C]Cimbi-36 as the first agonist PET radioligand to successfully image and quantify 5-HT2A receptors in the human brain.

Central 5-HT4 receptor binding as biomarker of serotonergic tonus in humans: a [11C]SB207145 PET study.

Identification of a biomarker that can inform on extracellular serotonin (5-HT) levels in the brains of living humans would enable greater understanding of the way brain circuits are modulated by serotonergic neurotransmission. Substantial evidence from studies in animals and humans indicates an inverse relationship between central 5-HT tonus and 5-HT type 4 receptor (5-HT4R) density, suggesting that 5-HT4R receptor density may be a biomarker marker for 5-HT tonus. Here, we investigated whether a 3-week administration of a selective serotonin reuptake inhibitor, expected to increase brain 5-HT levels, is associated with a decline in brain 5-HT4R binding. A total of 35 healthy men were studied in a placebo-controlled, randomized, double-blind study. Participants were assigned to receive 3 weeks of oral dosing with placebo or fluoxetine, 40 mg per day. Brain 5-HT4R binding was quantified at baseline and at follow-up with [11C]SB207145 positron emission tomography (PET). Three weeks of intervention with fluoxetine was associated with a 5.2% reduction in brain 5-HT4R binding (P=0.017), whereas placebo intervention did not change 5-HT4R binding (P=0.52). Our findings are consistent with a model, wherein the 5-HT4R density adjusts to changes in the extracellular 5-HT tonus. Our data demonstrate for the first time in humans that the imaging of central 5-HT4R binding may be used as an in vivo biomarker of the central 5-HT tonus.

Role of Serotonin Transporter Changes in Depressive Responses to Sex-Steroid Hormone Manipulation: A Positron Emission Tomography Study

BACKGROUND An adverse response to acute and pronounced changes in sex-hormone levels during, for example, the perimenopausal or postpartum period appears to heighten risk for major depression in women. The underlying risk mechanisms remain elusive but may include transiently compromised serotonergic brain signaling. Here, we modeled a biphasic ovarian sex hormone fluctuation using a gonadotropin-releasing hormone agonist (GnRHa) and evaluated if emergence of depressive symptoms was associated with change in cerebral serotonin transporter (SERT) binding following intervention. METHODS A double-blind, randomized, placebo-controlled study included 63 healthy female volunteers (mean age 24.3 ± 4.9 years) with regular menstrual cycles between 23 and 35 days. Participants were randomized to active (goserelin [GnRHa] 3.6 mg implant) or placebo intervention. Sixty women completed follow-up and entered the analyses. Primary outcome measures were changes from baseline in depressive symptoms assessed on the 17-item Hamilton Depression Rating Scale and SERT binding as imaged by [(11)C]DASB positron emission tomography. Outcome measures were acquired at baseline in the follicular phase (cycle day 6.6 ± 2.2) and at follow-up (16.2 ± 2.6 days after intervention start). RESULTS Sex hormone manipulation with GnRHa significantly triggered subclinical depressive symptoms within-group (p = .003) and relative to placebo (p = .02), which were positively associated with net decreases in estradiol levels (p = .02) from baseline within the GnRHa group. Depressive symptoms were associated with increases in neocortical SERT binding in the GnRHa group relative to placebo (p = .003). CONCLUSIONS Our 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.

Serotonin 1B Receptor Binding Is Associated With Trait Anger and Level of Psychopathy in Violent Offenders.

BACKGROUND The involvement of serotonin in aggression has traditionally been attributed to impaired prefrontal serotonergic inhibitory control of emotional reactions to provocations in antisocial individuals. However, it is unclear which specific serotonergic receptors are involved in the effects. A large body of preclinical research supports a specific role of serotonin 1B receptors (5-HT1BRs) in aggression and impulsivity, but this has never been evaluated in humans. METHODS Nineteen incarcerated violent offenders and 24 healthy control nonoffenders were included and examined with positron emission tomography, using the radioligand [11C]AZ10419369 for quantification of cerebral 5-HT1BR binding in three regions of interest: the anterior cingulate cortex, orbitofrontal cortex, and striatum. RESULTS Group status significantly moderated the association between striatal 5-HT1BRs and trait anger (difference in slopes, pcorrected = .04). In the violent offender group, striatal 5-HT1BR binding was positively correlated with self-reported trait anger (p = .0004), trait psychopathy (p = .008), and level of psychopathy according to the Psychopathy Checklist-Revised (p = .02). We found no group differences in 5-HT1BR binding. CONCLUSIONS Our data demonstrate for the first time in humans a specific involvement of 5-HT1BR binding in anger and psychopathy. 5-HT1BRs putatively represent a molecular target for development of pharmacologic antiaggressive treatments.

Anti-PSMA labeled liposomes loaded with Actinium-225 for potential antivascular alpha-radiotherapy

The serotonin (5-hydroxytryptamine [5-ΗΤ]) 7 receptor (5-HT7R) is the most recently discovered 5-HT receptor, and its physiologic and possible pathophysiologic roles are not fully elucidated. So far, no suitable 5-HT7R PET radioligand is available, thus limiting the investigation of this receptor in the living brain. Here, we present the radiosynthesis and in vivo evaluation of Cimbi-712 (3-{4-[4-(4-methylphenyl)piperazine-1-yl]butyl}p-1,3-dihydro-2H-indol-2-one) and Cimbi-717 (3-{4-[4-(3-methoxyphenyl)piperazine-1-yl]butyl}-1,3-dihydro-2H-indol-2-one) as selective 5-HT7R PET radioligands in the pig brain. The 5-HT7R distribution in the postmortem pig brain is also assessed. Methods: In vitro autoradiography with the 5-HT7R selective radioligand 3H-labeled (R)-3-(2-(2-(4-methylpiperidin-1-yl)ethyl)pyrrolidine-1-sulfonyl)phenol (SB-269970) was performed on pig brain sections to establish the 5-HT7R binding distribution. Radiolabeling of 5-HT7R selective compounds was performed in an automated synthesis module in which we conducted either palladium-mediated cross coupling (11C-Cimbi-712) or conventional O-methylation (11C-Cimbi-717) using 11C-MeI and 11C-MeOTf, respectively. After intravenous injection of the radioligands in Danish Landrace pigs, the in vivo brain distribution of the ligands was studied. Specific binding of 11C-Cimbi-712 and 11C-Cimbi717 to 5-HT7R was investigated by intravenous administration of SB-269970 before a second PET scan. Results: High 5-HT7R density was found in the thalamus and cortical regions of the pig brain by autoradiography. The radiosynthesis of both radioligands succeeded after optimization efforts (radiochemical yield, ∼20%–30% at the end of synthesis). Time–activity curves of 11C-Cimbi-712 and 11C-Cimbi-717 showed high brain uptake and distribution according to 5-HT7R distribution, but the tracer kinetics of 11C-Cimbi-717 were faster than 11C-Cimbi-712. Both radioligands were specific for 5-HT7R, as binding could be blocked by pretreatment with SB-269970 for 11C-Cimbi-717 in a dose-dependent fashion. For 11C-Cimbi-717, nondisplaceable binding potentials of 6.4 ± 1.2 (n = 6) were calculated in the thalamus. Conclusion: Both 11C-Cimbi-712 and 11C-Cimbi-717 generated a specific binding in accordance with 5-HT7R distribution and are potential PET radioligands for 5-HT7R. 11C-Cimbi-717 is the better candidate because of the more reversible tracer kinetics, and this radioligand showed a dose-dependent decline in cerebral binding after receptor blockade. Thus, 11C-Cimbi-717 is currently the most promising radioligand for investigation of 5-HT7R binding in the living human brain.