RESUMEN
Serotonergic neurotransmission is thought to underlie a dynamic interrelation between different key structures of the serotonin system. The serotonin transporter (SERT), which is responsible for the reuptake of serotonin from the synaptic cleft into the neuron, as well as the serotonin-1A (5-HT1A) and -1B (5-HT1B) receptors, inhibitory auto-receptors in the raphe region and projection areas, respectively, are likely to determine serotonin release. Thereby, they are involved in the regulation of extracellular serotonin concentrations and the extent of serotonergic effects in respective projection areas. Complex receptor interactions can be assessed in vivo with positron emission tomography (PET) and single-nucleotide-polymorphisms, which are thought to alter protein expression levels. Due to the complexity of the serotonergic system, gene × gene interactions are likely to regulate transporter and receptor expression and therefore subsequently serotonergic transmission. In this context, we measured 51 healthy subjects (mean age 45.5 ± 12.9, 38 female) with PET using [carbonyl-(11)C]WAY-100635 to determine 5-HT1A receptor binding potential (5-HT1A BPND). Genotyping for rs6296 (HTR1B) and 5-HTTLPR (SERT gene promoter polymorphism) was performed using DNA isolated from whole blood. Voxel-wise whole-brain ANOVA revealed a positive interaction effect of genotype groups (5-HTTLPR: LL, LS+SS and HTR1B: rs6296: CC, GC+GG) on 5-HT1A BPND with peak t-values in the bilateral parahippocampal gyrus. More specifically, highest 5-HT1A BPND was identified for individuals homozygous for both the L-allele of 5-HTTLPR and the C-allele of rs6296. This finding suggests that the interaction between two major serotonergic structures involved in serotonin release, specifically the SERT and 5-HT1B receptor, results in a modification of the inhibitory serotonergic tone mediated via 5-HT1A receptors.
Asunto(s)
Encéfalo/metabolismo , Receptor de Serotonina 5-HT1A/metabolismo , Receptor de Serotonina 5-HT1B/genética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Piperazinas , Polimorfismo de Nucleótido Simple , Tomografía de Emisión de Positrones , Unión Proteica , Piridinas , Antagonistas de la SerotoninaRESUMEN
PURPOSE: The adenosine A3 receptor (A3R) is involved in cardiovascular, neurological and tumour-related pathologies and serves as an exceptional pharmaceutical target in the clinical setting. A3R antagonists are considered antiinflammatory, antiallergic and anticancer agents, and to have potential for the treatment of asthma, COPD, glaucoma and stroke. Hence, an appropriate A3R PET tracer would be highly beneficial for the diagnosis and therapy monitoring of these diseases. Therefore, in this preclinical in vivo study we evaluated the potential as a PET tracer of the A3R antagonist [(18)F]FE@SUPPY. METHODS: Rats were injected with [(18)F]FE@SUPPY for baseline scans and blocking scans (A3R with MRS1523 or FE@SUPPY, P-gp with tariquidar; three animals each). Additionally, metabolism was studied in plasma and brain. In a preliminary experiment in a mouse xenograft model (mice injected with cells expressing the human A3R; three animals), the animals received [(18)F]FE@SUPPY and [(18)F]FDG. Dynamic PET imaging was performed (60 min in rats, 90 min in xenografted mice). In vitro stability of [(18)F]FE@SUPPY in human and rat plasma was also evaluated. RESULTS: [(18)F]FE@SUPPY showed high uptake in fat-rich regions and low uptake in the brain. Pretreatment with MRS1523 led to a decrease in [(18)F]FE@SUPPY uptake (p = 0.03), and pretreatment with the P-gp inhibitor tariquidar led to a 1.24-fold increase in [(18)F]FE@SUPPY uptake (p = 0.09) in rat brain. There was no significant difference in metabolites in plasma and brain in the treatment groups. However, plasma concentrations of [(18)F]FE@SUPPY were reduced to levels similar to those in rat brain after blocking. In contrast to [(18)F]FDG uptake (p = 0.12), the xenograft model showed significantly increased uptake of [(18)F]FE@SUPPY in the tissue masses from CHO cells expressing the human A3R (p = 0.03). [(18)F]FE@SUPPY was stable in human plasma. CONCLUSION: Selective and significant tracer uptake of [(18)F]FE@SUPPY was found in xenografted mice injected with cells expressing human A3R. This finding supports the strategy of evaluating [(18)F]FE@SUPPY in "humanized animal models". In conclusion, preclinical evaluation points to the suitability of [(18)F]FE@SUPPY as an A3R PET tracer in humans.
Asunto(s)
Ácidos Nicotínicos/farmacocinética , Tomografía de Emisión de Positrones , Radiofármacos/farmacocinética , Receptor de Adenosina A3/metabolismo , Animales , Células CHO , Cricetinae , Cricetulus , Humanos , Masculino , Ratones , Neoplasias Experimentales/diagnóstico por imagen , Unión Proteica , Radiofármacos/síntesis química , Ratas , Ratas Sprague-Dawley , Distribución TisularRESUMEN
Blocking of the serotonin transporter (SERT) represents the initial mechanism of action of selective serotonin reuptake inhibitors (SSRIs) which can be visualized due to the technical proceedings of SERT occupancy studies. When compared to the striatum, higher SERT occupancy in the midbrain and lower values in the thalamus were reported. This indicates that occupancy might be differently distributed throughout the brain, which is supported by preclinical findings indicating a regionally varying SERT activity and antidepressant drug concentration. The present study therefore aimed to investigate regional SERT occupancies with positron emission tomography and the radioligand [(11)C]DASB in 19 depressed patients after acute and prolonged intake of oral doses of either 10mg/day escitalopram or 20mg/day citalopram. Compared to the mean occupancy across cortical and subcortical regions, we detected increased SERT occupancies in regions commonly associated with antidepressant response, such as the subgenual cingulate, amygdala and raphe nuclei. When acute and prolonged drug intake was compared, SERT occupancies increased in subcortical areas that are known to be rich in SERT. Moreover, SERT occupancy in subcortical brain areas after prolonged intake of antidepressants was predicted by plasma drug levels. Similarly, baseline SERT binding potential seems to impact SERT occupancy, as regions rich in SERT showed greater binding reduction as well as higher residual binding. These findings suggest a region-specific distribution of SERT blockage by SSRIs and relate the postulated link between treatment response and SERT occupancy to certain brain regions such as the subgenual cingulate cortex.
Asunto(s)
Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Adulto , Encéfalo/diagnóstico por imagen , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/sangreRESUMEN
Suffering from anhedonia, patients with major depressive disorder (MDD) exhibit alterations in several parts of the serotonergic neurotransmitter system, which are in turn involved in reward processing. However, previous investigations of the serotonin transporter (SERT) focused on regional differences with varying results depending on the clinical syndrome. Here, we aimed to describe the serotonergic system of MDD patients on a network level by evaluating SERT associations across brain regions. Twenty medication free patients with major depression and 20 healthy controls underwent positron emission tomography using the radioligand [(11) C]DASB. SERT binding potentials (BPND ) were quantified voxel-wise with the multilinear reference tissue model 2. In addition, SERT BPND was extracted from the dorsal raphe nucleus (DRN) as an indicator of midbrain serotonergic neurotransmission. Whole-brain linear regression analysis was applied to evaluate the association of DRN SERT bindings to those in projection areas, which was followed by ANCOVA to assess differences in interregional relationships between patients and controls. Although both groups showed widespread positive correlations, group differences were restricted to decreased SERT associations between the DRN and the ventral striatum (right and left respectively: t=5.85, P<0.05 corrected and t=5.07, P<0.1 corrected) when comparing MDD patients (R(2)=0.11 and 0.24) to healthy subjects (R(2)=0.72 and 0.66, P<0.01 and 0.05 corrected). Adjusting for age and sex did not change these findings. This study indicates a disturbed regulation between key regions involved in reward processing via the SERT. Our interregional approach highlights the importance of evaluating pathophysiological alterations on a network level to gain complementary information in addition to regional investigations.
Asunto(s)
Trastorno Depresivo Mayor/metabolismo , Núcleo Dorsal del Rafe/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Estriado Ventral/metabolismo , Adulto , Bencilaminas , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Mapeo Encefálico , Radioisótopos de Carbono , Trastorno Depresivo Mayor/diagnóstico por imagen , Núcleo Dorsal del Rafe/diagnóstico por imagen , Femenino , Humanos , Masculino , Tomografía de Emisión de Positrones , Radiofármacos , Análisis de Regresión , Procesamiento de Señales Asistido por Computador , Fumar , Estriado Ventral/diagnóstico por imagenRESUMEN
INTRODUCTION: Present data indicate that merging beneficial structural elements from previously published DAT-ligands highest DAT affinity, selectivity and a suitable metabolic profile should be achieved. This combination led to the development of IPCIT and FE@IPCIT. METHODS: Precursor synthesis was done starting from cocaine in a six step reaction. O-[(11)C]-methylation was established using [(11)C]methyl iodide, optimized and subsequently automated. Small scale (18)F-fluroroethylation as well as optimization of reaction parameters and automation were performed. Affinity and selectivity of the candidate substances were tested in standard binding experiments on human membranes. Metabolic stability and blood-brain-barrier (BBB) penetration were determined. RESULTS: Precursor compound, IPCITacid, and reference compounds, IPCIT and FE@IPCIT, were obtained in 4.9%, 12.7% and 4.1% yield, respectively. Automated radiosynthesis of [(11)C]IPCIT yielded 1.9 ± 0.7 GBq (12.5 ± 4%, corrected for decay). Optimum parameters for (18)F-fluoroethylation were 110 °C for 15 min under TBAH catalysis, yielding 67 ± 16 % radiochemical incorporation. Affinity was determined as 1.7 ± 0.6 nM for IPCIT, 1.3 ± 0.2 nM for FE@IPCIT and 37 ± 13 nM for the precursor molecule, IPCIT-acid. Results from in vitro and in silico evaluations revealed high stability but also high lipophilicity. CONCLUSION: Present data indicate high affinity and stability of both IPCIT and FE@IPCIT. Radiolabelling, optimization of reaction parameters and automation succeeded. On the other hand, data concerning BBB-penetration are not promising.
Asunto(s)
Cocaína/análogos & derivados , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/análisis , Tomografía de Emisión de Positrones , Isótopos de Carbono , Cocaína/síntesis química , Cocaína/química , Cocaína/metabolismo , Radioisótopos de Flúor , Humanos , Conformación Molecular , Trazadores RadiactivosRESUMEN
The highly diverse serotonergic system with at least 16 different receptor subtypes is implicated in the pathophysiology of most neuropsychiatric disorders including affective and anxiety disorders, obsessive compulsive disorder, post-traumatic stress disorder, eating disorders, sleep disturbance, attention deficit/hyperactivity disorder, drug addiction, suicidal behavior, schizophrenia, Alzheimer, etc. Alterations of the interplay between various pre- and postsynaptic receptor subtypes might be involved in the pathogenesis of these disorders. However, there is a lack of comprehensive in vivo values using standardized procedures. In the current PET study we quantified 3 receptor subtypes, including the major inhibitory (5-HT(1A) and 5-HT(1B)) and excitatory (5-HT(2A)) receptors, and the transporter (5-HTT) in the brain of healthy human subjects to provide a database of standard values. PET scans were performed on 95 healthy subjects (age=28.0 ± 6.9 years; 59% males) using the selective radioligands [carbonyl-(11)C]WAY-100635, [(11)C]P943, [(18)F]altanserin and [(11)C]DASB, respectively. A standard template in MNI stereotactic space served for region of interest delineation. This template follows two anatomical parcellation schemes: 1) Brodmann areas including 41 regions and 2) AAL (automated anatomical labeling) including 52 regions. Standard values (mean, SD, and range) for each receptor and region are presented. Mean cortical and subcortical binding potential (BP) values were in good agreement with previously published human in vivo and post-mortem data. By means of linear equations, PET binding potentials were translated to post-mortem binding (provided in pmol/g), yielding 5.89 pmol/g (5-HT(1A)), 23.5 pmol/g (5-HT(1B)), 31.44 pmol/g (5-HT(2A)), and 11.33 pmol/g (5-HTT) being equivalent to the BP of 1, respectively. Furthermore, we computed individual voxel-wise maps with BP values and generated average tracer-specific whole-brain binding maps. This knowledge might improve our interpretation of the alterations taking place in the serotonergic system during neuropsychiatric disorders.
Asunto(s)
Encéfalo/metabolismo , Bases de Datos Factuales/normas , Tomografía de Emisión de Positrones/métodos , Tomografía de Emisión de Positrones/normas , Receptores de Serotonina/metabolismo , Neuronas Serotoninérgicas/diagnóstico por imagen , Neuronas Serotoninérgicas/metabolismo , Adolescente , Adulto , Encéfalo/diagnóstico por imagen , Femenino , Humanos , Masculino , Persona de Mediana Edad , Receptores de Serotonina/análisis , Valores de Referencia , Adulto JovenRESUMEN
Recent mathematical models suggest restored serotonergic burst-firing to underlie the antidepressant effect of selective serotonin reuptake inhibitors (SSRI), resulting from down-regulated serotonin transporters (SERT) in terminal regions. This mechanism possibly depends on the interregional balance between SERTs in the raphe nuclei and in terminal regions before treatment. To evaluate these hypotheses on a systems level in humans in vivo, we investigated SERT availability and occupancy longitudinally in patients with major depressive disorder using positron emission tomography (PET) and the radioligand [11C]DASB. Measurements were performed before and after a single oral dose, as well as after three weeks (mean 24.73±3.3 days) of continuous oral treatment with either escitalopram (10 mg/day) or citalopram (20 mg/day). Data were analyzed using voxel-wise linear regression and ANOVA to evaluate SERT binding, occupancy and binding ratios (SERT binding of the entire brain compared to SERT binding in the dorsal and median raphe nuclei) in relation to treatment outcome. Regression analysis revealed that treatment response was predicted by pre-treatment SERT binding ratios, i.e., SERT binding in key regions of depression including bilateral habenula, amygdala-hippocampus complex and subgenual cingulate cortex in relation to SERT binding in the median but not dorsal raphe nucleus (p<0.05 FDR-corrected). Similar results were observed in the direct comparison of responders and non-responders. Our data provide a first proof-of-concept for recent modeling studies and further underlie the importance of the habenula and subgenual cingulate cortex in the etiology of and recovery from major depression. These findings may indicate a promising molecular predictor of treatment response and stimulate new treatment approaches based on regional differences in SERT binding.
Asunto(s)
Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/metabolismo , Núcleos del Rafe/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Adulto , Bencilaminas , Radioisótopos de Carbono , Trastorno Depresivo Mayor/diagnóstico por imagen , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Radiofármacos , Núcleos del Rafe/diagnóstico por imagen , Núcleos del Rafe/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Tomografía Computarizada de Emisión de Fotón Único , Adulto JovenRESUMEN
Animal models revealed that the serotonin-1A (5-HT(1A)) receptor modulates gray matter structure. However, there is a lack of evidence showing the relationship between 5-HT(1A) receptor concentration and gray matter in the human brain in vivo. Here, to demonstrate an association between the 5-HT(1A) receptor binding potential, an index for receptor concentration, and the local gray matter volume (GMV), an index for gray matter structure, we measured 35 healthy subjects with both positron emission tomography (PET) and structural magnetic resonance imaging (MRI). We found that regional heteroreceptor binding was positively associated with GMV in distinctive brain regions such as the hippocampi and the temporal cortices in both hemispheres (R(2) values ranged from 0.308 to 0.503, p<0.05 cluster-level FDR-corrected). Furthermore, autoreceptor binding in the midbrain raphe region was positively associated with GMV in forebrain projection sites (R(2)=0.656, p=0.001). We also observed a broad range between 5-HT(1A) receptor binding and GMV. Given the congruence of altered 5-HT(1A) receptor concentrations and GMV reduction in depression or Alzheimer's disease as reported by numerous studies, these results might provide new insights towards understanding the mechanisms behind GMV alterations observed in these brain disorders.
Asunto(s)
Mapeo Encefálico/métodos , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Receptor de Serotonina 5-HT1A/metabolismo , Adulto , Femenino , Humanos , Interpretación de Imagen Asistida por Computador , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Adulto JovenRESUMEN
INTRODUCTION: Changes of the adenosine A(3) receptor subtype (A3AR) expression have been shown in a variety of pathologies, especially neurological and affective disorders, cardiac diseases and oncological and inflammation processes. Recently, 5-(2-fluoroethyl) 2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate (FE@SUPPY) was presented as a high-affinity ligand for the A3AR with good selectivity. Our aims were the development of a suitable labeling precursor, the establishment of a reliable radiosynthesis for the fluorine-18-labeled analogue [(18)F]FE@SUPPY and a first evaluation of [(18)F]FE@SUPPY in rats. METHODS: [(18)F]FE@SUPPY was prepared in a feasible and reliable manner by radiofluorination of the corresponding tosylated precursor. Biodistribution was carried out in rats, and organs were removed and counted. Autoradiography was performed on rat brain slices in the presence or absence of 2-Cl-IB-MECA. RESULTS: Overall yields and radiochemical purity were sufficient for further preclinical and clinical applications. The uptake pattern of [(18)F]FE@SUPPY found in rats mainly followed the described mRNA distribution pattern of the A3AR. Specific uptake in brain was demonstrated by blocking with a selective A3AR agonist. CONCLUSION: We conclude that [(18)F]FE@SUPPY has the potential to serve as the first positron emission tomography tracer for the A3AR.
Asunto(s)
Radioisótopos de Flúor , Ácidos Nicotínicos/síntesis química , Tomografía de Emisión de Positrones , Radiofármacos/síntesis química , Receptor de Adenosina A3/metabolismo , Animales , Autorradiografía , Masculino , Ácidos Nicotínicos/metabolismo , Radiofármacos/metabolismo , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Distribución TisularRESUMEN
PURPOSE: The present study aimed to develop convenient preparation and quality control protocols for [(68)Ga]-EDTMP, a potential radiotracer for skeletal PET imaging. Furthermore, bone binding characteristics with special focus on the influence of carrier addition were evaluated. METHODS: No-carrier-added (nca), carrier-added and novel cross-complexed [(68)Ga]-EDTMP formulations were prepared using [(68)Ga]-gallium chloride and a commercial EDTMP kit. Respective bone binding characteristics were determined on the basis of an established in-vitro method using hydroxyapatite and human bone powders as binding matrices. RESULTS: Pre-vivo evaluation of nca [(68)Ga]-EDTMP yielded irreversible binding on the mineral bone phase characterised by fast binding kinetics. Generally, nca [(68)Ga]-EDTMP showed low uptake values comparable to nca [(99m)Tc]-EDTMP. Interestingly, the bone binding affinity of [(68)Ga]-EDTMP could be increased by the addition of carriers, presumably by changing the complex structure. CONCLUSIONS: This fast and reliable preparation protocol could enable small PET facilities without onsite cyclotron to perform PET bone scans. A comparison of all cross-complexed [(68)Ga]-EDTMP preparations further strengthens the recently presented "foreign carrier theory", which highlights carrier addition as a factor strongly affecting bone uptake of radiolabelled polyphosphonates. The clinical applicability of [(68)Ga]-EDTMP - particularly with respect to lesion specificity and sensitivity - should be clarified in forthcoming in-vivo studies.
Asunto(s)
Portadores de Fármacos , Radioisótopos de Galio/química , Compuestos Organofosforados/química , Evaluación Preclínica de Medicamentos , Humanos , Compuestos Organofosforados/administración & dosificaciónRESUMEN
INTRODUCTION: The translation of 11C-labeled compounds into their respective 18F-labeled derivatives is an important tool in the rapid development of positron emission tomography (PET) tracers. Thus, our aim was the development of a general method for the preparation of 18F-fluoroethylated compounds that (a) is applicable to a variety of precursors, (b) can be performed in a fully automated commercially available synthesizer and (c) enables this rapid translation of 11C-methylated tracers into their 18F-fluoroethylated analogs sharing the same precursor molecules. METHODS: Ten methods for the preparation and purification of different 18F-fluoroethylating agents were compared. Subsequently, five 18F-labeled PET tracers were synthesized under fully automated conditions. RESULTS: Radiochemical yields ranged from 34.4% to 60.8%, and time consumption ranged from 20 to 55 min for all methods. Use of 1-bromo-2-[18F]fluoroethane and distillation evinced as the method of choice. CONCLUSIONS: We were able to develop a general method for the preparation of a variety of 18F-fluoroethylated molecules. The provided tool is solely based on commercially available resources and has the potential to simplify and accelerate innovative PET tracer development in the future.
Asunto(s)
Radioisótopos de Carbono/química , Radioisótopos de Flúor/química , Marcaje Isotópico/métodos , Radiofármacos/síntesis química , Marcaje Isotópico/instrumentación , MetilaciónRESUMEN
BACKGROUND: The melanin-concentrating hormone receptor 1 (MCHR1), which is highly expressed in the lateral hypothalamus, plays a key role in energy homeostasis, obesity and other endocrine diseases. Hence, there is a major interest in in vivo imaging of this receptor. A PET tracer would allow non-invasive in vivo visualization and quantification of the MCHR1. The aim of the study was the ex vivo evaluation of the MCHR1 ligand [(18)F]FE@SNAP as a potential PET tracer for the MCHR1. METHODS: [(18)F]FE@SNAP was injected directly into the jugular vein of awake naïve rats for ex vivo brain autoradiography, biodistribution and additional blood metabolite analysis. Blocking experiments were conducted using the unlabeled MCHR1 ligand SNAP-7941. RESULTS: A high uptake of [(18)F]FE@SNAP was observed in the lateral hypothalamus and the ventricular system. Both regions were significantly blocked by SNAP-7941. Biodistribution evinced the highest uptake in the kidneys, adrenals, lung and duodenum. Specific blocking with SNAP-7941 led to a significant tracer reduction in the heart and adrenals. In plasma samples, 47.73 ± 6.1 % of a hydrophilic radioactive metabolite was found 45 min after tracer injection. CONCLUSIONS: Since [(18)F]FE@SNAP uptake was significantly blocked in the lateral hypothalamus, there is strong evidence that [(18)F]FE@SNAP is a highly suitable agent for specific MCHR1 imaging in the central nervous system. Additionally, this finding is supported by the specific blocking in the ventricular system, where the MCHR1 is expressed in the ependymal cells. These findings suggest that [(18)F]FE@SNAP could serve as a useful imaging and therapy monitoring tool for MCHR1-related pathologies.
RESUMEN
BACKGROUND: Women are two times more likely to be diagnosed with depression than men. Sex hormones modulating serotonergic transmission are proposed to partly underlie these epidemiologic findings. Here, we used the cross-sex steroid hormone treatment of transsexuals seeking sex reassignment as a model to investigate acute and chronic effects of testosterone and estradiol on serotonin reuptake transporter (SERT) binding in female-to-male and male-to-female transsexuals. METHODS: Thirty-three transsexuals underwent [(11)C]DASB positron emission tomography before start of treatment, a subset of which underwent a second scan 4 weeks and a third scan 4 months after treatment start. SERT nondisplaceable binding potential was quantified in 12 regions of interest. Treatment effects were analyzed using linear mixed models. Changes of hormone plasma levels were correlated with changes in regional SERT nondisplaceable binding potential. RESULTS: One and 4 months of androgen treatment in female-to-male transsexuals increased SERT binding in amygdala, caudate, putamen, and median raphe nucleus. SERT binding increases correlated with treatment-induced increases in testosterone levels, suggesting that testosterone increases SERT expression on the cell surface. Conversely, 4 months of antiandrogen and estrogen treatment in male-to-female transsexuals led to decreases in SERT binding in insula, anterior, and mid-cingulate cortex. Increases in estradiol levels correlated negatively with decreases in regional SERT binding, indicating a protective effect of estradiol against SERT loss. CONCLUSIONS: Given the central role of the SERT in the treatment of depression and anxiety disorders, these findings may lead to new treatment modalities and expand our understanding of the mechanism of action of antidepressant treatment properties.
Asunto(s)
Andrógenos/administración & dosificación , Estradiol/administración & dosificación , Estrógenos/administración & dosificación , Proteínas de Transporte de Serotonina en la Membrana Plasmática/efectos de los fármacos , Testosterona/administración & dosificación , Personas Transgénero/clasificación , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Putamen/efectos de los fármacos , Núcleos del Rafe/efectos de los fármacos , Adulto JovenRESUMEN
The MCHR1 is an interesting pharmacological and pharmaceutical target, due to its involvement in pathologies as diabetes, gut inflammation and adiposity. in vivo PET-studies of the MCHR1 in energy homeostasis and diabetes could be of great value for deeper understanding of endocrinological hormone status and consequential pharmacological interactions. Furthermore, PET-tracers would facilitate compound dose selection of MCHR1 antagonists for treatment. Therefore, we developed two potential PET-tracers, [(11)C]SNAP-7941 and [(18)F]FE@SNAP, for the in vivo visualization of this receptor. Aim of this study was a preclinical in vitro evaluation of both unlabeled ligands. Therefore, a comparative autoradiographic investigation on CNS (coronal rat brain and 4 different human brain regions) and peripheral tissues (rat tongue as target and rat testes as non-target region) was conducted. Competition experiments, using the two radioligands [(125)I]-MCH and [(125)I]-S36057, were performed with selective and specific MCHR1 ligands as PMC-3886, a MCHR1 agonist, SNAP-7941 and FE@SNAP, two MCHR1 antagonists. Additionally, immunohistochemical staining with a specific MCHR1 antibody was performed. Specific binding was found in all tissues known to express the MCHR1 as human and rat CNS and peripheral rat tongue tissue. No specific binding was found in the non-target region of rat testes. MCHR1 antibody staining complemented the outcome of the autoradiographic experiments. The compounds SNAP-7941 and FE@SNAP were generally comparable with PMC-3886. Hence, the in vitro autoradiographic study of the unlabeled compounds SNAP-7941 and FE@SNAP further qualifies the potential of the PET-tracers [(11)C]SNAP-7941 and [(18)F]FE@SNAP as useful MCHR1 PET-tracers.
Asunto(s)
Encéfalo/metabolismo , Piperidinas , Pirimidinas , Receptores de Somatostatina/metabolismo , Lengua/metabolismo , Animales , Autorradiografía , Encéfalo/diagnóstico por imagen , Radioisótopos de Carbono , Radioisótopos de Flúor , Humanos , Ligandos , Masculino , Trazadores Radiactivos , Radiografía , Ratas Wistar , Testículo/diagnóstico por imagen , Testículo/metabolismo , Lengua/diagnóstico por imagenRESUMEN
BACKGROUND: The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism (rs6265) may impact on the in-vivo binding of important serotonergic structures such as the serotonin transporter (5-HTT) and the serotonin-1A (5-HT1A) receptor. Previous positron emission tomography (PET) studies on the association between Val66Met and 5-HTT and 5-HT1A binding potential (BPND) have demonstrated equivocal results. METHODS: We conducted an imaging genetics study investigating the effect of Val66Met genotype on 5-HTT or 5-HT1A BPND in 92 subjects. Forty-one subjects (25 healthy subjects and 16 depressive patients) underwent genotyping for Val66Met and PET imaging with the 5-HTT specific radioligand [11C]DASB. Additionally, in 51 healthy subjects Val66Met genotypes and 5-HT1A binding with the radioligand [carbonyl-11C]WAY-100635 were ascertained. Voxel-wise and region of interest-based analyses of variance were used to examine the influence of Val66Met on 5-HTT and 5-HT1A BPND. RESULTS: No significant differences of 5-HTT nor 5-HT1A BPND between BDNF Val66Met genotype groups (val/val vs. met-carrier) were detected. There was no interaction between depression and Val66Met genotype status. CONCLUSION: In line with previous data, our work confirms an absent effect of BDNF Val66Met on two major serotonergic structures. These results could suggest that altered protein expression associated with genetic variants, might be compensated in vivo by several levels of unknown feedback mechanisms. In conclusion, Val66Met genotype status is not associated with changes of in-vivo binding of 5-HTT and 5-HT1A receptors in human subjects.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/genética , Trastorno Depresivo/genética , Polimorfismo de Nucleótido Simple , Receptor de Serotonina 5-HT1A/genética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Serotonina/metabolismo , Adolescente , Adulto , Anciano , Sustitución de Aminoácidos , Compuestos de Anilina/farmacología , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Estudios de Casos y Controles , Trastorno Depresivo/diagnóstico por imagen , Trastorno Depresivo/metabolismo , Trastorno Depresivo/patología , Femenino , Expresión Génica , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Piperazinas/farmacología , Tomografía de Emisión de Positrones , Unión Proteica , Piridinas/farmacología , Radiofármacos/farmacología , Receptor de Serotonina 5-HT1A/metabolismo , Antagonistas de la Serotonina/farmacología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Sulfuros/farmacologíaRESUMEN
The serotonergic system modulates brain functions that are considered to underlie affective states, emotion and cognition. Several lines of evidence point towards a strong lateralization of these mental processes, which indicates similar asymmetries in associated neurotransmitter systems. Here, our aim was to investigate a potential asymmetry of the serotonin transporter distribution using positron emission tomography and the radioligand [(11)C]DASB in vivo. As brain asymmetries may differ between sexes, we further aimed to compare serotonin transporter asymmetry between females, males and male-to-female (MtF) transsexuals whose brains are considered to be partly feminized. Voxel-wise analysis of serotonin transporter binding in all groups showed both strong left and rightward asymmetries in several cortical and subcortical structures including temporal and frontal cortices, anterior cingulate, hippocampus, caudate and thalamus. Further, male controls showed a rightward asymmetry in the midcingulate cortex, which was absent in females and MtF transsexuals. The present data support the notion of a lateralized serotonergic system, which is in line with previous findings of asymmetric serotonin-1A receptor distributions, extracellular serotonin concentrations, serotonin turnover and uptake. The absence of serotonin transporter asymmetry in the midcingulate in MtF transsexuals may be attributed to an absence of brain masculinization in this region.
Asunto(s)
Corteza Cerebral/diagnóstico por imagen , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Transexualidad/diagnóstico por imagen , Transexualidad/patología , Adulto , Análisis de Varianza , Femenino , Lateralidad Funcional , Humanos , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Escalas de Valoración PsiquiátricaRESUMEN
Aim of this work was the implementation of a generalized in-loop synthesis for (11)C-carboxylations and subsequent (11)C-acylations on the TRACERlab FxC Pro platform. The set-up was tested using [carbonyl-(11)C]WAY-100635 and, for the first time, [(11)C]-(+)-PHNO. Its general applicability could be demonstrated and both [carbonyl-(11)C]WAY-100635 and [(11)C]-(+)-PHNO were prepared with high reliability and satisfying outcome.
RESUMEN
INTRODUCTION: The norepinephrine transporter (NET) is an important target for research in neurology and psychology and is involved in the pathophysiology of many neurodegenerative diseases such as Alzheimer's disease and attention deficient hyperactivity disorder. For visualization of NET abundance and deregulation, a novel PET tracer--[(11)C]Me@APPI--has been developed. METHODS: For precursor synthesis, a 4-step synthesis starting from N-phenyl-o-phenylenediamine was set up. Radiosynthesis was established and optimized using standard methods and subsequently automated in a GE TRACERlabFx C Pro synthesizer. Preclinical testing was performed comprising affinity and selectivity testing on human membranes as well as stability and blood-brain-barrier-penetration using in-vitro models. RESULTS: Precursor molecule (APPI:0) and reference compound (Me@APPI) were synthesized with 26.5% and 21.4% overall yield, respectively. So far, 1.25±0.72 GBq [(11)C]Me@APPI with 54.35±7.80 GBq/µmol specific activity were produced (n=11). Affinity of reference compounds was determined as 8.08±1.75 nM for Me@APPI and 19.31±2.91 nM for APPI:0, respectively (n≥9). IAM-chromatography experiments (n=3) revealed a P(m) value of 1.51±0.34 for Me@APPI. Stability testing using human liver microsomes revealed that 99.5% of the tracer was found to be still intact after 60 minutes (n=4). CONCLUSION: Present data indicate that [(11)C]Me@APPI has promising properties to become a clinically useful NET-PET-tracer. Further in-vitro and in-vivo evaluations are currently under way.
Asunto(s)
Bencimidazoles/química , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/metabolismo , Tomografía de Emisión de Positrones/métodos , Automatización , Bencimidazoles/metabolismo , Barrera Hematoencefálica/metabolismo , Radioisótopos de Carbono , Estabilidad de Medicamentos , Humanos , Marcaje Isotópico , Control de Calidad , RadioquímicaRESUMEN
INTRODUCTION: Image-derived input functions (IDIFs) represent a promising non-invasive alternative to arterial blood sampling for quantification in positron emission tomography (PET) studies. However, routine applications in patients and longitudinal designs are largely missing despite widespread attempts in healthy subjects. The aim of this study was to apply a previously validated approach to a clinical sample of patients with major depressive disorder (MDD) before and after electroconvulsive therapy (ECT). METHODS: Eleven scans from 5 patients with venous blood sampling were obtained with the radioligand [carbonyl-(11)C]WAY-100635 at baseline, before and after 11.0±1.2 ECT sessions. IDIFs were defined by two different image reconstruction algorithms 1) OSEM with subsequent partial volume correction (OSEM+PVC) and 2) reconstruction based modelling of the point spread function (TrueX). Serotonin-1A receptor (5-HT1A) binding potentials (BPP, BPND) were quantified with a two-tissue compartment (2TCM) and reference region model (MRTM2). RESULTS: Compared to MRTM2, good agreement in 5-HT1A BPND was found when using input functions from OSEM+PVC (R(2)=0.82) but not TrueX (R(2)=0.57, p<0.001), which is further reflected by lower IDIF peaks for TrueX (p<0.001). Following ECT, decreased 5-HT1A BPND and BPP were found with the 2TCM using OSEM+PVC (23%-35%), except for one patient showing only subtle changes. In contrast, MRTM2 and IDIFs from TrueX gave unstable results for this patient, most probably due to a 2.4-fold underestimation of non-specific binding. CONCLUSIONS: Using image-derived and venous input functions defined by OSEM with subsequent PVC we confirm previously reported decreases in 5-HT1A binding in MDD patients after ECT. In contrast to reference region modeling, quantification with image-derived input functions showed consistent results in a clinical setting due to accurate modeling of non-specific binding with OSEM+PVC.
Asunto(s)
Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/fisiopatología , Procesamiento de Imagen Asistido por Computador , Piperazinas , Tomografía de Emisión de Positrones , Piridinas , Venas/fisiopatología , Algoritmos , Radioisótopos de Carbono , Trastorno Depresivo Mayor/metabolismo , Trastorno Depresivo Mayor/terapia , Terapia Electroconvulsiva , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Receptor de Serotonina 5-HT1A/metabolismoRESUMEN
The intention for the present study was to implement a microfluidic set-up for N-(11)C-methylations in a flow-through microreactor device with [(11)C]DASB as model-compound and [(11)C]CH(3)I and [(11)C]CH(3)OTf, respectively, as (11)C-methylation agents. Due to an observed "aging" effect of the (11)C-methylation agents' solution, this goal was not achieved. Nevertheless, based on these observations, the time consumption for the vessel-based routine production of [(11)C]DASB was reduced (34±1 min) and RCY was increased to 45.1±4.6% (EOB; 5.2±0.95 GBq EOS).