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To describe the (18)F-fluorodihydro-xyphenylalanine ((18)F-DOPA), positron emission tomography (PET) and magnetic resonance imaging (MRI) appearance of pheochromocytomas, with a focus on the presence or absence of typical MRI features.Eleven patients with histologically-verified pheochromocytoma [sporadic (n=9), multiple endocrine neoplasia (MEN) 2A syndrome (n=2)] were enrolled retrospectively. All patients underwent an MRI examination of the upper abdomen. Nine out of 11 patients underwent (18)F-DOPA PET/CT, and the remaining two patients underwent independent PET and computed tomography (CT) examinations. (18)F-DOPA-PET/CT examinations were considered positive when an increased tracer accumulation in the adrenal region, as shown on CT images, was observed. When an adrenal mass was detected on MRI, the T1 and T2 signal intensity and contrast enhancement pattern were recorded. Based on MR characteristics, the lesions were divided into typical and atypical.Ten out of 11 patients had one lesion, while one patient had two lesions. All pheochromocytomas were detected by both PET/CT and MRI. On (18)F-DOPA scans, all lesions showed an increased tracer accumulation, with a mean maximum standardized uptake value (SUVmax) of 13.7±5.75. Eight out of 12 pheochromocytomas exhibited typical MRI features, with intermediate signal intensity on T1-weighted images in-phase, absence of signal drop on T1-weighted images out-of-phase, high signal intensity on T2-weighted images, and clear contrast enhancement in the arterial phase. The remaining four lesions exhibited atypical MRI features, namely absence of one of the listed criteria.In the assessment of pheochromocytoma, the combination of (18)F-DOPA PET with MRI is superior to MRI-alone. (18)F-DOPA PET/MRI may yield a higher diagnostic confidence for the detection of pheochromocytoma than (18)F-DOPA PET/CT.

Preclinical research points to a strong modulatory influence of gonadal hormones on the serotonin system. However, human data corroborating this association remains scarce. The aim of this study was to examine the effects of hormone replacement therapy on 5-HT₁A receptor binding in postmenopausal women using positron emission tomography (PET) and the radioligand [carbonyl-(11)C]WAY-100635. In this randomized, double-blind, longitudinal study, 30 postmenopausal women underwent treatment with either a combination of oral 17β-estradiol valerate and micronized progesterone (group 1, n=10), oral 17β-estradiol valerate (group 2, n=10), or placebo (group 3, n=10). Two PET measurements were performed, one the day before treatment start and the second after at least eight weeks of treatment. Plasma levels of estradiol (E₂), progesterone (P₄), sex hormone-binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEAS), follicle stimulating hormone (FSH) and luteinizing hormone (LH) were collected prior to PET measurements. As expected, hormone replacement therapy led to a significant increase in E₂ and P4 plasma levels in group 1 and to a significant increase in E₂ levels in group 2. The 5-HT₁A receptor binding did not change significantly after estrogen, combined estrogen/progesterone treatment or placebo in any of the investigated brain regions. There were no significant correlations between changes in E₂ or P4 values and changes in 5-HT₁A receptor binding. Although we were not able to confirm effects of gonadal hormone treatment on 5-HT₁A receptor binding, our data do not preclude associations between sex steroid levels and serotonin, the neurotransmitter implicated most strongly in the pathogenesis of affective and anxiety disorders. ClinicalTrials.gov Identifier: NCT00755963.

The synthesis of reference standards and expected in vivo metabolites of the first adenosine A3 PET radiotracer [18F]FE@SUPPY ([18F]fluoroethyl 4,6-diethyl-5-[(ethyl-sulfanyl)carbonyl]-2-phenylpyridine-3-carboxylate) was achieved by using a straightforward microwave assisted alkylation method, which allowed O/S-chemoselective alkylation of the starting material 1 to give each target compound 2–8 in a single step.

A sensitive and specific high-performance liquid chromatographic (HPLC) assay has been developed for the quantification of 2-methoxyphenylmetyrapone (2-MPMP) and its seven potential metabolites in rat urine and whole blood. 2-MPMP, 2-hydroxyphenylmetyrapone and their N-oxides, together with 2-methoxyphenylmetyrapol, 2-hydroxyphenylmetyrapol and their N-oxides were separated on an Isco Spherisorb ODS-2 reversed-phase column (250 x 4.6 mm, I.D., 5 microm), with an Isco Spherisorb ODS-2 guard cartridge (10 x 4.6 mm I.D.). A gradient elution was employed using solvent system A (acetonitrile-water-triethylamine-acetic acid, 27.3:69.1:0.9:2.7%, v/v) and solvent system B (methanol), the gradient program being as follows: initial 0-4 min A:B=74:26; 4-10 min linear change to A:B=50:50; 10-16 min maintain A:B=50:50; 16 min return to initial conditions (A:B=74:26). Flow-rate was maintained at 1.25 ml/min, and the eluent monitored using a diode array multiple wavelength UV detector set at 260 nm. Most of the analytes were baseline resolved, and analysis of samples recovered from blood or urine (pH 12, 3 x 5 ml of dichloromethane, recovery approximately 20-95%) revealed no interference from any co-extracted endogenous compounds in the biological matrices, except for 2-hydroxyphenylmetyrapol N-oxide (2-OHPMPOL-NO) at low concentrations. The calibrations (n=6) were linear (ror = 0.996) for all analytes (approximately 0.5-100 microg/ml), with acceptable inter- and intra-day variability. Subsequent validation of the assay revealed acceptable precision, as measured by coefficient of variation (C.V.) at the low (0.5 mg/ml), medium (50 microg/ml) and high (100 microg/ml) concentrations. The limits of detection for 2-MPMP and their available potential metabolites, except 2-OHPMPOL-NO, in rat urine and blood were both 0.5 microg/ml, respectively.

The adenosine triphosphate-binding cassette transporters P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) are 2 major gatekeepers at the blood-brain barrier (BBB) that restrict brain distribution of several clinically used drugs. In this study, we investigated the suitability of the radiolabeled Pgp/BCRP inhibitors (11)C-tariquidar and (11)C-elacridar to assess Pgp density in the human brain with PET.Healthy subjects underwent a first PET scan of 120-min duration with either (11)C-tariquidar (n = 6) or (11)C-elacridar (n = 5) followed by a second PET scan of 60-min duration with (R)-(11)C-verapamil. During scan 1 (at 60 min after radiotracer injection), unlabeled tariquidar (3 mg/kg) was intravenously administered. Data were analyzed using 1-tissue 2-rate-constant (1T2K) and 2-tissue 4-rate-constant (2T4K) compartment models and either metabolite-corrected or uncorrected arterial input functions.After injection of (11)C-tariquidar or (11)C-elacridar, the brain PET signal corrected for radioactivity in the vasculature was low (~0.1 standardized uptake value), with slow washout. In response to tariquidar injection, a moderate but statistically significant rise in brain PET signal was observed for (11)C-tariquidar (+27% ± 15%, P = 0.014, paired t test) and (11)C-elacridar (+21% ± 15%, P = 0.014) without changes in plasma activity concentrations. Low levels of radiolabeled metabolites (25%) were detected in plasma up to 60 min after injection of (11)C-tariquidar or (11)C-elacridar. The 2T4K model provided better data fits than the 1T2K model. Model outcome parameters were similar when metabolite-corrected or uncorrected input functions were used. There was no significant correlation between distribution volumes of (11)C-tariquidar or (11)C-elacridar and distribution volumes of (R)-(11)C-verapamil in different brain regions.The in vivo behavior of (11)C-tariquidar and (11)C-elacridar was consistent with that of dual Pgp/BCRP substrates. Both tracers were unable to visualize cerebral Pgp density, most likely because of insufficiently high binding affinities in relation to the low density of Pgp in human brain (∼1.3 nM). Despite their inability to visualize Pgp density, (11)C-tariquidar and (11)C-elacridar may find use as a new class of radiotracers to study the interplay of Pgp and BCRP at the human BBB in limiting brain uptake of dual substrates.

Purpose In neurodegenerative diseases and neuropsychiatric disorders dysregulation of the norepinephrine transporter (NET) has been reported. For visualization of NET availability and occupancy in the human brain PET imaging can be used. Therefore, selective NET-PET tracers with high affinity are required. Amongst these, [18F]FMeNER-D2 is showing the best results so far. Furthermore, a reliable fully automated radiosynthesis is a prerequisite for successful application of PET-tracers. The aim of this work was the automation of [18F]FMeNER-D2 radiolabelling for subsequent clinical use. The presented study comprises 25 automated large-scale syntheses, which were directly applied to healthy volunteers and adult patients suffering from attention deficit hyperactivity disorder (ADHD). Procedures: Synthesis of [18F]FMeNER-D2 was automated within a Nuclear Interface Module. Starting from 20–30 GBq [18F]fluoride, azeotropic drying, reaction with Br2CD2, distillation of 1-bromo-2-[18F]fluoromethane-D2 ([18F]BFM) and reaction of the pure [18F]BFM with unprotected precursor NER were optimized and completely automated. HPLC purification and SPE procedure were completed, formulation and sterile filtration were achieved on-line and full quality control was performed. Results Purified product was obtained in a fully automated synthesis in clinical scale allowing maximum radiation safety and routine production under GMP-like manner. So far, more than 25 fully automated syntheses were successfully performed, yielding 1.0–2.5 GBq of formulated [18F]FMeNER-D2 with specific activities between 430 and 1707 GBq/μmol within 95 min total preparation time. Conclusions A first fully automated [18F]FMeNER-D2 synthesis was established, allowing routine production of this NET-PET tracer under maximum radiation safety and standardization.

The melanin-concentrating hormone (MCH) system is a new target for the treatment of human disorders. Since the knowledge of the MCH system's involvement in a variety of pathologies (obesity, diabetes, and deregulation of metabolic feedback mechanism) is based on in vitro or preclinical studies, a suitable positron emission tomography (PET) tracer needs to be developed. We herein present the preparation and first preclinical evaluation of [(18)F]FE@SNAP - a new PET tracer for MCH receptor-1 (MCHR1). The synthesis was performed using a microfluidic device. Preclinical evaluation included binding affinity, plasma stability, plasma free fraction, stability against the cytochrome P-450 (CYP450) system using liver microsomes, stability against carboxyl-esterase, and methods to assess the penetration of the blood-brain barrier (BBB) such as logD analysis and immobilized artificial membrane (IAM) chromatography. Levels at 374 ± 202 MBq [(18)F]FE@SNAP were obtained after purification. The obtained K d value of [(18)F]FE@SNAP was 2.9 nM. [(18)F]FE@SNAP evinced high stability against carboxylesterase, CYP450 enzymes, and in human plasma. LogD (3.83) and IAM chromatography results (Pm=0.51) were in the same range as for known BBB-penetrating compounds. The synthesis of [(18)F]FE@SNAP was reliable and successful. Due to high binding affinity and stability, [(18)F]FE@SNAP is a promising tracer for MCHR1.

Introduction Due to its involvement in a variety of pathologies (obesity, diabetes, gut inflammation and depression), the melanin concentrating hormone receptor 1 (MCHR1) is a new target for the treatment of these lifestyle diseases. We previously presented the radiosynthesis of [ 11 C]SNAP-7941, the first potential PET tracer for the MCHR1. Methods We herein present its in vitro and in vivo evaluation, including binding affinity, plasma stability, stability against liver mircrosomes and carboxylesterase, lipohilicity, biodistribution, in vivo metabolism and small-animal PET. Results [ 11 C]SNAP-7941 evinced high stability against liver microsomes, carboxylesterase and in human plasma. The first small-animal PET experiments revealed a 5 fold increased brain uptake after Pgp/BCRP inhibition. Therefore, it can be assumed that [ 11 C]SNAP-7941 is a Pgp/BCRP substrate. No metabolites were found in brain. Conclusion On the basis of these experiments with healthy rats, the suitability of [ 11 C]SNAP-7941 for the visualisation of central and peripheral MCHR1 remains speculative.

1. The metabolism of 1-(2-methoxyphenyl)-2-methyl-2-(3-pyridyl)-1-propanone (2-MPMP) was studied in the male Sprague-Dawley rat after 50 mg/kg, i.v. dose. 2. Organic solvent extracts of urine samples were directly analysed by reversed-phase gradient hplc. The identified metabolites were also isolated by preparative tlc, and analyzed by direct probe mass spectrometry. In the case of conjugated metabolites, the urine samples were deconjugated by enzyme hydrolysis prior to extraction. The structures of metabolites were confirmed by comparison of their chromatographic behaviours, UV spectra, and mass spectra with those of authentic standards. 3. The metabolites identified in the 0-24-h urine samples were 2-hydroxyphenyl-metyrapone (2-OHPMP) and 2-hydroyphenylmetyrapone N-oxide (2-OHPMP-NO), which were present predominantly as their glucuronide and/or sulphate conjugates. 4. 2-MPMP and four of its metabolites present in the 0-24-h urine samples were quantified by a reversed-phase hplc method. The mean total urinary excretion was 75.4% of the administered dose. The major metabolites present in the urine were conjugates of 2-OHPMP-NO (54.4%) and of 2-OHPMP (18.6%). The excretion of the unchanged drug, unconjugated 2-OHPMP and 2-OHPMP-NO accounted for 1.1, 1.1 and 0.2% of the dose respectively.

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.

Alterations of the inhibitory serotonin-1A receptor (5-HT1A) constitute a solid finding in neuropsychiatric research, particularly in the field of mood and anxiety disorders. Manifold factors influencing the density of this receptor have been identified, e.g., steroid hormones, sunlight exposure and genetic variants of serotonin-related genes. Given the close interactions between serotonergic and dopaminergic neurotransmission, we investigated whether a common single-nucleotide-polymorphism of the catechol-O-methyltransferase (COMT) gene (VAL158MET or rs4680) coding for a key enzyme of the dopamine network that is associated with the pathogenesis of mood disorders and antidepressant treatment response, directly affects 5-HT1A receptor binding potential. Fifty-two healthy individuals (38 female, mean age ± standard deviation = 40.48 ± 14.87) were measured via positron emission tomography using the radioligand [carbonyl-(11)C]WAY-100635. Genotyping for rs4680 was performed using DNA isolated from whole blood with the MassARRAY platform of the software SEQUENOM(®). Whole brain voxel-wise ANOVA resulted in a main effect of genotype on 5-HT1A binding. Compared to A carriers (AA + AG) of rs4680, homozygote G subjects showed higher 5-HT1A binding potential in the posterior cingulate cortex (F (2,49) = 17.7, p = 0.05, FWE corrected), the orbitofrontal cortex, the anterior cingulate cortex, the insula, the amygdala and the hippocampus (voxel-level: p 0.01 uncorrected, t 2.4; cluster-level: p 0.05 FWE corrected). In light of the frequently reported alterations of 5-HT1A binding in anxiety and mood disorders, this study proposes a potential implication of the COMT genotype, more specifically the VAL158MET polymorphism, via modulation of the serotonergic neurotransmission.

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).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).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, p0.001), which is further reflected by lower IDIF peaks for TrueX (p0.001). 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.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.

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±0.72GBq [ 11 C]Me@APPI with 54.35±7.80GBq/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 60minutes (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.

To compare fused gadoxetate-enhanced Ga-68-DOTANOC PET/MRI and Ga-68-DOTANOC PET/DWI (diffusion-weighted imaging) for the assessment of abdominal neuroendocrine tumours (NETs).Eighteen patients with suspected or histologically proven NETs of the abdomen were enrolled in this retrospective study. All patients underwent Ga-68-DOTANOC PET/CT for a primary search, staging, or restaging, and received an additional MRI, including dynamic gadoxetate-enhanced T1-weighted sequences and DWI (b-values 50, 300 and 600). Co-registered gadoxetate-enhanced PET/MRI and PET/DWI were separately analysed for NET lesions by a nuclear medicine physician and a radiologist in consensus. Sensitivity and specificity were calculated on a per-region, per-organ and per-patient basis.Eighty-seven out of 684 anatomical regions, and 23 out of 270 organs, were NET-positive in 14 out of 18 patients. Region-based sensitivities and specificities were 97.7 % and 99.7 % for gadoxetate-enhanced PET/MRI and 98.9 % and 99.7 % for PET/DWI. Organ-based sensitivities and specificities were 91.3 % and 99.6 % for gadoxetate-enhanced PET/MRI and 95.7 % and 99.6 % for PET/DWI. Finally, patient-based sensitivities and specificities were 100 % and 100 % for gadoxetate-enhanced PET/MRI and 100 % and 75 % for PET/DWI. Sensitivities and specificities of the two methods did not differ significantly.Gadoxetate-enhanced Ga-68-DOTANOC PET/MRI and Ga-68-DOTANOC PET/DWI are equally useful for the assessment of abdominal NETs.• Positron emission tomography and magnetic resonance imaging can both assess neuroendocrine tumours. • Fusion of PET/MR imaging provides helpful information. • Gadoxetate-enhanced Ga-68-DOTANOC PET/MRI and Ga-68-DOTANOC PET/DWI assess neuroendocrine tumours equally well. • PET/DWI is inherently simpler than gadoxetate-enhanced PET/MRI. • Only benign hepatic lesions pose a potential diagnostic dilemma for PET/DWI.

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.

Background We evaluated the effects of nebivolol, a third generation beta-blocker capable of increasing NO-bioavailability on portal pressure, and on splachnic and systemic haemodynamics in a cirrhotic portal hypertensive rat model. Methods Male Sprague–Dawley rats underwent sham operation (SO) or bile duct ligation (BDL). When cirrhosis was fully developed, the animals were orally treated with low-dose (5 mg/kg) or high-dose (10 mg/kg) nebivolol (NEBI) or vehicle (VEH) for 7 days. Heart rate (HR), mean arterial pressure (MAP), portal pressure (PP) and superior mesenteric artery blood flow (SMABF) were measured. Portosystemic collateral blood flow (PSCBF) was quantified using radioactive microspheres. Hepatic and splanchnic NOx levels and GSH/GSSG ratios (RedOx state) were determined using commercially available kits. Results BDL-VEH rats showed increased HR, PP and PSCBF, whereas MAP was decreased compared to SO-VEH rats. Nebivolol significantly reduced HR both in SO (P

[ Carbonyl - 11 C]WAY-100635 is a potent and effective antagonist for the 5-HT 1A receptor subtype. We aimed to assess the status of [ carbonyl - 11 C]WAY-100635 and its main radio-metabolites, [ carbonyl - 11 C]desmethyl-WAY-100635 and [ carbonyl- 11 C]cyclohexanecarboxylic acid, on the basis of an improved radio-HPLC method. Common methods were characterized by preparative HPLC columns with long runtimes and/or high flow rates. Considering the short half-life of C-11, we developed a more rapid and solvent saving HPLC assay, allowing a fast, efficient and reliable quantification of these major metabolites.

Graphical abstract SNAP-7941 derivatives 1–4 (1: SNAP-7941; 2: [18F]FE@SNAP; 3: SNAP-acid; 4: Tos@SNAP)., Changes in the expression of the melanin concentrating hormone receptor 1 (MCHR1) are involved in a variety of pathologies, especially obesity and anxiety disorders. To monitor these pathologies in-vivo positron emission tomography (PET) is a suitable method. After the successful radiosynthesis of [11C]SNAP-7941—the first PET-Tracer for the MCHR1, we aimed to synthesize its [18F]fluoroethylated analogue: [18F]FE@SNAP. Therefore, microfluidic and vessel-based approaches were tested. [18F]fluoroethylation was conducted via various [18F]fluoroalkylated synthons and direct [18F]fluorination. Only the direct [18F]fluorination of a tosylated precursor using a flow-through microreactor was successful, affording [18F]FE@SNAP in 44.3 ± 2.6%.

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

Reflecting one's mental self is a fundamental process for evaluating the personal relevance of life events and for moral decision making and future envisioning. Although the corresponding network has been receiving growing attention, the driving neurochemical mechanisms of the default mode network (DMN) remain unknown. Here we combined positron emission tomography and functional magnetic resonance imaging to investigate modulations of the DMN via serotonin-1A receptors (5-HT 1A ), separated for 5-HT autoinhibition (dorsal raphe nucleus) and local inhibition (heteroreceptors in projection areas). Using two independent approaches, regional 5-HT 1A binding consistently predicted DMN activity in the retrosplenial cortex for resting-state functional magnetic resonance imaging and the Tower of London task. On the other hand, both local and autoinhibitory 5-HT 1A binding inversely modulated the posterior cingulate cortex, the strongest hub in the resting human brain. In the frontal part of the DMN, a negative association was found between the dorsal medial prefrontal cortex and local 5-HT 1A inhibition. Our results indicate a modulation of key areas involved in self-referential processing by serotonergic neurotransmission, whereas variations in 5-HT 1A binding explained a considerable amount of the individual variability in the DMN. Moreover, the brain regions associated with distinct introspective functions seem to be specifically regulated by the different 5-HT 1A binding sites. Together with previously reported modulations of dopamine and GABA, this regional specialization suggests complex interactions of several neurotransmitters driving the default mode network.

Introduction Our aim was the optimization of radiochemical parameters for the microfluidic preparation of [18F]altanserin. The four main parameters evaluated were (1) precursor concentration, (2) reaction temperature, (3) bolus flow rate through the microreactor and (4) bolus volume. Methods For the determination of optimal reaction conditions within a flow-through microreactor synthesizer, 5–400 μL of precursor and dried [18F]fluoride solution were simultaneously pushed through the temperature-controlled reactor (180–220 °C) with defined bolus flow rates of 10–60 μL/min. Radiochemical incorporation yields (RCIYs) were examined using a thin layer chromatography (TLC) set-up and radio- high-performance liquid chromatography (HPLC). Results Optimum reaction parameters for the microfluidic set-up were determined as following: 220 °C, 5–10 μL/min pump rate per reactant (10–20 μL/min reaction overall flow rate) and 2 mg/mL precursor concentration in the reaction mixture. Applying these optimized conditions, RCIYs of 53.7 ± 7.9 were observed for scaled-up preparations. A positive “bolus effect” was observed: applying higher reaction volume resulted in increased RCIYs. Conclusion This study proved that the reaction bolus volume is an essential parameter influencing the RCIY of [18F]altanserin. A possible explanation is the inhomogeneous distribution within the reaction volume probably caused by diffusion at the bolus interface. This important finding should be considered an important variable for the evaluation of all novel radiotracers labeled using a flow-through reactor device.

Climate, in particular sunshine, influences mood and energy levels, creating a positive upswing of mood on bright, sunny days and negative downswing in cold, dark winter seasons. Higher serotonin transporter availability in healthy human subjects in times of lesser light exposure and lower serotonin levels have been shown in winter.We examined the light-dependent variations in serotonin-1A receptor binding in limbic regions in 36 drug-naive healthy human subjects. Receptor binding was quantified using positron emission tomography and the radioligand [carbonyl-¹¹C]WAY-100635. Binding potential values were related to the amount of individual exposure to sunlight (daily duration of sunshine) and global radiation (total light intensity).We found a 20-30% lower serotonin-1A receptor binding in the group exposed to a lower amount of global light radiation. Partial correlation analysis revealed significant positive correlations between the regional postsynaptic serotonin-1A receptor binding and global radiation accumulated over a period of 5 days.Seasonal factors, such as daily amount of sunshine and global radiation, influence serotonin-1A receptor binding in limbic brain regions of healthy human subjects. Combined with recently demonstrated seasonal fluctuations in the serotonin transporter availability, our results underline the importance of seasonal factors in the regulation of the serotonergic transmission.

[(11)C]PIB is still the standard PET compound for Alzheimer imaging targeting beta-amyloid plaques. We aimed to establish a fully-automated procedure for the synthesis and purification of [(11)C]PIB with a high degree of reliability and improved specific activity as well as a suitable and fast quality control assay. The optimum reaction conditions were 75°C, 4 mg/mL precursor yielding at 48.0±2.7% (EOS, based on [(11)C]CH(3)OTf, corrected for decay), 183±14 GBq/μmol specific activity and >99% radiochemical purity. Time consumption was kept to a minimum (40 min from EOB) and overall yields were enough to serve 2 consecutive patients with a single preparation.

Background: Progesterone (P) is thought to influence mood and affective states. Alterations of the inhibitory serotonin-1A (5-HT1A) receptor distribution are associated with depression and anxiety. This study evaluates the influence of plasma P levels on the 5-HT1A receptor binding in healthy male subjects. Methods: Molecular neuroimaging of the 5-HT1A receptor distribution using positron emission tomography and hormone assays for total plasma P and cortisol were done in a sample of 18 healthy men. Results: Plasma P levels explained up to 65% of the variability in 5-HT1A receptor binding in limbic regions including the amygdala, orbitofrontal cortex and retrosplenial cortex. When controlling for cortisol in the model, there was an expected decline in explained variances of 5-HT1A binding attributed to P. Conclusions: The results of this study provide further support for the effect of P on 5-HT1A receptor expression and raise the possibility that P mediates the vulnerability to mood disorders by affecting the serotonergic system.

We performed positron emission tomography using [carbonyl-(11)C]WAY-100635, a serotonin 1A (5-HT(1A)) receptor antagonist, in 13 patients with temporal lobe epilepsy (TLE) and in 13 controls. 5-HT(1A) receptor distribution mapping allowed correct lateralization of the epileptogenic temporal lobe in all patients. 5-HT(1A) receptor binding potential (BP(ND)) was significantly reduced in almost all temporal regions of the epileptogenic lobe. Compared with controls, the patients had significantly decreased BP(ND) values in the hippocampus, parahippocampal gyrus, and amygdala. The asymmetry index (AI), which characterizes the interhemispheric asymmetry in BP(ND), was significantly higher in patients than in controls in most regions. Depression scores were not significantly correlated with BP(ND) or AI values. Our data provide further evidence of functional changes in the serotonergic system in TLE. Molecular imaging of the 5-HT(1A) receptor may help to define the in vivo neurochemistry of TLE, and may provide a valuable tool in the noninvasive presurgical assessment of patients with medically refractory TLE.

The presented review provides general background on PET radiopharmaceuticals for oncological applications. Special emphasis is put on radiopharmacological, radiochemical and regulatory aspects. This review is not meant to give details on all different PET tracers in depth but to provide insights into the general principles coming along with their preparation and use. The PET tracer plays a pivotal role because it provides the basis both for image quality and clinical interpretation. It is composed of the radionuclide (signaller) and the molecular vehicle which determines the (bio-)chemical properties (e.g. binding characteristics, metabolism, elimination rate).

Introduction Recently, [ 18 F]FE@SUPPY and [ 18 F]FE@SUPPY:2 were introduced as the first positron emission tomography (PET) tracers for the adenosine A 3 receptor. Thus, aim of the present study was the metabolic characterization of the two adenosine A 3 receptor PET tracers. Methods In vitro carboxylesterase (CES) experiments were conducted using incubation mixtures containing different concentrations of the two substrates, porcine CES and phosphate-buffered saline. Enzymatic reactions were stopped by adding acetonitrile/methanol (10:1) after various time points and analyzed by a high-performance liquid chromatography (HPLC) standard protocol. In vivo experiments were conducted in male wild-type rats; tracers were injected through a tail vein. Rats were sacrificed after various time points ( n =3), and blood and brain samples were collected. Sample cleanup was performed by an HPLC standard protocol. Results The rate of enzymatic hydrolysis by CES demonstrated Michaelis–Menten constants in a micromolar range (FE@SUPPY, 20.15 μM, and FE@SUPPY:2, 13.11 μM) and limiting velocities of 0.035 and 0.015 μM/min for FE@SUPPY and FE@SUPPY:2, respectively. Degree of metabolism in blood showed the following: 15 min pi 47.7% of [ 18 F]FE@SUPPY was intact compared to 33.1% of [ 18 F]FE@SUPPY:2; 30 min pi 30.3% intact [ 18 F]FE@SUPPY was found compared to 15.6% [ 18 F]FE@SUPPY:2. In brain, [ 18 F]FE@SUPPY:2 formed an early hydrophilic metabolite, whereas metabolism of [ 18 F]FE@SUPPY was not observed before 30 min pi Conclusion Knowing that metabolism in rats is several times faster than in human, we conclude that [ 18 F]FE@SUPPY should be stable for the typical time span of a clinical investigation. As a consequence, from a metabolic point of view, one would tend to decide in favor of [ 18 F]FE@SUPPY.

Introduction: Since the Adenosine-A3-receptor was identified in the late 1990´s, there is little data available de- scribing its distribution in vivo. Recently, we introduced ( 18 F)FE@SUPPY as the first PET-tracer for this receptor. In the present investigation we translated this fluoroethyl-ester into the fluoroethyl-thioester ( 18 F)FE@SUPPY:2 (5-ethyl 2,4- diethyl-3-((2-( 18 F)fluoroethyl) sulfanylcarbonyl)-6-phenylpyridine-5-carboxylate). Aims of the present study were the evaluation of (1) the automatized preparation of both ( 18 F)FE@SUPPY-derivatives, (2) the biodistribution of ( 18 F)FE@SUPPY:2, (3) the lipophilicity and (4) the comparison of the findings of ( 18 F)FE@SUPPY and ( 18 F)FE@SUPPY:2. Methods: The automated preparations of both ( 18 F)FE@SUPPY-analogs were performed on a GE TRACERlab FxFN syn- thesizer using suitable precursors. Biodistribution experiments were performed using Sprague-Dawley rats/Him:OFA. Lipophilicity of the compounds was determined using an HPLC assay. Results: 22 automated radiosyntheses were performed for both radiotracers. Specific radioactivity was 70 ± 26GBq/� mol for ( 18 F)FE@SUPPY and 340 ± 140GBq/� mol for ( 18 F)FE@SUPPY:2. Biodistribution experiments evinced bowels and liver as organs with highest uptake and intermediate uptake in kidney, lung and heart. LogP values of both molecules ranged from 3.99 to 4.12 at different pH. Conclusion: From a radiopharmaceutical perspective, drastically better specific radioactivities would militate in favour of ( 18 F)FE@SUPPY:2; preclinical evaluations, so far, do not permit the decision upon the selection of the optimum ( 18 F)FE@SUPPY-derivative. With ( 18 F)FE@SUPPY:2, we are able to provide a second potential tracer that could help to further characterize the still quite unexplored Adenosine-A3-receptor.

Lateralization is a well described aspect of the human brain. A plethora of morphological, cytological and functional studies describes hemispheric asymmetry in auditory and language areas. However, no study has reported cortical lateralization in the healthy human brain in vivo on the level of neurotransmitter receptors and in relation to functional organization so far. In this study, we assessed the distribution of the main inhibitory serotonergic receptor (the 5-HT1A receptor) and analyzed its regional binding with regard to hemisphere, sex and plasma levels of sex steroid hormones (testosterone, estradiol, progesterone). We quantified the 5-HT1A receptor binding potential by positron emission tomography (PET) using the highly selective and specific radioligand [carbonyl-11C]WAY-100635 and measured hormone levels in thirty-four (16 females, 18 males) healthy right-handed subjects. The obtained data were analyzed in an automated region of interest (ROI) based approach investigating 14 auditory, language and limbic areas. We found significantly higher 5-HT1A receptor binding in the superior and middle frontal gyri of the right hemisphere, the triangular and orbital parts of the inferior frontal gyrus, the supramarginal gyrus, the superior gyrus of the temporal pole and the middle temporal gyrus. Regions of the primary and secondary auditory cortex (Heschl's gyrus and superior temporal gyrus) and the Rolandic operculum displayed significantly higher receptor binding in the left hemisphere. 5-HT1A receptor binding was 1.8-2.9% higher in right frontal ROIs and 2-3.6% higher in left primary and secondary auditory regions. There was no hemispheric difference in 5-HT(1A) receptor binding in the hippocampus, amygdala, and insula. Post-hoc testing suggested that lateralization of 5-HT1A receptor binding differed between the sexes in the triangular part of the inferior frontal gyrus. For the first time, this PET study shows lateralization of the main inhibitory receptor of the serotonergic system in functionally asymmetric organized regions of the healthy human brain in vivo.