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Objective. 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. Methods. 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). Results. 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. Conclusions. 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. [ABSTRACT FROM AUTHOR]

Dysregulation of the hypothalamic-pituitary-adrenocortical axis with deficient glucocorticoid feedback and alterations in the serotonergic system have been identified as biological correlates of mood disorders. Close examination of the interaction between these systems may offer insights into the pathophysiology of anxiety disorders and depression to understand how stress and these disorders are related. In this study, we investigated the relationship between plasma levels of cortisol and the dominant inhibitory serotonergic receptor, serotonin-1A (5-HT1A). Using positron emission tomography (PET) and the radioligand [carbonyl-11C]WAY-100635, we quantified the 5-HT1A receptor binding. Data from 12 male patients with social phobia and 18 matched control subjects were analysed. Seven brain regions were investigated: the anterior and posterior cingulate cortices, hippocampus, amygdala, medial orbitofrontal and retrosplenial cortices, and dorsal raphe nucleus. Partial correlation analysis, controlled for age and radiochemical variables, was performed to demonstrate the association between cortisol plasma levels and 5-HT1A receptor binding. Cortisol plasma levels were significantly lower in patients with social phobia compared to healthy controls. Moreover, we found strong negative correlations between cortisol plasma levels and 5-HT1A binding in the amygdala (r=x0.93, p=0.0004), hippocampus (r=x0.80, p=0.009), and retrosplenial cortex (r=x0.48, p=0.04) in patients with social phobia. Within the former two regions, these associations were significantly higher in patients than in healthy controls. This PET study confirms a negative association between plasma cortisol levels and the 5-HT1A receptor distribution consistent with studies in rodents and non-human primates. Dysregulation of the cortisol level might increase the vulnerability for mood disorders by altering limbic 5-HT1A receptors. [ABSTRACT FROM AUTHOR]

( R)-[11C]verapamil is a new PET tracer for P-glycoprotein-mediated transport at the blood-brain barrier. For kinetic analysis of ( R)-[11C]verapamil PET data the measurement of a metabolite-corrected arterial input function is required. The aim of this study was to assess peripheral ( R)-[11C]verapamil metabolism in patients with temporal lobe epilepsy and compare these data with previously reported data from healthy volunteers. Arterial blood samples were collected from eight patients undergoing ( R)-[11C]verapamil PET and selected samples were analysed for radiolabelled metabolites of ( R)-[11C]verapamil by using an assay that measures polar N-demethylation metabolites by solid-phase extraction and lipophilic N-dealkylation metabolites by HPLC. Peripheral metabolism of ( R)-[11C]verapamil was significantly faster in patients compared to healthy volunteers ( AUC of ( R)-[11C]verapamil fraction in plasma: 29.4 ± 3.9 min for patients versus 40.8 ± 5.0 min for healthy volunteers; p < 0.0005, Student’s t-test), which resulted in lower ( R)-[11C]verapamil plasma concentrations ( AUC of ( R)-[11C]verapamil concentration, normalised to injected dose per body weight: 25.5 ± 2.1 min for patients and 30.5 ± 5.9 min for healthy volunteers; p = 0.038). Faster metabolism appeared to be mainly due to increased N-demethylation as the polar [11C]metabolite fraction was up to two-fold greater in patients. Faster metabolism of ( R)-[11C]verapamil in epilepsy patients may be caused by hepatic cytochrome P450 enzyme induction by antiepileptic drugs. Based on these data caution is warranted when using an averaged arterial input function derived from healthy volunteers for the analysis of patient data. Moreover, our data illustrate how antiepileptic drugs may decrease serum levels of concomitant medication, which may eventually lead to a loss of therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Nuclear imaging may have an increasing role in the diagnosis of hepatocellular carcinoma (HCC). The aim of this study was to compare prospectively the Gallium-67 citrate (67Ga) scintigraphy results with those obtained by positron emission tomography (PET) using 11C-acetate in patients with HCC. Methods: We prospectively analysed 21 patients (mean age, 64±11 years) with histopathologically verified HCC undergoing 11C-acetate PET and 67Ga scintigraphy. 67Ga scans were not performed in three of these 21 patients due to the exacerbation of the disease. Whole-body 11C-acetate PET were performed following intravenous injection of 850 MBq of 11C-acetate. For 67Ga scintigraphy, whole-body, planar and single photon emission computed tomography imaging acquisitions were performed after intravenous application of a mean dose of 189 MBq 67Ga. Results: 67Ga scintigraphy found abnormalities only in 10 of 18 patients (56%) and detected 22 of 46 clinically involved sites (48%); it was false-positive in two patients. 11C-acetate PET found abnormalities in 14 of 18 patients (78%) and detected 36 of 46 clinical lesions (78%); it was false-positive in one patients. In one patient with left supraclavicular lymph node metastases, neither the 67Ga scintigraphy nor the conventional computed tomography have shown the lesions, which were clearly demonstrated by the 11C-acetate PET. Conclusion: Our results indicate significantly higher sensitivity and specificity of 11C-acetate PET than 67Ga scan in detection of HCC lesions. This study suggests that imaging with 11C-acetate PET might play a potential role in the diagnostic workup of patients with HCC. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Recently, first applications of microfluidic principles for radiosyntheses of positron emission tomography compounds were presented, but direct comparisons with conventional methods were still missing. Therefore, our aims were (1) the set-up of a microfluidic procedure for the preparation of the recently developed adenosine A3-receptor tracers [18F]FE@SUPPY [5-(2-[18F]fluoroethyl)2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate] and [18F]FE@SUPPY:2 [5-ethyl-2,4-diethyl-3-((2-[18F]fluoroethyl)sulfanylcarbonyl)-6-phenylpyridine-5-carboxylate] and (2) the direct comparison of reaction conditions and radiochemical yields of the no-carrier-added nucleophilic substitution with [18F]fluoride between microfluidic and conventional methods. Methods: For the determination of optimal reaction conditions within an Advion NanoTek synthesizer, 5–50 μl of precursor and dried [18F]fluoride solution were simultaneously pushed through the temperature-controlled reactor (26°C–180°C) with defined reactant bolus flow rates (10–50 μl/min). Radiochemical incorporation yields (RCIYs) and overall radiochemical yields for large-scale preparations were compared with data from conventional batch-mode syntheses. Results: Optimal reaction parameters for the microfluidic set-up were determined as follows: 170°C, 30-μl/min pump rate per reactant (reaction overall flow rate of 60 μl/min) and 5-mg/ml precursor concentration in the reaction mixture. Applying these optimized conditions, we observed a significant increase in RCIY from 88.2% to 94.1% (P<.0001, n≥11) for [18F]FE@SUPPY and that from 42.5% to 95.5% (P<.0001, n≥5) for [18F]FE@SUPPY:2 using microfluidic instead of conventional heating. Precursor consumption was decreased from 7.5 and 10 mg to 1 mg per large-scale synthesis for both title compounds, respectively. Conclusion: The direct comparison of radiosyntheses data applying a conventional method and a microfluidic approach revealed a significant increase of RCIY using the microfluidic approach. [Copyright &y& Elsevier]

Abstract: Serotonin modulates the activity of the hypothalamic–pituitary–adrenal (HPA) axis particularly via the serotonin-1A receptor (5-HT1A). Therefore, the rationale of this positron emission tomography (PET) study was to investigate the influence of the 5-HT1A receptor distribution in the human brain on plasma levels of dehydroepiandrosterone sulfate (DHEAS) and cortisol in vivo. Eighteen healthy female were measured with PET and the selective 5-HT1A receptor radioligand [carbonyl-11C]WAY-100635. Nine a priori defined brain regions (hypothalamus, orbitofrontal cortex, amygdala, hippocampus, anterior and posterior cingulate cortices, dorsal raphe nucleus, retrosplenial cortex, and insula) and the cerebellum (reference region) were delineated on coregistered MR images. DHEAS and cortisol plasma levels were collected by blood sampling in the morning of the PET day. Linear regression analysis of DHEAS plasma level as dependent variable and hypothalamic 5-HT1A receptor binding potential (BP) as independent variable showed a highly significant association (r =.691, p =.002). The hypothalamic 5-HT1A BP predicted 47.7% of the variability in DHEAS plasma levels. Regressions were borderline significant (p <.01, Bonferroni corrected threshold <.0056) between 5-HT1A BP in the anterior cingulate and orbitofrontal cortices and free cortisol levels. No significant associations between DHEAS or cortisol and the 5-HT1A receptor BP in other investigated brain regions were found. In conclusion, the serotonergic system may influence the DHEAS plasma level by modulating CRH and ACTH release via hypothalamic 5-HT1A receptors as reported for cortisol before. As disturbances of the HPA axis as well as changes of the 5-HT1A receptor distribution have been reported in affective disorders, future studies should focus on these interactions. [Copyright &y& Elsevier]

Abstract: Introduction: Recently, [18F]FE@SUPPY and [18F]FE@SUPPY:2 were introduced as the first positron emission tomography (PET) tracers for the adenosine A3 receptor. Thus, aim of the present study was the metabolic characterization of the two adenosine A3 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 [18F]FE@SUPPY was intact compared to 33.1% of [18F]FE@SUPPY:2; 30 min pi 30.3% intact [18F]FE@SUPPY was found compared to 15.6% [18F]FE@SUPPY:2. In brain, [18F]FE@SUPPY:2 formed an early hydrophilic metabolite, whereas metabolism of [18F]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 [18F]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 [18F]FE@SUPPY. [Copyright &y& Elsevier]

Abstract: Receptor distribution patterns of neurotransmitters and distinct functional fields of the human brain appear to be tightly connected with respect to their topological allocation along the cerebral cortex. There is, however, considerable lack of human data directly demonstrating this association in vivo. Here, we assessed the relationship between the distribution of the major inhibitory serotonergic neurotransmitter receptor, the 5-HT1A subtype, and the functional organization within early visual cortex defined by retinotopic mapping. The 5-HT1A receptor-binding potential was quantified by positron emission tomography (PET) using the highly selective and specific radioligand [carbonyl-11C]WAY-100635 in seven healthy subjects. The retinotopic maps and borders determined by functional magnetic resonance imaging (fMRI) were compared to the receptor distribution employing surface-based region of interest analysis in each of these subjects. We found a significant difference in receptor-binding potential in the functionally defined primary (V1) compared to secondary (V2) visual area, as V1 exhibits only 68% of receptor binding found in V2 in both hemispheres, which is consistent with postmortem data. Our in vivo findings clearly support prior assumptions of a link between receptor distribution and functional fields of the human cortex. [Copyright &y& Elsevier]

Abstract: Purpose: The present study aimed to develop convenient preparation and quality control protocols for [68Ga]-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 [68Ga]-EDTMP formulations were prepared using [68Ga]-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 [68Ga]-EDTMP yielded irreversible binding on the mineral bone phase characterised by fast binding kinetics. Generally, nca [68Ga]-EDTMP showed low uptake values comparable to nca [99mTc]-EDTMP. Interestingly, the bone binding affinity of [68Ga]-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 [68Ga]-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 [68Ga]-EDTMP – particularly with respect to lesion specificity and sensitivity – should be clarified in forthcoming in-vivo studies. [Copyright &y& Elsevier]

Abstract: Introduction: Changes of the adenosine A3 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 [18F]FE@SUPPY and a first evaluation of [18F]FE@SUPPY in rats. Methods: [18F]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 [18F]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 [18F]FE@SUPPY has the potential to serve as the first positron emission tomography tracer for the A3AR. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: Introduction: The objectives of this study were to develop a simple preparation method for [68Ga]-EDTMP and to evaluate the applicability of [68Ga]-EDTMP as a potential positron emission tomography (PET) bone imaging agent using pre vivo, ex vivo and in vivo models. Methods: [68Ga]-EDTMP was prepared using [68Ga]-gallium chloride eluted from the 68Ge/68Ga generator and commercially available Multibone kits. Binding affinity to bone compartments was evaluated using a recently established pre vivo model. In vivo (microPET) and ex vivo experiments were performed in mice, and the results of which were compared with those obtained with [18F]-fluoride. Results: [68Ga]-EDTMP was accessible via simple kit preparation and predominantly accumulated in bone tissue in vivo, ex vivo and pre vivo. Binding to mineral bone was irreversible, and low binding was observed in organic bone. In vivo microPET evaluation revealed predominant uptake in bone with renal excretion. Compared with [18F]-fluoride, the uptake was lower and the PET image quality was reduced. Conclusions: From the present evaluation, apart from the autonomy for PET centers without an onsite cyclotron, the advantage of [68Ga]-EDTMP over [18F]-fluoride is not apparent and the future clinical prospect of [68Ga]-EDTMP remains speculative. [Copyright &y& Elsevier]

Background: Results from studies in serotonin-1A (5-HT1A) knockout mice and previous positron emission tomography (PET) studies in humans imply a role for 5-HT1A receptors in normal state anxiety as well as in certain anxiety disorders. The objective of this study was to investigate 5-HT1A receptor binding potential (BP) in social anxiety disorder (SAD). Methods: Using PET and [carbonyl-11C]WAY-100635, we compared a homogeneous group of 12 unmedicated, male SAD patients with 18 healthy control subjects (HC). A multivariate ANOVA with all regional BP values as dependent variables, age and four radiochemical variables as covariates was performed. Results: We found a significantly lower 5-HT1A BP in several limbic and paralimbic areas but not in the hippocampus (p = .234) of SAD patients. The difference in 5-HT1A binding was most significant in the amygdala (−21.4%; p = .003). There was also a more than 20% lower 5-HT1A BP of SAD patients in the anterior cingulate cortex (p = .004), insula (p = .003), and dorsal raphe nuclei (p = .030). Conclusions: The lower 5-HT1A binding in the amygdala and mesiofrontal areas of SAD patients is consistent with 1) preclinical findings of elevated anxiety in 5-HT1A knockout mice, 2) a previous PET study in healthy volunteers showing an inverse correlation between 5-HT1A BP and state anxiety, and 3) another human PET study in patients with panic disorder showing reduced 5-HT1A binding, thus corroborating the potential validity of 5-HT1A receptors as targets in the treatment of human anxiety disorders. [Copyright &y& Elsevier]

Abstract: Nucleophilic aromatic substitution is a challenging task in radiochemistry. Therefore, a thorough evaluation and optimisation of this step is needed to provide a satisfactory tool for the routine preparation of [18F]fluorinated aromatic amino acids. Two methods, already proposed elsewhere, were evaluated and improved. The yields for the radiofluorination were increased whereas activity loss during solid phase extraction was observed. Radiochemical yields for the two methods were 92.7±5.5% (method 1) and 92.1±12.3% (method 2) for conversion and 11.1±2.8% (method 1) and 34.8±0.6% (method 2) for purification, respectively. In total, we demonstrate an optimised method for the preparation of this important class of [18F]fluorinated synthons for PET. [Copyright &y& Elsevier]

Abstract: At present, most data available on PET imaging of brain tumors using amino acids are based on l-[S-methyl-11C]methionine (MET). This radiopharmaceutical accurately delineates tumor extent, sometimes even better than CT. Since MET is playing such an important role for PET, a potent preparation method for this radiotracer allowing frequent syntheses for PET routine is desirable. Therefore, a simple disposable synthesis module was conceived without HPLC purification. Using a solid supported [11C]methylation on Al2O3 leads to the simplification of the preparation requiring only filtration for separation of precursor and MET. The presented method is able to produce high purity MET in excellent yields enough to serve several consecutive patients. [Copyright &y& Elsevier]

[11C]Acetate, initially developed for nuclear cardiology has gained increased interest also for oncological problems. A conjoint problem of all preparation methods is the high sensitivity of the Grignard-precursor to moisture, demanding long cleaning and drying procedures of apparatus and reaction vials. Our rationale was to simplify and accelerate the preparation of [11C]acetate by the development of an inert, sterile and disposable system. The present publication deals with the remote-controlled preparation of [11C]acetate via distillation into a buffer ready to use. [Copyright &y& Elsevier]

[11C]Flumazenil, a highly selective benzodiazepine antagonist is the most extensively used GABAA ligand for PET so far. To overcome half life disadvantages of 11C a [18F]-labeled flumazenil derivative, 2′-[18F]fluoroflumazenil (FFMZ) was developed and biologically evaluated with respect to the GABAA receptor. Organ with the highest uptake was the pituitary gland. Brain uptake was high and followed the order cortex>thalamus>cerebellum>rest brain. Fluoroflumazenil displaced [3H]flumazenil binding from membrane GABAA receptors with an IC50value (3.5 nM) comparable to that of Flumazenil (2.8 nM). The presented data confirm the potential of [18F]FFMZ for PET imaging of the GABA-ergic system. [Copyright &y& Elsevier]