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Selective serotonin reuptake inhibitors (SSRIs) represent one of the most common treatment options in major depression and anxiety disorders. By blocking the serotonin transporter, SSRIs modulate serotonergic neurotransmission as well as the function of autoreceptors and heteroreceptors. However, treatment-induced changes on a network level primarily remain unknown. Thus, we evaluated the association between serotonin-1A (5-HT1A) autoreceptors and heteroreceptors before and after SSRIs. Twenty-one patients with anxiety disorders underwent positron emission tomography using [carbonyl-11C]WAY-100635 before and after 12 weeks of escitalopram treatment; 15 of them completed the study protocol. Additionally, 36 drug-naive healthy controls were measured once. The 5-HT1Areceptor binding potential (BPND) was quantified for the dorsal raphe nucleus (DRN) using a region-of-interest approach and for the entire brain by calculating parametric maps. Voxel-wise linear regression was applied between DRN autoreceptor and whole-brain heteroreceptor 5-HT1ABPND. Consistent with previous observations, healthy subjects showed widespread positive correlations of 5-HT1ABPNDbetween autoreceptors and heteroreceptors. Comparing patients before versus after escitalopram treatment revealed enhanced associations of autoreceptor-to-heteroreceptor 5-HT1ABPNDwithin the amygdala and hippocampus (R2= 0.21–0.28 vs 0.49–0.81;p< 0.05–0.001). In contrast, no significant SSRI-induced changes were found for correlations of heteroreceptor-to-heteroreceptor 5-HT1ABPNDbetween several limbic regions. This interregional approach suggests a treatment-induced reinforcement of the association of 5-HT1Abinding between autoreceptors and heteroreceptors specifically in areas involved in anxiety disorders. These findings provide complementary information about treatment effects on a network level and confirm the central role of the DRN as a prime regulatory area.

For the development and process optimization of pharmaceutical equipment, it is important to investigate the underlying processes. Taking the fluidized bed technology as an example, the study of particle flow pattern and convection of the particles within the functional unity is essential for construction and process improvement. With positron emission particle tracking (PEPT) it is possible to study the real-time particle motion with radiolabelled particles. We established a fast and simple labelling technique with [(18)F]fluoride for pellets composed of Avicel and anion exchange resin. The uptake of activity ranged from 1.3% to 1.7% per mg and 8.6% to 16.3% per pellet. A specific binding of [(18)F]fluoride with increasing degree of anion exchange resin in the pellets could be observed.

Since, to date very limited information on the distribution and function of the adenosine A3 receptor is available, the development of suitable radioligands is needed. Recently, we introduced [ 18F]FE@SUPPY (5-(2-[ 18F]fluoroethyl) 2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate) as the first PET-ligand for the A3R. Regarding the metabolic profile – this class of dialkylpyridines comprises two ester functions within one molecule, one carboxylic and one thiocarboxylic – one could expect carboxylesterases significantly contributing to cleavage and degradation. Therefore, our aim was the development of [ 18F]FE@SUPPY:2 (5-ethyl 2,4-diethyl-3-((2-[ 18F]fluoroethyl)sulfanylcarbonyl)-6-phenylpyridine-5-carboxylate), the functional isomer containing the label at the thiocarboxylic moiety. For satisfactory yields in high scale radiosyntheses, a reaction temperature of 75 °C has to be applied for at least 20 min using 20 mg/mL of precursor. So far, 6 complete high-scale radiosyntheses were performed. Starting from an average of 51.2±21.8 GBq (mean±SD) [ 18F]fluoride, 5.8±4.1 GBq of formulated [ 18F]FE@SUPPY:2 (12.0±5.4%, based on [ 18F]fluoride, not corrected for decay) were prepared in 75±8 min.

The higher prevalence rates of depression and anxiety disorders in women compared to men have been associated with sexual dimorphisms in the serotonergic system. The present positron emission tomography (PET) study investigated the influence of sex on the major inhibitory serotonergic receptor subtype, the serotonin-1A (5-HT(1A)) receptor.Sixteen healthy women and 16 healthy men were measured using PET and the highly specific radioligand [carbonyl-(11)C]WAY-100635. Effects of age or gonadal hormones were excluded by restricting the inclusion criteria to young adults and by controlling for menstrual cycle phase. The 5-HT(1A) receptor BP(ND) was quantified using (1) the 'gold standard' manual delineation approach with ten regions of interest (ROIs) and (2) a newly developed delineation method using a PET template normalized to the Montreal Neurologic Institute space with 45 ROIs based on automated anatomical labeling.The 5-HT(1A) receptor BP(ND) was found equally distributed in men and women applying both the manual delineation method and the automated delineation approach. Women had lower mean BP(ND) values in every region investigated, with a borderline significant sex difference in the hypothalamus (p = 0.012, uncorrected). There was a high intersubject variability of the 5-HT(1A) receptor BP(ND) within both sexes compared to the small mean differences between men and women.To conclude, when measured in the follicular phase, women do not differ from men in the 5-HT(1A) receptor binding. To explain the higher prevalence of affective disorders in women, further studies are needed to evaluate the relationship between hormonal status and the 5-HT(1A) receptor expression.

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.

Summary. So far, [carbonyl- 11 C]WAY-100635 is the PET-tracer of choice for 5HT 1A -receptor-imaging. Since thepreparation is still a challenge, we aimed at (1) the eval-uation of various essential parameters for the successfulpreparation, (2) the simplification of the radiosynthesis and(3) the establishment of a safe and fully automated system.The preparation is based on a commercial synthesizer andall chemicals are used without further processing. We founda low failure rate (7 . 7%), high average yield (4 . 0±1 . 0GBq)and a specific radioactivity of 292 ±168 GBq / µmol (both atthe end of synthesis, EOS). Introduction Carbon-11 labelled WAY-100635 ( N -(2-(1-(4-(2-methoxy-phenyl)-1-piperazinyl)ethyl))- N -(2-pyridyl)-cyclohexane-carboxamide; WAY) was introduced into positron emis-sion tomography (PET) as a highly potent and selectiveantagonist at the 5HT 1A receptors more than a decade ago.Since 5HT 1A receptors are implicated in the pathogenesisof anxiety, depression, eating disorders and motion sick-ness, they are an important target for drug therapy [1,2].The visualisation and quantification of this receptor is a ba-sis for further exploration of molecular pathologies causingpsychiatric conspicuousness. The most extensively studiedtracers are two carbon-11 labelled WAY-100635 derivatives,[O-methyl

PET imaging of the μ-opioid receptor (OR) is still restricted to [11C]carfentanil ([11C]CFN) but its use is limited due to its short half-life and high agonistic potency. Recently, the radiosynthesis of [18F]fluoroalkyl esters of CFN was proposed, unfortunately yielding products not suitable for human PET due to their low specific activities. Therefore, our rationale was to develop a reliable radiosynthesis of a [18F]fluoroethylated CFN derivative overcoming these drawbacks. The [18F]fluoroethyl ester of carfentanil, [18F]FE@CFN (2-[18F]fluoroethyl 4-[N-(1-oxopropyl)-N-phenylamino]-1-(2-phenylethyl)-4-piperidinecarboxylate), and its corresponding inactive standard compound were prepared. Purification of [18F]FE@CFN was achieved via a simple solid phase extraction method. [18F]FE@CFN was prepared with excellent purity (> 98%) and sufficient yields. Specific activity surpassed the level required for safe administration. We therefore conclude that our simplified synthesis of [18F]FE@CFN, for the first time, overcomes the shortcomings of [11C]CFN and the previously suggested alternatives, namely, (1) longer half-life; (2) easy production and (3) adequate specific activity, should make a wider application possible. Hence, [18F]FE@CFN may become a valuable PET tracer for the imaging of the μ-OR in human brain and heart.

11beta-Hydroxylase is a key enzyme in the biosynthesis of adrenocortical steroid hormones and is a suitable target for the imaging of the adrenal cortex. [(11)C]Metomidate (MTO), [(11)C]etomidate (ETO) and desethyl-[(18)F]fluoroethyl-etomidate (FETO) are potent inhibitors of this enzyme and are used for PET imaging of adrenocortical pathologies. The aims of this study were (1) to evaluate and compare the metabolic stability of MTO, ETO and FETO against esterases and (2) to investigate the metabolic pattern of FETO in vivo.In vitro assays were performed using different concentrations of MTO, ETO and FETO with constant concentrations of carboxylesterase. Human in vivo studies were performed with human blood samples drawn from the cubital vein. After sample clean-up, the serum was analysed by HPLC methods.In vitro assays showed Michaelis-Menten constants of 115.1 mumol for FETO, 162.0 mumol for MTO and 168.6 mumol for ETO. Limiting velocities were 1.54 mumol/min (FETO), 1.47 mumol/min (MTO) and 1.35 mumol/min (ETO). This implies insignificantly decreased esterase stability of FETO compared with MTO and ETO. In vivo investigations showed a rapid metabolisation of FETO within the first 10 min (2 min: 91.41%+/-6.44%, n=6; 10 min: 23.78%+/-5.54%, n=4) followed by a smooth decrease in FETO from 20 to 90 min (20 min: 11.23%+/-3.79% n=4; 90 min: 3.68%+/-3.65%, n=4). Recovery rate was 61.43%+/-3.19% (n=12).In vitro experiments demonstrated that FETO stability against esterases is comparable to that of ETO and MTO. The metabolic profile showed that FETO kinetics in humans are fast.

Functional imaging of the adrenal cortex by means of PET may play an important clinical role. Recently, we presented the synthesis and first evaluation of a novel 11beta-hydroxylase inhibitor, [(18)F]FETO, in rats displaying high tracer accumulation in the adrenals. In this study, we aimed to investigate for the first time the potency of [(18)F]FETO as a PET tracer for the adrenal cortex in humans.An average preparation yielded 1-2 GBq of [(18)F]FETO ready to use. Ten healthy volunteers aged 24-57 years (five male and five female) were included in the study. After i.v. administration of 365 MBq [(18)F]FETO (246-391 MBq), dynamic images were acquired in 2D standard mode in 14 frames over 45 min. Afterwards, whole-body scanning was performed. In addition to visual interpretation, semi-quantitative analysis using standardised uptake values (SUVs) was conducted.[(18)F]FETO distribution was similar in all scanned volunteers. Visually, pronounced accumulation of [(18)F]FETO was found in the adrenals, whereas moderate uptake was observed-at least in some of the subjects-for liver, renal calices, gallbladder, stomach walls and pancreas. Kidney and bowels showed only faint uptake. Median SUVs for the right and left adrenal glands were 15.6 (10.0-28.6) and 15.7 (10.3-35.9), respectively. The reference tissue (liver) displayed a median SUV of 2.5 (2.2-4.6).[(18)F]FETO is a valuable tracer for adrenocortical PET imaging, combining the longer half-life of( 18)F with a high 11beta-hydroxylase selectivity. In accordance with our findings in rats, FETO PET revealed very high accumulation in the adrenal glands in healthy volunteers.

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 [(18)F]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 [(18)F]fluorinated synthons for PET.

Although polyphosphonates (PPs) were introduced as bone imaging agents in nuclear medicine in the early 1970s, the mechanisms involved in their uptake still remain unclear. Suggested mechanisms range from mineral adsorption with disputed binding to the organic phase, over incorporation into the mineralisation process to a combination of both mechanisms. Thus, our investigations aimed to: (1) evaluate adsorption parameters of (99m)Tc-MDP, (153)Sm-EDTMP and (18)F-fluoride on mineralising osteoblast cultures, (2) correlate the radiotracer binding measured in the cell cultures with binding values from our previously presented mineral model and (3) compare binding with cell number.Primary osteoblasts were obtained by sequential digestion of foetal mice calvariae. The cells were incubated with 0.3 mumol of radiolabelled PPs or 25 MBq (18)F-fluoride for 120 min. Gamma signals from labelled samples were detected with a Millennium Hawkeye SPECT camera or with a dedicated Advance full-ring PET scanner and the binding percentages were calculated.From days 8 to 15 of culture, the percent binding of all evaluated tracers increased significantly, whereas the protein concentration showed insignificant changes. Additional comparisons of the binding values with our recently published pre-vivo model revealed remarkable agreement, suggesting solely bone-forming minerals to be responsible for radiotracer binding.This study provides evidence that binding of the evaluated radiotracers is not associated with osteoblast numbers but only with the concentration of bone-forming minerals. The presented correlations substantiate our recently presented pre-vivo model for the evaluation of bone-seekers: mechanisms associated with the uptake of bone-seekers are irreversible and mineral-associated processes.

[(11)C]Flumazenil, a highly selective benzodiazepine antagonist is the most extensively used GABA(A) ligand for PET so far. To overcome half life disadvantages of (11)C a [(18)F]-labeled flumazenil derivative, 2'-[(18)F]fluoroflumazenil (FFMZ) was developed and biologically evaluated with respect to the GABA(A) 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 [(3)H]flumazenil binding from membrane GABA(A) receptors with an IC(50)value (3.5 nM) comparable to that of Flumazenil (2.8 nM). The presented data confirm the potential of [(18)F]FFMZ for PET imaging of the GABA-ergic system.

In the last decade radiolabeled tropane analogs based on β-CIT have proven indispensable for the imaging of the dopamine transporter. However, further improvements in their pharmacodynamic and pharmacokinetic features are desirable. An important improvement, yielding in higher affinity to the dopamine transporter (DAT) vs. serotonin transporter (SERT), can be achieved by a simple replacement of the carboxylic methyl ester group in β-CIT by a fluoroethyl ester. The preparation and ex vivo evaluation of this new β-CIT-analog ([18F]FE@CIT) is presented here. Precursor and standard were prepared from β-CIT and analyzed by spectroscopic methods. Yields of precursor and standard preparation were 61% and 42%, respectively. [18F]FE@CIT was prepared by distillation of [18F]bromofluoroethane ([18F]BFE) and reaction with (1R-2-exo-3-exo)8-methyl-3-(4-iodo-phenyl)-8-azabicyclo[3.2.1] octane-2-carboxylic acid. After 10 min at 150°C the product was purified using a C-18 SepPak. The radiosynthesis evinced radiochemical yields of >90% (based on [18F]BFE), the specific radioactivity was >416 GBq/μmol. An average 30 μAh cyclotron irradiation yielded more than 2.5 GBq [18F]FE@CIT. For the ex vivo bioevaluation, 20 male Sprague-Dawley rats were sacrificed at 5, 15, 30, 60, and 120 min after injection. Organs were removed, weighed, and counted. For autoradiographic experiments, transverse brain slices of about 100 μm were prepared. The ex vivo evaluation showed highest brain uptake in striatal regions, followed by thalamus and cerebellum. The highest striatum to cerebellum ratio was 3.73 and the highest thalamus to cerebellum ratio was 1.65. Autoradiographic images showed a good and differentiated uptake in striatal regions with a good target-to-background ratio. Synapse 55:73–79, 2005. © 2004 Wiley-Liss, Inc.

Recently, two fluorine-18 labelled derivatives of flumazenil were described: 5-(2′-[18F]fluoroethyl)-5-desmethylflumazenil (ethyl 8-fluoro-5-[18F]fluoroethyl-6-oxo-5,6-dihydro-4H-benzo-[f]imidazo[1,5-a] [1,4]diazepine-3-carboxylate; [18F]FEFMZ) and 3-(2′-[18F]fluoro)-flumazenil (2′-[18F]fluoroethyl 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-benzo-[f]imidazo[1,5-a]-[1,4]diazepine-3-carbo- xylate; [18F]FFMZ). Since the biodistribution data of the latter were superior to those of the former we developed a synthetic approach for [18F]FFMZ starting from a commercially available precursor, thereby obviating the need to prepare a precursor by ourselves. The following two-step procedure was developed: First, [18F]fluoride was reacted with 2-bromoethyl triflate using the kryptofix/acetonitrile method to yield 2-bromo-[18F]fluoroethane ([18F]BFE). In the second step, distilled [18F]BFE was reacted with the tetrabutylammonium salt of 3-desethylflumazenil (8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-benzo-[f]imidazo[1,5-a] [1,4]diazepine-3-carboxylic acid) to yield [18F]FFMZ. The synthesis of [18F]FFMZ allows for the production of up to 7 GBq of this PET-tracer, enough to serve several patients. [18F]FFMZ synthesis was completed in less than 80 min and the radiochemical purity exceeded 98%. Copyright © 2003 John Wiley & Sons, Ltd.

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.

There is an increasing interest in the underlying mechanisms of the antidepressant and anxiolytic treatment effect associated with changes in serotonergic neurotransmission after treatment with selective serotonin (5-HT) reuptake inhibitors (SSRIs) in humans. The 5-HT(1A) receptor is known to play a crucial role in the pathophysiology of affective disorders, and altered 5-HT(1A) receptor binding has been found in anxiety patients. SSRI treatment raises the 5-HT level in the synaptic cleft and might change postsynaptic receptor densities. Therefore, our study in patients suffering from anxiety disorders investigated the effects of long-term treatment with escitalopram on the 5-HT(1A) receptor. A longitudinal positrone emission tomography (PET) study in 12 patients suffering from anxiety disorders was conducted. Two dynamic PET scans were performed applying the selective 5-HT(1A) receptor antagonist [carbonyl-(11)C]WAY-100635. Eight regions of interest were defined a priori (orbitofrontal cortex, amygdala, hippocampus, subgenual cortex, anterior and posterior cingulate cortex, dorsal raphe nucleus and cerebellum as reference). After the baseline PET scan, patients were administered escitalopram (average dose of 11.2+/-6.0 mg day(-1)) for a minimum of 12 weeks. A second PET scan was conducted after 109+/-27 days. 5-HT(1A) receptor binding potentials in 12 patients were assessed by PET applying the Simplified Reference Tissue Model.There was a significant reduction in the 5-HT(1A) receptor binding potential after a minimum of 12 weeks of escitalopram treatment in the hippocampus (P=0.006), subgenual cortex (P=0.017) and posterior cingulate cortex (P=0.034). The significance of the hippocampus region survived the Bonferroni-adjusted threshold for multiple comparisons. These PET data in humans in vivo demonstrate a reduction of the 5-HT(1A) binding potential after SSRI treatment.

Introduction The translation of 11 C-labeled compounds into their respective 18 F-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 18 F-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 11 C-methylated tracers into their 18 F-fluoroethylated analogs sharing the same precursor molecules. Methods Ten methods for the preparation and purification of different 18 F-fluoroethylating agents were compared. Subsequently, five 18 F-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-[ 18 F]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 18 F-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.

Introduction The objectives of this study were to develop a simple preparation method for [ 68 Ga]-EDTMP and to evaluate the applicability of [ 68 Ga]-EDTMP as a potential positron emission tomography (PET) bone imaging agent using pre vivo, ex vivo and in vivo models. Methods [ 68 Ga]-EDTMP was prepared using [ 68 Ga]-gallium chloride eluted from the 68 Ge/ 68 Ga 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 [ 18 F]-fluoride. Results [ 68 Ga]-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 [ 18 F]-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 [ 68 Ga]-EDTMP over [ 18 F]-fluoride is not apparent and the future clinical prospect of [ 68 Ga]-EDTMP remains speculative.

Background Results from studies in serotonin-1A (5-HT 1A ) knockout mice and previous positron emission tomography (PET) studies in humans imply a role for 5-HT 1A receptors in normal state anxiety as well as in certain anxiety disorders. The objective of this study was to investigate 5-HT 1A receptor binding potential (BP) in social anxiety disorder (SAD). Methods Using PET and [carbonyl- 11 C]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-HT 1A BP in several limbic and paralimbic areas but not in the hippocampus (p = .234) of SAD patients. The difference in 5-HT 1A binding was most significant in the amygdala (−21.4%; p=.003). There was also a more than 20% lower 5-HT 1A BP of SAD patients in the anterior cingulate cortex (p = .004), insula (p = .003), and dorsal raphe nuclei (p = .030). Conclusions The lower 5-HT 1A binding in the amygdala and mesiofrontal areas of SAD patients is consistent with 1) preclinical findings of elevated anxiety in 5-HT 1A knockout mice, 2) a previous PET study in healthy volunteers showing an inverse correlation between 5-HT 1A BP and state anxiety, and 3) another human PET study in patients with panic disorder showing reduced 5-HT 1A binding, thus corroborating the potential validity of 5-HT 1A receptors as targets in the treatment of human anxiety disorders.

The present study focused on the preparation of novel bone tracers containing yttrium as radionuclide or carrier. Moreover, these preparations were comparatively evaluated in vitro on the basis of a recently presented pre vivo model comprising binding studies on synthetic and human bone powder. It was shown that among the therapeutic radionuclides, no carrier added [ 90 Y]-EDTMP exceeded [ 188 Re]-EDTMP while yielding lower binding values than [ 153 Sm]-EDTMP. Furthermore, the authors investigated the influence of “foreign” carriers added to [ 90 Y]-EDTMP, [ 99m Tc]-EDTMP and [ 111 In]-EDTMP by the method of cross-complexation. The findings reveal a new paradigm: a carrier more foreign to the complexed radionuclide causes a higher binding increase on human bone matrices in vitro than a more “related” carrier.

Introduction Although the first polyphosphonates (PP) were introduced to nuclear medicine as bone imagers in the early 70s, mechanisms involved in uptake still remain speculative. Controversies range from adsorption onto the mineral phase with disputed binding to the organic phase, over incorporation into the mineralisation process to a combination of both mechanisms. Other factors such as solubility of the complex, concentration of ligand or effects of the radionuclide have also been discussed as possible parameters influencing bone uptake. Therefore, the present work aimed to verify the recently presented pre vivo model which was developed to rate the influence of various factors on the binding of differently radiolabelled PP and [ 18 F]-fluoride on synthetic bone matrix. Methods Radiolabelled polyphosphonates and [ 18 F]-fluoride were added to a vial containing lyophilised and milled spongiosa (Sp) or cortical bone (Co) in Hank's Balanced Salt Solution. After incubation, the radioactivity was measured in the gamma-counter before and after filtration. The percentage of irreversibly bound radioactivity was calculated. Same experiments were performed after decalcification of Sp and Co with hydrochloric acid. Results Descriptively, [ 111 In] increases the uptake of EDTMP in each case compared to similarly prepared [ 99m Tc]-analogues: [ 111 In]-EDTMP > [ 99m Tc]-EDTMP, [ 111 In]-/In-EDTMP > [ 99m Tc]-/In-EDTMP and [ 111 In]-/Re-EDTMP > [ 99m Tc]-/Re-EDTMP. [ 188 Re]-EDTMP shows higher binding than the carrier-added analogue, contradicting recent in vivo findings of [ 188 Re]-PP. However, our findings on human matrix are consistent with those of a previous study using artificial bone material. Binding on decalcified tissue was very low (PP) to moderate ([ 18 F]-fluoride) and reversible. Remarkable is also the unrivalled high uptake of [ 18 F]-fluoride, showing no reduced uptake on Co and Sp as compared to hydroxyapatite (HA) and amorphous calcium phosphate (ACP). Conclusion The binding of the evaluated bone seekers on these human bone matrices follows a comparable pattern as on artificial bone. The present study substantiates the fact that binding predominantly occurs on the inorganic compartment of bone. The best correlation was found between HA and Co. Therefore, HA can serve as a matrix for representative binding studies.

Introduction . Although the first polyphosphonates were already introduced in the early 1970s, mechanisms involved in uptake still remain speculative. The present work aimed to establish a new method to rate the influence of various factors on the uptake and to evaluate new bone-seekers on these bone compartments. Methods . Radioactive-labelled diphosphonates and [ 18 F]-fluoride were added to a vial containing hydroxyapatite (HA), collagen, or amorphous calcium phosphate (ACP) in 3 ml of Hanks' Balanced Salt Solution (HBSS). After incubation, these suspensions were filtered, the radioactivity was measured in the gamma-counter, and the percentage of irreversibly bound radioactivity was calculated. Results . Kinetic experiments revealed uptake increase over time for [ 99m Tc]-MDP and [ 18 F]-fluoride on various amounts of matrix. After 120 min, static studies on HA yielded: [ 99m Tc]-EDTMP 188 Re]-/Re-EDTMP 99m Tc]-/11 μl Re-EDTMP 99m Tc]-/In-EDTMP 99m Tc]-/15 μl Re-EDTMP 188 Re]-EDTMP 111 In]-/Re-EDTMP 111 In]-EDTMP 111 In]-/In-EDTMP 99m Tc]-DPD 99m Tc]-/80 μl Re-EDTMP 99m Tc]-EDTMP “boiled” 99m Tc]-/150 μl Re-EDTMP 153 Sm]-EDTMP 99m Tc]-/11 μl Re-EDTMP “boiled” 18 F]-ions 99m Tc]-MDP. Collagen showed very low uptake. Reincubation experiments suggest that bone tracers are irreversibly bound. Conclusion . The presented method is rapid and feasible to examine the adsorption of radioactive-labelled substances on bone components. Correlations between our findings and published in vivo data support the application as a simple model.

Visualization and biopsy of sentinel lymph nodes play an important role in planning and controlling the therapy of breast cancer. Hitherto two methods—scintigraphy or gamma probe detection after injection of [ 99m Tc]-nanocolloids and visual detection after injection of patent blue dye—are used routinely. There are no conclusive publications elucidating such important parameters as injection site, injection method and colloidal parameters. The present work aims to label Nanocoll ® with [ 111 In] to provide an alternative method, a simultanous one-compound dual-isotope application. Methods : [ 111 In]-Indiumchloride was buffered with acetate and transferred to the nanocolloid. The colloid labelling reaction was complete after 30 min and filtrated through 100 nm Nuclepore ® filters. Results : Incorporation yield of [ 111 In]-Indium into the nanocolloid was nearly quantitative, the step associated with the major loss of activity was the particle sizing with a mean yield of 55%. Conclusion : The presented method allows for the routine supply of [ 111 In]-nanocolloids. Size-filtered [ 111 In]-Nanocoll ® shows the same particle size range as [ 99m Tc]-Nanocoll ® .