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Purpose: 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 11β-hydroxylase inhibitor, [18F] FETO, in rats displaying high tracer accumulation in the adrenals. In this study, we aimed to investigate for the first time the potency of [18F]FETO as a PET tracer for the adrenal cortex in humans. Methods: An average preparation yielded 1-2 GBq of [18F]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 [18F] 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. Results: [18F]FETO distribution was similar in all scanned volunteers. Visually, pronounced accumulation of [18F] 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). Conclusion: [18F]FETO is a valuable tracer for adrenocortical PET imaging, combining the longer half-life of 18F with a high 11β-hydroxylase selectivity. In accordance with our findings in rats, FETO PET revealed very high accumulation in the adrenal glands in healthy volunteers. [ABSTRACT FROM AUTHOR]

Purpose: 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 99mTc-MDP, 153Sm-EDTMP and 18F-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. Methods: Primary osteoblasts were obtained by sequential digestion of foetal mice calvariae. The cells were incubated with 0.3 µmol of radiolabelled PPs or 25 MBq 18F-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. Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Purpose: The suitability of the 18F-labelled fluoroquinolone antibiotic ciprofloxacin ([18F]ciprofloxacin) for imaging of bacterial infections with positron emission tomography (PET) was assessed in vitro and in vivo. Methods: For the in vitro experiments, suspensions of various E. coli strains were incubated with different concentrations of [18F]ciprofloxacin (0.01-5.0 μg/ml) and radioactivity retention was measured in a gamma counter. For the in vivo experiments, 725 ± 9 MBq [18F]ciprofloxacin was injected intravenously into four patients with microbiologically proven bacterial soft tissue infections of the lower extremities and time-radioactivity curves were recorded in infected and uninfected tissue for 5 h after tracer injection. Results: Binding of [18F]ciprofloxacin to bacterial cells was rapid, non-saturable and readily reversible. Moreover, bacterial binding of the agent was similar in ciprofloxacin-resistant and ciprofloxacin-susceptible clinical isolates. These findings suggest that non-specific binding rather than specific binding to bacterial type II topoisomerase enzymes is the predominant mechanism of bacterial retention of the radiotracer. PET studies in the four patients with microbiologically proven bacterial soft tissue infections demonstrated locally increased radioactivity uptake in infected tissue, with peak ratios between infected and uninfected tissue ranging from 1.8 to 5.5. Radioactivity was not retained in infected tissue and appeared to wash out with a similar elimination half-life as in uninfected tissue, suggesting that the kinetics of [18F]ciprofloxacin in infected tissue are governed by increased blood flow and vascular permeability due to local infection rather than by a binding process. Conclusion: Taken together, our results indicate that [18F]ciprofloxacin is not suited as a bacteria-specific infection imaging agent for PET. [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: 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: 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]

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: 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 [18F]-fluoride on synthetic bone matrix. Methods : Radiolabelled polyphosphonates and [18F]-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, [111In] increases the uptake of EDTMP in each case compared to similarly prepared [99mTc]-analogues: [111In]-EDTMP > [99mTc]-EDTMP, [111In]-/In-EDTMP > [99mTc]-/In-EDTMP and [111In]-/Re-EDTMP > [99mTc]-/Re-EDTMP. [188Re]-EDTMP shows higher binding than the carrier-added analogue, contradicting recent in vivo findings of [188Re]-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 ([18F]-fluoride) and reversible. Remarkable is also the unrivalled high uptake of [18F]-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. [Copyright &y& Elsevier]

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 [18F]-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 [99mTc]-MDP and [18F]-fluoride on various amounts of matrix. After 120 min, static studies on HA yielded: [99mTc]-EDTMP < [188Re]-/Re-EDTMP < [99mTc]-/11 μl Re-EDTMP < [99mTc]-/In-EDTMP < [99mTc]-/15 μl Re-EDTMP < nca [188Re]-EDTMP < [111In]-/Re-EDTMP < [111In]-EDTMP < [111In]-/In-EDTMP < [99mTc]-DPD < [99mTc]-/80 μl Re-EDTMP < [99mTc]-EDTMP “boiled” < [99mTc]-/150 μl Re-EDTMP < [153Sm]-EDTMP < [99mTc]-/11 μl Re-EDTMP “boiled” < [18F]-ions < [99mTc]-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. [Copyright &y& Elsevier]