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The limited availability and the increasing demands of [18O]H2O force the reuse of bombarded [18O]H2O for the production of [18F]F‒ at least for the purposes of research. Therefore inorganic and organic contaminants have to be removed from the [18O]water. We present a simple and effective method of [18O]water purification including oxidation and distillation. The obtained recycled [18O]water has comparable properties to unused [18O]water. This was confirmed by a detailed comparison of produced radionuclides and their activities and the application of [18F]F‒ in standardised radiotracer synthesis.

Rapid development of PET and the design of larger targets cause a greater need of oxygen-18 enriched water as target material for fluorine-18 production and entail increased costs for oxygen-18 enriched water. This forced us to consider its re-use for research purposes. Used O-18 water is mainly contaminated with metal radionuclides, non-radioactive salts and organic solvents. Here, we present (i) two methods for the removal of organic contaminants, (ii) analytical methods for quality assessment and (iii) findings for irradiation and radiosyntheses using activity produced from re-cycled water. Samples of used target water (1 L containing 44 mg L>sup-1 acetone and 396 mg L>sup-1 ethanol) were treated with UV irradiation (254 nm) [1] or with KMnO4/NaOH at 50°C to reduce the concentration of these contaminants below 50 mg L>sup-1, respectively. Both methods allowed close-to-zero decrease of acetone and decrease of ethanol to 23 ± 20 mg L>sup-1 (n = 8). After vacuum distillation pure re-cycled water was obtained as proven by gamma spectrometry, gas chromatography, ICP-OES, and ion chromatography. Loss of O-18 enrichment (83%, pycnometry) was not observed. A reference study on O-16 water, contaminated by addition of 150 to 200 mg L>sup-1 methanol, ethanol, acetone and acetonitrile, showed a comparable oxidation potential of both methods for methanol, ethanol and acetone (decrease within 48 h below 50 mg L>sup-1). Oxidation of acetonitrile was only achieved with the UV-lamp within 7 days. Re-cycled water and virgin water (Hyox 18 Enriched Water), partly diluted to 83% O-18 enrichment, were irradiated in the Nirtra® Fluor L-target at a CYCLONE 18/9 (iba) with 35 µA and 11.7 µAh. Comparison of produced activities of F-18, N-13 and metal radionuclides confirmed the high quality of the re-cycled water. Compared to undiluted virgin water a loss of the production yield of ~19% was observed. No significant influence on the radionuclide purity or radiochemical reactivity was detected. F-18 obtained from virgin water or re-cycled water irradiation was comparably used for radiosyntheses. Results of automated radiosyntheses (TRACERLAB™ FX-FN) of our new α4β2 nicotinic receptor ligand [18F]flubatine (n=5) and σ1 receptor ligand [18F]fluspidine (n=8) as well as radiosyntheses for development of the α7 nicotinic receptor ligand [18F]NS14490 and 18F-labelled CB2-selective N-aryl-oxdiazolyl-propionamides revealed equivalent yields and unchanged product qualities. The described purification procedures enable a multiple re-cycling of target water for successful F-18 production and application for research purposes with reasonable production yields and efficient economical use of the target water. [1] DE 29504388 U1, 1995

Ziel/Aim: Bestrahltes [18O]H2O kann nach Aufbereitung erneut für Bestrahlungen eingesetzt werden1. Wir berichten über einen einfachen Aufbereitungsprozess und eine genaue Charakterisierung des [18O]H2O. Methodik/Methods: 1 l bestrahltes [18O]Wasser mit 396 mg l–1 Ethanol und 44 mg l–1 Aceton sowie Ionen im g-l–1-Bereich wurde in unterschiedlichen Ansätzen zur Oxidation der organischen Lösungsmittel mit KMnO4/NaOH bei 50°C bzw. mit UV-Strahlung1 (254 nm, 1 W) behandelt. Anschließend erfolgte eine Vakuumdestillation. Nach genauer Charakterisierung mit Gas- und Ionenchromatographie Pyknometrie wurde das gewonnene Wasser in einem Nirta®Fluor - Target an einem Cylcone®18/9 (IBA, Belgien) bestrahlt und die Produktionsaktivitäten mit denen von (verdünntem) [18O]Originalwasser verglichen. Das produzierte [18F]Fluorid wurde für die Entwicklung von Radiosynthesen und für standardisierte Herstellungsverfahren eingesetzt. Für einen Vergleich der beiden Oxidationsmethoden wurde [16O]H2O mit Methanol, Ethanol, Aceton und Acetonitril kontaminiert und entsprechend aufbereitet. Ergebnisse/Results: Mit beiden Oxidationsmethoden wurden die organischen Lösungsmittel innerhalb von max. 2 Tagen unter einen Grenzwert von 50 mg l–1 abgebaut. Nach der Vakuumdestillation zeichneten sich die einzelnen Chargen durch übereinstimmende 18O-Anreicherungen sowie geringe Ionengehalte aus. Der Vergleich der Produktionsaktivitäten zeigt eine Übereinstimmung zu verdünntem Originalwasser. Die Verwendung des [18F]F– in radiochemischen Umsetzungen war erfolgreich. Abbildung 1: Produktionsaktivitäten mit aufbereitetem Wasser und verdünntem Originalwasser Die Aufbereitung von Modelllösungen mit [16O]H2O ergab, dass Acetonitril durch KMnO4/NaOH defakto nicht abgebaut wird. Es wurden für beide Methoden ≥97% des eingesetzten Wassers gewonnen. Schlussfolgerungen/Conclusions: Die Ergebnisse zeigen einen zuverlässigen, nahezu verlustfreien Aufbereitungsprozess von bestrahltem [18O]H2O. Dies ermöglicht einen ökonomisch sinnvollen Gebrauch von [18O]H2O. Referenzen/References: [1] Gebrauchsmuster DE 29504388 U1 (15.03.95), Forschungszentrum Jülich GmbH

Advantages of a stacked assembly of target support components for 64Cu production via 64Ni(p,n)64Cu reaction were reported recently.1 The present work shows the applicability of these composit targets for beam currents up to 22 µA. Gold and platinum foils were evaluated as 64Ni backing. The effective specific activity (ESA) and specific activity (SA) were determined by TETA titration at room temperature and at 80 °C and compared with additional copper quantification results via stripping voltammetric trace analysis (VA).

Die Erfindung betrifft die Herstellung von Radiopharmaka, insbesondere in Verfahren, und eine Anordnung zur Reinigung des Reaktionsgemisches bei der Herstellung von Radiopharmaka, insbesondereF-markierte Radiopharmaka, wie z. B. [F]FDOPA und [F]OMFD sowie [F]FMeMcN. Erfindungsgemäß wird zur Reinigung des Raktionsgemisches eine Vorsäule als Vorreinigungssäule, gefüllt mit RP-Material (Reversed Phase Material), zur Abtrennung des bei der Reaktion verwendeten Lösungsmittels (Matrix) bzw. unerwünschter Nebenprodukte verwendet, während die eigentliche chromatographische Trennung des Reaktionsgemisches auf einer HPLC-Säule, bevorzugt einer RP-HPLC-Säule, durchgeführt wird.

An increasing demand of radiopharmaceuticals based on electrophilic reaction with [18F]F2 gas (for instance [18F]FDOPA) led to an upgrade of the IBA [18F]F2 gas target system in summer 2007. The more than 10 years operated [18F]F2 deuteron target [20Ne(p,α)18F] was not able to meet the increasing requirements in terms of activity anymore and was thus replaced by an IBA [18F]F2 proton gas target [18O(p,n)18F] based on the so-called “double-shot” ‘irradiation method by R.J. Nickles [1]. The upgrade itself was done by IBA. We run the Cyclone® 18/9 cyclotron in routine operation for more than 14 years. One of the specific features of the Rossendorf PET Center is the Radionuclide transport system (RATS) [2], 500 m in length that bridges the distance from the cyclotron to the radiopharmaceutical laboratories. The activity at the end of bombardment (EOB) is calculated taking in account the transfer time and experimental data of activity losses (about 30%) in the transfer tube [2].

Objectives: Radiopharmaceuticals are usually synthesised by reaction of simple radiolabeled compounds with a non-radioactive precursor. Afterwards the labeled precursor compound undergoes frequently a deprotection reaction. The resulting reaction mixture is often quite complex and needs HPLC purification to isolate the labeled target compound in high chemical and radiochemical purity. In some cases the composition of the reaction mixture is such complex, that an off-line solid phase extraction (SPE) step is carried out before HPLC purification to separate matrix components and/or interfering solvents. This SPE prepurification of the reaction mixture is difficult to automate and needs special hardware and solvents for rinsing and eluting the SPE cartridge. Additionally, remote controlled synthesis modules become more complex.The general aim of the present work is to develop a process, which allows the pre-cleaning of reaction mixtures from disturbing matrix components by online SPE using HPLC. In detail it results from the need to improve the radiochemical purity of [18F]FDOPA and to reduce the solvent content of dimethylformamide (DMF) during manufacturing of the serotonin transporter radioligand [18F]FMeMcN 5652. Methods: The figure shows the scheme of the HPLC hardware, whereas a pre- or guard-column is used as pre-clean-up-column (X) instead of an injection loop. The selectivity of the packing material of both columns (III & X) can be selected in accordance with the separation requirements.The process includes following steps:1. Injection valve (I) in “load position”, The reaction mixture is transferred from the reaction vessel (IX) onto the pre-clean-up-column. The diameter of the packing material of the pre-clean-up-column is in the range, which allows the feeding by gas overpressure. The disturbing matrix components are passed to waste and the target compound is retained.2. The rinsing liquid is filled into the reaction vessel and rinse out the dead volume of the pre-clean-up-column. The target compound is cleaned-up and concentrated.3. Injection valve in “inject position”, The target compound is back flushed out of the pre-clean-up-column onto the separation column (III) by the HPLC mobile phase. The finely purification takes place on the separation column. The eluate is fractionated and the target compound is collected in the common way.For the purification of [18F]FDOPA from the critical radiochemical impurity [18F]fluoride a pre-clean-up-column filled with polymer-based reversed phase (RP) material is used. The finely separation was performed on a silica-based RP column.In case of [18F]FMeMcN 5652 production the clean-up from the solvent, needed for the radiolabeling, and the finely separation is carried out on columns filled with silica-based RP materials. Results: ...........................................................................[18F]FDOPA............................[18F]FMeMcN HPLC purification method ...........................................................................[18F]Fluoride [%].....................DMF [mg/ml] ------------------------------------------------------------------------------------------------------------------------------ Injection loop.........................................................7.7 (n=93)..............................1.4 (n=5) Pre-clean-up-column............................................1.4 (n=25)..............................< 0.001 (n=4) Conclusions: Using the interlinked on-line SPE / HPLC system, reaction mixtures of radiopharmaceutical synthesis can be cleaned up and disturbing matrix components can be separated from the target compound more efficiently.

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Aim: Replacement of the ecologically harmful solvent Freon 11 (CFCl3) by chloroform for the module-assisted preparation of 6-[18F]fluoro-L-DOPA based on the electrophilic radiofluorodestannylation of the precursor N-formyl-3,4-di-tert-butoxycarbonyloxy-6-(trimethylstannyl)-L-phenylalanine ethyl ester. Materials and methods: The TRACERlab Fx FDOPA module (GE Medical Systems) was used for the preparation of 6-[18F]fluoro-L-DOPA. Cyclotron-produced [18F]F2 gas (5 GBq) was passed through a cooled solution (5°C) of the stannyl precursor (45 mg) in CDCl3 (10 ml). After the [18F]fluorination step, HCl (2 ml, 6 M) was added to the solution. Then the reaction mixture was heated at 80°C for 5 min under vacuum to evaporate the chloroform. The hydrolysis to remove the protecting groups was completed by heating the closed reactor at 130°C for 8 min. After cooling to 20°C the reaction mixture was purified by HPLC with two polymer-based RP columns (PRP 1, 7 μm, 10×250 mm, Hamilton) using a solution of AcOH/AcONa (pH 4.7) as eluent. The [18F]fluoro-L-DOPA fraction was collected and sterile filtrated. Results: Three types of stabilised chloroform were tested for the radiofluorination of the precursor. Only by use of deuterochloroform stabilised with silver no significant losses of radioactivity were observed. Thus, 6 [18F]fluoro-L-DOPA purified by HPLC was obtained in decay-corrected radiochemical yields of 25±3%, ready for human use. Conclusion: CDCl3 has proved to be a convenient solvent for the module-assisted preparation of 6-[18F]fluoro-L-DOPA. In this way the use of the polluting Freon 11 can be avoided.

Context: In congenital hyperinsulinism (CHI), the identification and precise localization of a focal lesion is essential for successful surgery. Objective: Our objective was to evaluate the predictive value and accuracy of integrated [F-18] fluoro-L-DOPA ([F-18]FDOPA) positron emission tomography (PET)-computed tomography (CT) for the surgical therapy of CHI. Design: This was an observational study. Setting: The study was performed in the Department of Pediatric Surgery at a university hospital. Patients: From February 2005 to September 2007, 10 children with the clinical signs of CHI and an increased radiotracer uptake in a circumscribed area of the pancreas in the [F-18]FDOPA PET-CT were evaluated. Interventions: Guided by the [F-18]FDOPA PET-CT report, all children underwent partial pancreatic resection, in two cases twice. Main Outcome Measures: Correlation of the anatomical findings at surgery with the report of the [F-18] FDOPA PET-CT, and the results of surgery and clinical outcome were determined. Results: In nine children the intraoperative situation corresponded exactly to the description of the [F-18] FDOPA PET-CT. A limited resection of the pancreas was curative in eight cases at the first surgery, in one case at the second intervention. We observed no diabetes mellitus or exocrine insufficiency in the follow up so far. In one child, hypoglycemia persisted even after two partial resections of the pancreatic head. Histological analysis finally revealed an atypical intermediate form of CHI. Conclusions: The integrated [F-18]FDOPA PET-CT is accurate to localize the lesion in focal CHI and is a valuable tool to guide the surgeon in limited pancreatic resection.

In recent years, considerable progress has been made in the biochemical, morphological and molecular genetic differentiation of congenital hyperinsulinism (CHI). Fluorine-18 L -3,4-dihydroxyphenylalanine positron emission tomography ( 18 F-DOPA-PET) has been introduced for differentiation between focal and diffuse CHI. The ability to take up L -DOPA and convert it into dopamine is correlated with the activity of the aromatic amino acid decarboxylase and increased in the hyperfunctional affected pancreatic area in comparison to normally functioning pancreas. The high sensitivity of this method allows the surgeon to perform a curative limited resection of a focus without the risk of long-term diabetes. The exact preoperative planning by 18 F-DOPA-PET/CT computer tomography allows laparoscopic operation in selected cases with the focus in the tail and limits necessity to open the pancreatic duct in cases with focus in the head. Patients with persistent CHI should be managed within a strong network of diagnostic, treatment, and research institutions.

Aim: Amino acid PET has become an important diagnostic tool for brain tumour imaging. In this data analysis, the potential impact of amino acid PET with 3-O-methyl-6-[18F]fluoro-L-DOPA ([18F]OMFD) on radiation treatment planning is addressed by the following questions: 1. Was tumour tissue identified with OMFD-PET which was not covered by the conventionally derived planning target volume (PTV)? 2. Would the PTV have been changed incorporating OMFD-PET? Patients, methods: OMFD-PET of 25 patients after subtotal resection of malignant glioma was evaluated. The region of elevated tracer uptake of PET and of contrast enhancing masses on MRI were outlined as separate gross tumour volumes (GTVMRI and GTVOMFD) and reconstructed in the planning CT for comparison with the conventionally drawn GTVconv. A PTVnew based on GTVconv+MRI was calculated. Pairwise differential volumes were calculated to estimate overlap and differential volumes delineation by each image modality and the PTVconv and PTVnew respectively. Results: Differential volume analysis showed > 10 cm3 of GTVOMFD outside GTVconv and GTVMRI in 5/25 patients respectively. From GTVMRI >10 cm3 were found outside GTVOMFD in 8/25 patients. Although all tumour areas indicated by [18F]OMFD were covered by the conventionally derived PTV, based on a GTVOMFD+MRI, the PTVnew would have been enlarged >20% in seven patients. In seven patients the PTVnew would have been reduced. Conclusion: OMFD-PET indicated tumour tissue outside the tumour region identified with MRI, adding valuable information for the delineation of the GTV in radiation treatment planning. OMFD-PET contains the potential to tailor the high dose radiation to the appropriate tumour volume, especially if dose escalation is desired.

Aim: Characterisation of the influence of different polymeric tube materials of a water target system, used for the production of 18F activity, on the specific activity of radiotracers. Material, methods: Target water samples taken from different locations of the 18F water target system of a Cyclone® 18/9 cyclotron, equipped with Teflon® (PTFE) or polypropylene (PP) tubes, were analyzed for non-radioactive [19F]fluoride content. [19F]Fluoride content was measured by ion chromatography (IC20, Dinoex) with suppressed conductivity detection. Both the ion chromatographic results and the amount of 18F activity produced were used for the calculation of the specific activity (SA) of [18F]fluoride at the start of the labelling synthesis. To check these results, the SA of the labelled receptor ligand [18F]ZK811460 was also determined by using the different tubing materials. Results: Dose-exposed PTFE tubes of the target dispensing (loading) system were identified to be a major source of [19F]fluoride contamination. Conclusion: By replacing PTFE tubes of the target dispensing system with PP tubes, the content of 19F was reduced considerably resulting in an increase of SA of the radiotracer [18F]ZK811460 by factor of two.

Expression of system L amino acid transporters (LAT) is strongly increased in many types of tumor cells. The purpose of this study was to demonstrate that 18F-labeled amino acids, e.g., 3-O-Methyl-6-18F-Fluoro-L-Dopa (18F-OMFD), that were accumulated in tumors via LAT, represent an important class of imaging agents for visualization of tumors in vivo by positron emission tomography (PET). Methods: In the present study 18F-OMFD uptake kinetics, transport inhibition, and the system L mRNA expression were studied in vitro in human adenocarcinoma (HT-29), squamous cell carcinoma (FaDu) cells, macrophages (THP-1) and primary aortic endothelial cells (HAEC), and in vivo in the corresponding mouse tumor xenograft models. Results: It was demonstrated that uptake of 18F-OMFD in all cell lines tested was mediated mainly by the sodium-independent high-capacity LAT. We found an increased uptake in FaDu cells (Vmax 10.6±1.1 nmol/min ´ mg cell protein) and in the corresponding FaDu tumor xenografts in comparison to the other cells and corresponding xenograft models studied. Quantitative mRNA analysis revealed that tumor cells and xenografts have a higher expression of LAT1 compared to HAEC and THP-1 macrophages. However, only in the FaDu tumor model an increased OMFD uptake seems to be explained by increased LAT expression. Furthermore, we demonstrated a high expression for LAT4, a recently new identified system L amino acid transporter. Conclusion: Our findings support the hypothesis that 18F-OMFD is a tracer for visualization of tumor cells, and, in particular, seems to be a suitable tracer for diagnostic imaging of amino acid transport in poorly differentiated squamous cell head and neck carcinoma with increased LAT1 and LAT4 expression.

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System L amino acid transport is increased in various types of cancer. The new positron emission tomography (PET) tracer 3-O-methyl-6-18F-fluoro-L-DOPA (OMFD) is mainly accumulated via the system L and could serve to image cancer in vivo. However the differentiation between tumor and inflammatory reaction in tissues is often complicated. Therefore, we studied in vitro the accumulation mechanisms of OMFD in model systems of human tumors and inflammation, respectively. It is suggested that the high uptake of amino acid tracers is primarily caused by the higher transporter expression in tumors when compared to other tissues, e.g., inflammatory cells. As previously shown, the subtype L-type amino acid transporter 1 (LAT1) is playing a key role of L amino acid transport in tumor cells. The functional LAT1 is a heterodimeric complex comprising a single membrane-spanning catalytic light chain protein (hLAT1) and the heavy chain of 4F2 antigen (h4F2hc), which are covalently linked via a disulfide bond. For molecular characterization of L-type amino acid transporters focusing on the hLAT1-h4F2hc subtype quantitative RT-PCR was performed using the two different human tumor cell lines FaDu (squamous cell carcinoma) and HT-29 (colorectal adenocarcinoma). In comparison, phorbol ester stimulated THP-1 cells (a human monocyte/macrophage cell line) representing inflammatory cells were used. In vitro uptake assays were performed with HT-29, FaDu and THP-1 cells with OMFD under physiological amino acid concentrations. OMFD demonstrated a saturable and sodium- and energy-independent accumulation in vitro in the different tumor cell lines, suggesting its uptake to be mediated mainly by sodium-independent LAT1. However, OMFD showed a significantly higher uptake in tumor cells when compared to inflammatory cells. Our data demonstrate that OMFD could be a promising PET tracer for imaging of specific amino acid transport via LAT1 in tumors and, furthermore, for possible differentiation of tumorigenic from inflammatory processes. In conclusion, the identification and characterization of tumor specific amino acid transporters like LAT1 will be a helpful tool for diagnosis and therapy monitoring.

Ziel/Aim: Die Bestrahlungsplanung beruht auf einem komplexen Zielvolumenkonzept, dass die Tumorregion erfassen (gross tumor volumen,GTV), subklinische Tumorausdehnung beinhalten und Lagerungsinkonsistenzen zwischen den einzelnen Bestrahlungsfraktionen ausgleichen soll (planning target volumen, PTV). Der Einfluss der OMFD-PET auf die Bestrahlungsplanung von Hirntumoren wurde anhand folgender Fragen untersucht: Wurden mit OMFD-PET Tumorareale angezeigt, die nicht vom konventionell erstellten PTV erfasst wurden? Könnte das Einbeziehen von OMFD-PET in die Bestrahlungsplanung das PTV im Vergleich zur konventionellen Planung potenziell verkleinern? Methodik/Methods: Bei 30 Patienten mit malignen Hirntumoren wurde OMFD-PET nach subtotaler Resektion und vor Strahlentherapie durchgeführt. Die PET-Daten und soweit vorhanden prä- und postoperative T1-gewichtete MRT-Studien wurden retrospektiv mit dem Planungs-CT am Bestrahlungsplanungssystem Pinnacle 3 überlagert. Die Tumorareale im PET und Kontrastmittelanreicherung im MRT wurden als einzelne GTV markiert und in das Planungs-CT integriert. Es erfolgte der Vergleich der GTV-OMFD und GTV-MRTprä/post mit dem GTV-konv, das allein auf dem Planungs-CT und der visuellen Bildbeurteilung des MRT beruht. Ergebnisse/Results: Bei 28 von 30 Patienten war Tumorgewebe mittels OMFD-PET abgrenzbar. Ein Patient zeigte einen multifokalen Befall, so dass die primär kurative Therapieintention in ein palliatives Konzept geändert wurde. Alle im OMFD-PET abgrenzbaren Tumorregionen waren im konventionell erstellten PTV enthalten. Die mittleren Volumina betrugen 69,2 #±# 42,2ccm für das GTV-konv, 48,0 #±# 43,8ccm für das GTV-MRTprä, 16,8 #±# 15,5ccm für das GTV-MRTpost und 14,8 #±# 12,3ccm für GTV-OMFD. Der differentielle Vergleich der Volumina ergab, dass bei 5 von 29 Patienten mehr als 10 ccm der GTV-OMFD außerhalb des GTV-konv und bei 8 von 26 Patienten außerhalb des GTV-MRTpost lokalisiert waren. Bei 6 von 26 Patienten lagen mehr als 10ccm des GTV-MRTpost außerhalb des GTV-OMFD. Schlussfolgerungen/Conclusions: Die funktionelle Bildgebung von Hirntumoren mittels OMFD-PET detektiert relevantes Tumorgewebe außerhalb der im MRT detektierten Tumorregion und erbringt somit wichtige Informationen für die Abgrenzung des GTV für die Bestrahlungsplanung. Multimodale Strahlentherapieplanung beinhaltet das Potential die Hochdosisregion genauer abgrenzen und so möglicherweise die Ausdehnung des PTV begrenzen zu können.

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The 11C-labelling of the taxane derivative BAY 59-8862 (1), a potent anticancer drug, was carried out as a module-assisted automated multi-step synthesis procedure. The radiotracer [11C]1 was synthesized by reacting [1-11C]acetyl chloride (6) with the lithum salt of the secondary hydroxy group of precursor 3 followed by deprotection. After HPLC purification of the final product [11C]1, its solid phase extraction, formulation and sterile filtration, the decay-corrected radiochemical yield of [11C]1 was in the range between 12 and 23% (related to [11C]CO2; n = 10). The total synthesis time was about 54 min after EOB. The radiochemical purity of [11C]1 was greater than 96% and the chemical purity exceeded 80%. The specific radioactivity was up to 20 GBq/µmol at EOS starting from 80 GBq of [11C]CO2.

The synthesis of 1-(5-chloro-2-{2-[(2R)-4-(4-[18F]fluorobenzyl)-2methylpiperazin-1-yl]-2-oxoethoxy}phenyl)urea ([18F]4), a potent nonpeptide CCR1 antagonist, is described as a module-assisted two-step one-pot procedure. The final product was obtained utilizing the reductive amination of the formed 4-[18F]fluorobenaldehyde with a piperazine derivative and sodium cyanoborohydride. After HPLC purification of the final product ([18F]4, its solid phase extraction, formulation and sterile filtration, the isolated (not decay-corrected) radiochemical yields of ([18F]4 were between 7 and 13% (n=28). The time of the entire manufacturing process did not exceed 95 min. The radiochemical purity of ([18F]4 was higher than 95%, the chemical purity ≥60% and the enantiomeric purity >99.5%. The specific radioactivity was in the range of 59-226 GBq/µmol at starting radioactivities of 23.6-65.0 GBq ([18F]fluoride

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There is evidence that intrauterine growth restriction (IUGR) is associated with altered dopaminergic function in the immature brain. Compelling evidence exists that in the newborn brain, specific structures are especially vulnerable to O2 deprivation. The dopaminergic system is shown to be sensitive to O2 deprivation in the immature brain. However, the respective enzyme activities have not been measured in the living neonatal brain after IUGR under hypercapnic hypoxia (H/H). Therefore, 18F-labeled 6-fluoro-L-3,4-dihydroxyphenylalanine (FDOPA) together with positron emission tomography was used to estimate the aromatic amino acid decarboxylase activity of the brain of seven normal weight (body weight 2078 +/- 434g) and seven IUGR newborn piglets (body weight 893 +/- 109 g). Two positron emission tomography scans were performed in each piglet. All animals underwent a period of normoxia and moderate H/H. Simultaneously, cerebral blood flow was measured with colored microspheres and cerebral metabolic rate of O2 was determined. In newborn normal-weight piglets, the rate constant for FDOPA decarboxylation was markedly increased in mesostriatal regions during H/H, whereas brain oxidative metabolism remained unaltered. In contrast, moderate H/H induced in IUGR piglets a marked reduction of clearance rates for FDOPA metabolites (p < 0.05), which was accompanied by a tendency of lowering the rate constant for FDOPA conversion. Furthermore, IUGR piglets maintained cerebral O2 uptake in the early period of H/H, but during the late period of H/H, a significantly reduced cerebral metabolic rate of O2 occurred (p < 0.05). Thus, IUGR is accompanied by a missing activation of dopaminergic activity and attenuated brain oxidative metabolism during moderate H/H. This may indicate endogenous brain protection against O2 deprivation.

An increasing number of PET centers is using 6-[18F]fluoro-L-DOPA ([18F]FDOPA) to study presynaptic dopamine metabolism in vivo. Currently the electrophilic radiofluoro-destannylation reaction of N-Boc-3,4-di(Boc-O)-6-trimethylstannyl-L-phenylalanine ethyl ester with [18F]F2 has emerged as the preparation method of choice for the reliable and reproducible radiosynthesis of [18F]FDOPA (1-5). Up to now the radiofluorination step of the trimethyltin precursor is carried out in trichlorofluoromethan (CFCl3, Freon 11) as the solvent. De Vries et al. (4) have reported Freon 11 as the superior solvent to provide the highest radiochemical yields for the radiofluorination step. The authors also have investigated the possibility to substitute Freon 11 with other solvents. They observed considerable losses of radioactivity (61-71%) during the evaporation step of the solvents (e.g. chloroform and acetonitrile). They discussed this finding with the formation of volatile radiofluorine compounds originating from the reaction of [18F]F2 gas with the solvents. For Freon 11 is hardly available in Europe for environmental protection reasons, we investigated the possibility of substituting Freon 11 with chloroform. In contrast to (4) we use 5 M HCl for protecting group hydrolysis. The acid is added directly after the radiofluorination step and the solvent was evaporated at 130°C. First results with chloroform also show increased losses of radioactivity in comparison to Freon 11. However, we found that the rate of radioactivity loss depends on the quality of the chloroform used. The radioactivity losses using chloroform stabilised with ethanol were in the range of 25%, whereas the amylene stabilised chloroform gave losses of 40%. In contrast, using deuterated chloroform (CDCl3) for NMR analysis purposes stabilised with silver no significant losses of radioactivity were observed in comparison with Freon 11. We conclude that no competitive radiofluorination of the solvent chloroform, neither CHCl3 nor CDCl3, with [18F]F2 occures. Instead of that the observed radioactivity losses can be explained by the radiofluorination of stabilisers present in CHCl3.The non-decay-corrected total yield for [18F]FDOPA preparation using Freon 11 as the solvent is 17% (n = 26). Using CDCl3 (silver stabilised) instead of CFCl3 the average non-decay-corrected total yield is slightly higher, being 20% (n = 17). The use of CDCl3 has further advantages: - easy handling (boiling point = 61°C) and unlimited availability, - better environmental protection properties, - the radiofluoro-destannylation reaction can be carried out at temperatures above freezing-point The results of our investigations indicate the possibility to substitute Freon 11 with CDCl3 stabilised with silver.

Objectives: PET imaging of cardiac reporter gene expression holds promise for noninvasive monitoring of gene therapy. Two approaches based on herpesviral thymidine kinase gene(HSV1-tk) habe been applied. Wild-type HSV1-tk was imaged with 2´-fluoro-2´-deoxy-5[124I]-iodo-arabinofuranosyluracil([124I]FIAU), and mutant HSV1-sr39tk was imaged with 9-[4-[18F]-fluoro-3-(hydroxymethylbutyl)guanine([18F]FHBG). Methods: Adenovirus expressing wild-type HSV1-tk(Adtk), mutant HSV1-sr39tk (Adsr39tk), or control gene (AdLacZ) were directly injected into myocarcardium of 24 rats and 8 pigs. Two days later, dynamic PET imaging was performed for 120 min after injection of [124I]FIAU or [18F]FHBG with a clinical scanner. Imaging with [13N]-ammonia was performed to identify cardiac regions of interest. Pig hearts were sliced into 5 short-axis slices for ex vivo imaging, and regional tracer uptake was analyzed. Results: For [124I]FIAU, the largest difference of cardiac uptake between Adtk rats and controls was found at 10-30 min after injection (1.7±0.25 vs 0.87±0.22 %dose/ml, p=0.035). No difference was observed at later imaging times due to [124I]FIAU washout. For [18F]FHBG, difference between Adsr39tk rats and controls continuously increased over time and was largest at 105-120 min (1.45±0.45 vs 0.35±0.05 %dose/ml, P=0.0066). Global cardiac reporter probe kinetics in rats was confirmed by regional myocardial analysis in pigs. Transgene expression was specifically visualized by both approaches. Highest target/background ratio of [124I]FIAU in Adtk infected myocardium was 1.50±0.20 vs 2.64±0.49 for [18F]FHBG in Adsr39tk infected areas (P=0.01). In vivo results of rats were confirmed by ex vivo counting and autoradiography. In vivo segmental reporter probe uptake in pigs correlated well with those in ex vivo images. Conclusions: Both combinations were feasible for PET of cardiac transgene expression in different species. Specific probe kinetics suggests different myocardial handling of pyrimidine ([124I]FIAU) and acycloguanosine ([18F]FHBG) derivatives. Results are in favour of [18F]FHBG because of continuous accumulation over time and higher imaging contrast.

Pigs of three different age groups (newborns, 1 week old, 6 weeks old) were used to study the transport of the large neutral amino acids 6-[F-18]fluoro-L-DOPA ([F-18]FDOPA) and 3-O-methyl-6-[F-18]fluoro-L-DOPA ([F-18]OMFD) across the blood-brain barrier (BBB) with positron emission tomography (PET). Compartmental modeling of PET data was used to calculate the blood-brain clearance (K-1) and the rate constant for the brain-blood transfer (k(2)) of [F-18]FDOPA and [F-18]OMFD after i.v. injection. A 40-70% decrease of K-1(OMFD), K-1(FDOPA) and k(2)(OMFD) from newborns to juvenile pigs was found whereas k(2)(FDOPA) did not change. Generally, K-1(OMFD) and k(2)(OMFD) are lower than K-1(FDOPA) and k(2)(FDOPA) in all regions and age groups. The changes cannot be explained by differences in brain perfusion because the measured regional cerebral blood flow did not show major changes during the first 6 weeks after birth. In addition, alterations in plasma amino acids cannot account for the described transport changes. In newborn and juvenile pigs, HPLC measurements were performed. Despite significant changes of single amino acids (decrease: Met, Val, Leu; increase: Tyr), the sum of large neutral amino acids transported by LAT1 remained unchanged. Furthermore, treatment with a selective inhibitor of the LAT1 transporter (BCH) reduced the blood-brain transport of [F-18]FDOPA and [F-18]OMFD by 35% and 32%, respectively. Additional in-vitro studies using human LAT1 reveal a much lower affinity of FDOPA compared to OMFD or L-DOPA. The data indicate that the transport system(s) for neutral amino acids underlie(s) developmental changes after birth causing a decrease of the blood-brain barrier permeability for those amino acids during brain development. It is suggested that there is no tight coupling between brain amino acid supply and the demands of protein synthesis in the brain tissue. (C) 2004 Elsevier B.V. All rights reserved.