Introduction In last decade increasing demand for clinical F-18 Fludeoxyglucose requires a greater F-18 fluoride production. From the other side increasing price of enriched O-18 water compel us to find the most effective way of F-18 activity production. One of the possible way, how to optimize and increase yield of F-18, is to increasing target current with retaining the same or less volume of enriched water. Optimization of F-18 production on IBA Large Volume cylindrical target is presented. Material and Methods Irradiations of [18O]H2O by 18MeV proton beams with intensities 40–55 μA were performed on CYCLON 18/9, IBA cyclotron and on LV cylindrical IBA target. Irradiated enriched water was transported to the hot cell using RDS (Radioactive Delivery System) system and was measured in Curriementor 4 Isotope Calibrator made by PTW. At the beginning it was necessary to satisfy several requirements: i) target and water cooling. Using a simple two dimensional equation we can roughly estimate the equilibrium temperature inside the target [1]: Δt = HT/Ak where: Δt = the temperature rise in the target chamber over cooling water temperature H = is the heat load T = thickness of metal wall A = area of metal in contact with target water k = thermal conductivity In our case with heat load 720 W (40 μA×18 MeV) is Δt = 78 oC. From the curve of boiling point of water as a function of pressure [2], we can observe t = 212 °C at 20 bar or 243 °C at 35 bar, respectively, which corresponds to max. heat load up to 90–95 µA of target current. ii) pressure and filling water volume. Filling water volume was from 2 to 2.15 ml to guarantee stop all beam in water. Also during experiments for safety reasons the operating pressure was limited to 35 bar as the window rupture pressure is > 50 bar for used 0.05 mm Havar foil. In this case increasing target volume with increasing current was provided with longer tube. Results and Conclusion The saturated yields of F-18 for 40 µA to 55 µA target currents are given in TABLE 1. No systematic decrease in yields with increasing target current was observed and yields were in line with the 230 ± 10 mCi/µA measured at acceptance test of target. The [18F]FDG yields from productions using the TRACERlab-Mx module are shown in FIGURE 1. All presented productions of F-18 were prepared with LV target with 55 µA. No decrease in the yield was observed with increasing beam current. It has been demonstrated that it is possible to produce routinely 250 GBq/2hr (6.8 Ci/2hr) of 18F-Fluoride using LV cylindrical target (operating conditions: 55 µA, 18 MeV, 98% enriched water). As the next step we want to test dual beam – 2×55 µA with two LV targets and expected activity about 500 GBq of 18F-Fluoride in 2 hours is expected.

Ce travail de thèse réalisé à l’Institut de Chimie Moléculaire de l’Université de Bourgogne et en collaboration avec le PET Research Centre, porte sur la synthèse d’une nouvelle classe de pinces à fluorures dérivés d’aminoacides dans le but de piéger les ions [18F]-fluorures par formation d’une liaison B-F et d’évaluer leur potentiel en tant qu’agent d’imagerie TEP. Les travaux ont tout d’abord concerné la conception, la synthèse et la caractérisation des nouveaux sels de phosphoniums boronatés et trifluoroborates dérivés d’aminoacides. Ainsi, par quaternisation de l’o-boronate phényl phosphine avec des β-iodo amino esters ou des γ-iodo amino esters, les sels correspondants sont obtenus sans racémisation et avec des rendements atteignant 88%. La saponification des phosphoniums boronatés aminoesters donne les dérivés avec la fonction acide libre, tandis que l’acidolyse par HCl mène à l’amine correspondante offrant ainsi, l’opportunité d’un couplage ultérieur à une biomolécule. Ensuite, les dérivés trifluoroboratés sont facilement préparés par réaction de KHF2 en solution dans un mélange hydroalcoolique. Les études de stabilités en milieux aqueux des phosphoniums o-trifluoroborates aminoacides ont permis d’établir que ces dérivés sont extrêmement stables à l’hydrolyse. Enfin, la [18F]-radiosynthèse des sels de phosphonium boronatés a été étudiée selon deux méthodes: par échange isotopique 18F-19F direct à partir d’un trifluoroborate et par marquage direct d’un sel de phosphonium boronaté en présence d’un mélange de fluorures [18F] et KHF2. Intéressement, après une synthèse totale de 50 minutes comprenant le séchage azéotropique, la synthèse et la purification, [18F]-203c a été obtenu avec un rendement radiochimique de 10% corrigé de la décroissance, une pureté radiochimique ≥97% et une activité spécifique de 0.13 GBq/µmol. / This thesis project, which is part of a collaboration between the Institut de Chimie Moléculaire de l’Université de Bourgogne and the Positron Emission Tomography Research Centre, is about the synthesis of fluoride pincers derived from amino acids based on 18F-B bond construction to get a new class of PET imaging agents. First, this project concerned the design, synthesis and characterisation of new boronato and trifluoroborato phosphonium amino acid salts. Quaternisation of o-boronate phenyl phosphine with β-iodo amino esters or γ-iodo amino ester leads to the corresponding salts without racemisation and in yields up to 88%. Saponification of boronato phosphonium amino esters afford the free carboxylic acid derivatives, whereas HCl acidolysis leads to the corresponding amino compounds which offers the opportunity of further biomolecule coupling. Then, o-trifluoroborate phosphonium salts are efficiently prepared by reaction with KHF2 in solution on hydroalcoholic mixture. The kinetic stabilities of these o-trifluoroborate phosphoniums have shown extremely stable compounds to hydrolysis. Finally, [18F]-radiosyntheses of phosphonium salts was studied according to two methods : by 18F-19F isotopic exchange from trifluoroborate or by carrier added preparation of [18F]-fluoride ions from boronate phosphonium salts. Satisfactingly, after a total synthesis of 50 minutes (including azeotropic drying, synthesis and purification), [18F]-203c was obtained with a RCY on 10% decay corrected, a RCP ≥ 97% and a specific activity of 0.13 GBq/µmol.

Introduction The increasing demand for [18F]FDG for clinical PET-CT and the efficiencies associated with large production runs have encouraged endeavors to increase the amount of 18F− produced by cyclotrons in a single run. The amount of 18F− is determined by the saturation yield of the nuclear reaction, the irradiation time and the beam current striking the target. The saturation yield is a function of beam energy (typically fixed for PET cyclotrons), the enrichment of the H218O (typically > 97 %) and the efficiency of the target design. Target design has already been optimized on current systems. Diminishing gains in activity are achieved by extending the irradiation time much beyond 3 hrs, so the main focus has been to increase beam current onto the targets. Increasing the beam current requires: i) a cyclotron capable of producing the increased beam current; ii) targets that tolerate the beam current without appreciable loss in saturation yield; iii) sufficient shielding of the cyclotron and hot cells to accommodate the proportionally larger radiation dose rates during higher current irradiation and from the larger activities delivered to the hot cells. We reported [1] that the self-shielded targets fitted to our cyclotron can accommodate 100 µA currents without appreciable loss in saturation yield. We also identified the potential of routine production at 200 A (100 A per target in dual target irradiation mode), but had not establish its long-term viability in routine use. We present our experience in using 200 µA for routine production of 18F- since September 2012. Material and Methods Our PETtrace cyclotron was installed in 2002 and has been used for routine production of various 18F and 11C tracers since January 2003. It has been upgraded incrementally so that it is now equivalent to a current generation PETtrace 880 cyclotron, which is specified at a total beam current of 130 µA. The only components on our cyclotron currently not part of the standard PETtrace 880 cyclotron configuration are the self-shielded targets and a license which allows total target beam current of 200 µA. The self-shielded targets utilize a W/Cu alloy for the main body of the target surrounding the Havar foil to provide shielding from the Havar foil by a factor of about 10 and shielding of any remnant 18F- activity in the targets by a factor of about 100 [1]. The niobium target chamber is the same size as used in the standard GE Nb25 targets. However, it dispenses with the He cooling and the vacuum foil. Only the water foil is used, which is directly exposed to the vacuum in the chamber. Foil cooling is through the water in the target chamber. One of the issues that we previously identified [1] is beam stripping by gas molecules in the vacuum tank. The amount of beam that is stripped and which impacts on components in the cyclotron is proportional to the beam current. At high currents, this can result in a runaway condition, where the effects of the stripped beam deteriorate vacuum; this then results in more beam stripping and more severe effects. The effect of diffusion pump maintenance on vacuum system performance and on the reduction of beam stripping was investigated as part of this study. We have previously found that running the ion source gas at a low flow rate (2 sccm) when cyclotron is not used greatly reduces deterioration of ion source performance over time and with use [1]. This gas flow also appears to have a beneficial effect on the vacuum. Ion source gas flow when cyclotron is off has been employed throughout the evaluation period. [18F]FDG was produced with TRACERlab MXFDG modules or FASTlab modules using both Phosphate and Citrate cassettes. Stability studies of [18F]FDG were performed to ensure it met specifications over the specified expiry time. Our current stabilization regime did not have to be adjusted for the higher activities produced with the higher beam currents. [18F]FDG yields were calculated using input activity estimates from saturation yield and beam time and current and the non-decay corrected [18F]FDG activity measured at the end of synthesis. Thus yield calculations include target yield variations and losses in the transfer lines and not just synthesis yield. Results and Conclusion The flip-in probe to extraction foil transmissions as a function of ion source gas flow are given in TABLE 1. Transmission decreases with increasing ion source gas flow, as expected for a system with an internal ion source. In addition, diffusion pump maintenance had a positive impact on the transmission and this is of particular benefit at the higher beam currents where minimising beam stripping becomes more critical. The ion source output, however, decreases with decreasing ion source gas flow; hence ion source gas flow is a compromise between ion source output and probe to foil transmission. We currently use a gas flow of 5.5 sccm for our 200 µA runs. Over the period from 1st September 2012 to end of March 2014, a total of 419 [18F]FDG produc-tions were performed at total target beam currents ranging from 160 µA to 200 µA, with 227 production runs being performed at 200 µA. Beam times were typically 90 to 120 min, with some productions up to 180 min. The [18F]FDG yields are summarized in TABLE 2. The yields for the FASTlab phosphate and citrate cassettes have been listed separately in TABLE 2 as they are known to be different [2,3]. The yields obtained with the TRACERlab MXFDG are also shown. The yields at 200 µA total target current are not appreciably different from those at < 200 µA current, irrespective of the synthesis method. Consistency of yield is also not adversely impacted by the higher beam current. For a 180 min, 200 µA test production, the [18F]FDG activity produced using the FASTlab phosphate cassette was 763 GBq (20.6 Ci). Clinical productions with the FASTlab phosphate were limited to 130 min maximum beam time for 200 µA and achieved a maximum [18F]FDG activity of 656 GBq (17.7 Ci). The tolerance to a reduction in performance of the critical components to achieve high current operation (RF, ion source output and vacuum system) is reduced at high beam currents. The requirements for routine maintenance of ion source, targets and extraction system, however, have not increased with the increase in beam current from 160 µA to 200 µA. Extraction foil life and ion source maintenance intervals have remained at about 2000 Ah and >120 µAh, respectively. As more experience has been gained with the self-shielded targets, service interval is actually being extended from about 10,000 µAh to 20,000 µAh, despite the higher beam currents. Diffusion pump maintenance is currently recommended every 5 years, but a 2 year maintenance interval may be advantageous for 200 µA, given the observed deterioration over a 5 year period and the improvement in performance post service (Table 1). The more frequent service is associated with the additional costs of diffusion pump oil and an extra day of scheduled down-time. Typically, vacuum is sufficiently well established 24 h after opening of the vacuum tank to run 200 µA beams with the vacuum and beam conditioning that we employ. The targets generally have coped well with the 100 µA per target current (200 µA total beam current for dual target irradiation) over this 18 month period. However, currents of 80 µA to µ100 A per target in dual target irradiation mode reduce the tolerance to sudden increases in one of the target currents. There were 4 occasions (2 test beams and 2 production beams) when there were sudden increases of target current from 90 µA and 100 µA to about 150 µA. The rapid increase in heat deposited on the foil and target chamber and the resultant rapid pressure rise in the target chamber could not be withstood by the foil and target foil rupture ensued. This compared to 1 target foil issue over a similar period of time (18 months) at lower beam currents on the standard Nb25 target. Three separate causes were identified for these overshoots in target current: 1) behavior of control system when beam is allowed to continue past the set time; 2) large changes of set current of one of the two targets irradiated during a dual irradiation test beam and 3) an issue with DEE voltage regulation caused by the mechanical flap controls. These issues have been addressed by procedural changes (issues 1 and 2) and by fitting an available upgrade of the mechanical flap control mechanism (issue 3). The two target foil ruptures during production did not cause cancellation or delays to patient scanning, as the demand could be met by multi-ple productions and deliveries from the unaf-fected target. No unscheduled down-days occurred during the evaluation period. We have been able to achieve routine operation at 200 µA beam current through careful optimization of the critical components and parameters and a maintenance regime that we have detailed previously [1]. This maintenance scheme has not changed for the routine 200 µA operation. The safety margin, however, is reduced and so careful monitoring of the system is required to ensure that issues in one of the subsystems do not cause major events such as target foil ruptures. Our [18F]FDG yields have been maintained at the higher current and 200 µA allows large quantities of [18F]FDG to be produced routinely in a single run with relatively short beam times.

Introduction In order to address the increasing demand for Fluorine-18 and the rising cost per mL of 18O enriched water, IBA developed improvements to their 18F- production systems. For this new design we started from scratch, with the main objectives of reducing the required enriched water volume and improving the cooling of the insert. A better cooling allows increasing the target current and thus the produced activity. Finally, we aimed to reduce the number of parts and improve the design of auxiliary components. Material and Methods Six Niobium conical inserts with different target chamber volumes were machined and tested. Only 4 of these were selected to create the new range of IBA 18F− targets shown in TABLE 1. The new Niobium target inserts have a complex shape with drilled channels on the outside of the chamber and a deep channel next to the beam strike area (FIG. 1, green circle) to ensure efficient cooling. The 18O water inlet lines are now directly inserted in the Niobium body (FIG. 1, blue circle) to improve 18F- quality (no more contact with small o-rings). In operation, a 35µm Havar® target window is used. All tests were performed using IBA Cyclone® 18 cyclotron. The targets were filled with different volumes of enriched 18O water (enrichment > 92 %) and irradiated with 18 MeV protons on target with beam currents up to 145 μA for 30 to 150 minutes, while the internal pressure rise of the target was recorded. For each target, a pressure-current curve was plotted and an optimum balance between target water fill volume, pressure and current has been determined, which maximises available activity after two hours, in each case. Results and Conclusion Radionuclidic impurities were measured and more than 100 FDG syntheses on various synthesizers confirmed the effectiveness of the new design. Increasing the current up to 145µA in Conical 16, the production reached 18 Ci in 2 hours, single beam, with a target pressure under 43 bar. Today, the use of these new targets for daily commercial production is increasing within the IBA Cyclone® installed base.

Introduction Activity measurement of the produced radionuclide prior its transport to further processing in the clean rooms indicates proper irradiation settings and target functioning. It is particularly true for shortlived radionuclides. Precise online activity measurement of the radionuclides transported from the target to the hot cells in a liquid phase was highly desirable in order to estimate compliance with the required value. In this paper, we present simple operational systems for activity measurement of the irradiated enriched (18O) water for 18F labelled PET radiopharmaceuticals and 81Rb aqueous solution for manufacturing radionuclide generator 81Rb/81mKr. Material and Methods Irradiated aqueous solution (2.5 ml of enriched water with 18F up to 200 GBq) is transported via capillary to a synthesis module. Due to spreading out the liquid product on measuring vial walls, measured activity may vary up to 12 %. In order to avoid this variability, we have introduced simple system based on the measurement of several loops of the transporting capillary. The product is then evenly distributed around GM tube positioned in the loops’ centre. Typical GM tube response is displayed on FIG. 1. The data are recorded and processed online. Maximum mean value of 20 consecutive values is calculated. The GM tube response was calibrated by precise activity measurement of the same product in a calibrated ionizing chamber (Atomlab). Calibration covers full range of the produced 18F activities. Radionuclide 81Rb for the 81Rb/81mKr generator is produced via proton irradiation of pressurized enriched 82Kr gas. The product deposited on the target walls is washed out by water and transported to a container in a hot cell for filtration before transfer to a clean lab. The solution activity in the container (7–25 GBq) is measured with a GM tube in constant geometry. Typical response of the GM tube to the measured activity of 81Rb is displayed on FIG. 2. For activity determination, the mean value of 200 consecutive readouts starting from the 120th readout following maximum is used. The calibration for the whole range of the produced activities was performed via precise measurement of the cumulative 81Rb activity concentration by standard γ-spectrometry using HPGe detector. Results and Conclusion A simple operational system for online activity measurement of 18F and 81Rb in aqueous solutions using GM tube was designed, calibrated and implemented. Long term statistics show that the measured activities do not differ from the values obtained on calibrated ionizing chamber (18F) or γ-spectrometer (81Rb) for more than ± 2.5 %. The method seems to be cheap and rapid for reliable estimate of the produced activities online.

Introduction In last decade increasing demand for clinical F-18 Fludeoxyglucose requires a greater F-18 fluoride production. From the other side increasing price of enriched O-18 water compel us to find the most effective way of F-18 activity production. One of the possible way, how to optimize and increase yield of F-18, is to increasing target current with retaining the same or less volume of enriched water. Optimization of F-18 production on IBA Large Volume cylindrical target is presented. Material and Methods Irradiations of [18O]H2O by 18MeV proton beams with intensities 40–55 μA were performed on CYCLON 18/9, IBA cyclotron and on LV cylindrical IBA target. Irradiated enriched water was transported to the hot cell using RDS (Radioactive Delivery System) system and was measured in Curriementor 4 Isotope Calibrator made by PTW. At the beginning it was necessary to satisfy several requirements: i) target and water cooling. Using a simple two dimensional equation we can roughly estimate the equilibrium temperature inside the target [1]: Δt = HT/Ak where: Δt = the temperature rise in the target chamber over cooling water temperature H = is the heat load T = thickness of metal wall A = area of metal in contact with target water k = thermal conductivity In our case with heat load 720 W (40 μA×18 MeV) is Δt = 78 oC. From the curve of boiling point of water as a function of pressure [2], we can observe t = 212 °C at 20 bar or 243 °C at 35 bar, respectively, which corresponds to max. heat load up to 90–95 µA of target current. ii) pressure and filling water volume. Filling water volume was from 2 to 2.15 ml to guarantee stop all beam in water. Also during experiments for safety reasons the operating pressure was limited to 35 bar as the window rupture pressure is > 50 bar for used 0.05 mm Havar foil. In this case increasing target volume with increasing current was provided with longer tube. Results and Conclusion The saturated yields of F-18 for 40 µA to 55 µA target currents are given in TABLE 1. No systematic decrease in yields with increasing target current was observed and yields were in line with the 230 ± 10 mCi/µA measured at acceptance test of target. The [18F]FDG yields from productions using the TRACERlab-Mx module are shown in FIGURE 1. All presented productions of F-18 were prepared with LV target with 55 µA. No decrease in the yield was observed with increasing beam current. It has been demonstrated that it is possible to produce routinely 250 GBq/2hr (6.8 Ci/2hr) of 18F-Fluoride using LV cylindrical target (operating conditions: 55 µA, 18 MeV, 98% enriched water). As the next step we want to test dual beam – 2×55 µA with two LV targets and expected activity about 500 GBq of 18F-Fluoride in 2 hours is expected.

L'athérosclérose est une maladie progressive qui peut débuter durant l'enfance et s'aggraver en vieillissant. De nos jours, les chercheurs ne l'étudient plus comme une maladie focale caractérisée par des symptômes produits par des sténoses mais plutôt comme une maladie systémique typifiée par des dysfonctions endothéliales et par l'inflammation. La tomographie d'émission par positrons (TEP), utilisée avec le fluorodésoxyglucose (FDG), est une technique d'imagerie non invasive qui fournit des images tomographiques de l'activité glycolytique dans les athéromes. Cette recherche a demandé une étude répétée de la consommation de FDG dans l'aorte et les artères iliaques et fémorales chez des personnes âgées en utilisant l'imagerie TEP-FDG. Ce projet a impliqué trois groupes distincts de sujets âgés. Aussi, il incluait l'utilisation de la rosuvastatine pour le traitement de l'hypercholestérolémie. La technique de la TEP-FDG a permis de détecter une augmentation des niveaux d'inflammation artérielle durant les 12 mois de l'étude. L'analyse quantitative par TEP-FDG serait efficace pour localiser l'inflammation et évaluer sa progression durant le processus de l'athérosclérose.

Losartan is a selective antagonist of the angiotensin II type 1 receptor (AT1R). Several reports have highlighted the AT1R expression in several cancers enhancing tumor development and cancer progression. The aim of this thesis is the synthesis and evaluation of [18F]fluoroethyl-losartan ([18F]FEtLos) and [18F]ammoniomethyltrifluoroborate-losartan ([18F]AMBF3Los) as two novel losartan analogs to image AT1R-positive tumors using the positron emission tomography (PET). Initially, the cold compounds FEtLos and AMBF3Los were synthetized by alkylation and click chemistry reactions respectively, and characterized by spectroscopic techniques. Then, radiosynthesis of 2-[18F]fluoroethyl-tosylate was optimized from a radiation safety point of view. Next, [18F]FEtLos was manually synthetized by [18F]fluoroethylation of losartan with low molar activity and greater than 99% radiochemical purity. [18F]AMBF3Los was easily synthetized with greater than 97% radiochemical purity by one step 18F-19F isotopic exchange approach using low and high activities of [18F]fluoride that afforded molar activities ranging from 2 to 139 GBq/&mu;mol. In vitro competition binding assays showed that FEtLos and AMBF3Los have low and high binding affinity to human AT1R, respectively. AT1R expression was confirmed in breast, ovarian and gastric derived-tumors implanted on Nude mice. In spite of the low affinity, [18F]FEtLos was specific for renal AT1R. However, [18F]FEtLos did not showed specificity for tumor AT1R binding. &mu;PET imaging, autoradiography and ex vivo biodistribution studies showed the specificity of [18F]AMBF3Los for both kidney and tumor AT1R binding. However, [18F]AMBF3Los was not able to reach the tumor site once injected intravenously probably because of its rapid metabolism and very fast clearance. Nonetheless our results demonstrate that 18F-Angiotensin II Receptor Blockers (ARBs) derivatives could be suitable tracers to cancer imaging AT1R-expressing tumor microenvironment, however, radiolabeled ARBs that possess better pharmacokinetics profile may be required. / O losartan é um antagonista seletivo do receptor tipo 1 de angiotensina II (AT1R). Vários reportes têm destacado a expressão do AT1R em vários cânceres favorecendo o desenvolvimento tumoral e progressão do câncer. O objetivo desta tese é a síntese e avaliação do [18F]fluoroetil-losartan ([18F]FEtLos) e [18F]amoniometiltrifluoroborato-losartan ([18F]AMBF3Los) como dois novos análogos do losartan para imagem de tumores AT1R-positivos usando a tomografia por emissão de pósitrons (PET). Inicialmente, os compostos padrões FEtLos e AMBF3Los foram sintetizados por reações de alquilação e química click respetivamente, e caraterizados por técnicas espectroscópicas. A seguir, a radiosíntese do 2-[18F]fluoroetil-tosilato foi otimizada do ponto de vista de seguridade radiológica. O [18F]FEtLos foi depois sintetizado por alquilação do losartan utilizando o grupo prostético 2-[18F]fluoroetil-tosilato, com baixa atividade molar, e pureza radioquímica maior do 99%. [18F]AMBF3Los foi facilmente sintetizado com pureza radioquímica maior do 97% por troca isotópica 18F-19F usando baixas e altas atividades de [18F]fluoreto o que providenciou atividades molares entre 2 e 139 GBq/&mu;mol. Ensaios de ligação por competição in vitro mostraram que FEtLos e AMBF3Los têm baixa e alta afinidade de ligação ao AT1R humano respetivamente. A expressão do AT1R foi confirmada em tumores de mama, ovário e gástrico, implantados em camundongos Nude. A pesar da baixa afinidade, o [18F]FEtLos foi específico pelo AT1R renal. Não entanto, [18F]FEtLos não mostrou especificidade pela ligação ao AT1R no tumor. A imagem &mu;PET, autoradiografia, e os estudos de biodistribuição ex vivo mostraram a especificidade do [18F]AMBF3Los pela ligação ao AT1R nos rins e no tumor. O radiotraçador [18F]AMBF3Los não foi capaz de ligar no tumor quando injetado intravenosamente, provavelmente devido ao seu rápido metabolismo e rápida depuração sanguínea. Apesar disso, nossos dados demonstram que os derivados de Bloqueadores do Receptor de Angiotensina II (ARBs) radiomarcados com 18F podem ser potenciais radiofármacos para o imageamento do microambiente tumoral positivo para AT1R, no entanto o perfil farmacocinético dos ARBs radiomarcados ainda precisa ser melhorado.

Introduction Liquid targets using top-of-foil loading concept have been succesfully employed for routine high current production of 18F and 13N at Cyclotope (Houston,TX), over the past ten years1,2. These targets are typically filled with 3.5 ml of water, then pressurized with helium gas at 22 bar and bombarded with 18MeV protons (70–100 µA). Average calculated saturation yield for produc-tion of 18F is ~7.8 GBq/µA (210 mCi/µA) using in-house recycled [18O]-water at approximately 93% enrichment. Reduction of beam power per unit of area is one of the advantages of a tilted entrance-foil geo-metry. Implementation of this target geometry on the ACSI TR19 cyclotron 25degrees upwards irradiation port results in an almost horizontal target entrance foil. A 6ml total cavity volume target allows variable liquid fill volumes of 1.2–4.5 ml for beam current operation from 30–120 µA, resulting in a very efficient use of the costly 18O-water. In a near horizontal installation as in the mayority of cyclotrons, the fill volume flexibility is drastically reduced, having a minimum fill volume of 3.3 ml. At the requirement of Laboratorios Bacon, Cyc-lotope modified the target design with a front mounted collimator compatible with the IBA Cyclone 18/9 cyclotron. A second requirement was to reduce the minimum fill volume for horizontally mounted targets to 2.5 ml or less, while maintaining saturation yield performance. To preserve compatibility with existing IBA targets, the target hardware was modified to operate in self-pressurization mode. This paper presents the results obtained with high and low volume Niobium target inserts (6ml and 4 ml) mounted near horizontally on the IBA Cyclone 18/9 cyclotron and operated in self-pressurization mode. We present pressure/current characteristics, target performance (saturation yield, produced activities, maintenance frequency, FDG yields, etc.). Material and Methods The following targets manufactured by Cyclotope were tested and routinely used for production at Laboratorios Bacon: 1-High Volume Target CY2 model (“American Standard”), 6ml Niobium cavity. 2-Low Volume Target, CY3a model (“Traful”), 4ml Niobium cavity. 3- Low volume Target, CY3b model (“Ferrum”), 4.1ml Niobium cavity. Results and Conclusion The advantages of self-pressurization mode (Laboratorios Bacon setup) are: - Using the vapor pressure as a performance parameter - heat removal by boiling/condensation cycle starts at lower temperature (beam cur-rent) . While, the advantages of the pre-pressurized targets (Cyclotope setup) are: - reduced pressure fluctuations - performance is basically unaffected by plumbing dead volume - flexibility to locate instrumentation farther away from radiation fields - less dependence on fill volume - potential target leaks can be detected before starting an irradiation No significant differences were found in target performance when operated in either pressu-rization mode. The self-pressurizing setup seems to require a sligthly lower fill volume (approxi-mately 5%). The maximum beam current was limited by the foil rupture pressure (~ 40 bar). Safe maximum operating pressure was determined as 30 bar. No foil rupture was experienced during nine months of daily irradiation of these targets in self-pressurizing mode at Laboratorios Bacon. The irradiation parameters and target performance for the different targets are shown in Tables 1 and 2 below. The low volume Traful and Ferrum targets have the best saturation activity vs. fill volume, A(sat)/V, relation. Both targets produce 310 ± 31GBq (8.4 ± 0.8 Ci) of high quali-ty fluoride (F-18) in two hours of irradiation at 70 µA. The low volume targets have a low operation pressure (20bar @ 70µA) when compared to the IBA (NIRTA XL) targets. The typical saturation activity for the low volume targets was 592 ± 59 GBq (16 ± 1.6 Ci) of F-18 at 70 µA, 8.5 GBq/µA (228 mCi/µA) using 2.7ml enriched O-18 water (98 % +). The maintenance interval (> 10 mA.h) is very conveniente to reduce personnel radiation dose. No reduction in FDG yields was observed during that operation interval. In contrast, operation of the high volume targets in pre-presurization mode at the Cyclotope facility results in a higher maximum beam current limit (135 µA) for the same operating pressure (25 bar). Nevertheless, more O-18 water will be required to irradiate at this high current (4.5 ml vs. 3.0 ml). In self-pressurizing mode, a higher filling volume will reduce the expansion volume and, in consequence, the maximum beam current.

Parkinson’s disease (PD) is the second most common neurodegenerative condition to affect humans, and is characterised by the loss of dopaminergic neurons from the substantia nigra pars compacta (SNpc) in the midbrain along with the deposition of abnormal aggregates of alpha-synuclein protein in the brain which are in the form of Lewy bodies. Dopaminergic neurons from the SNpc project into a large subcortical structure known as the striatum, and positron emission tomography (PET) studies have demonstrated the dysfunction of the dopaminergic system in the striatum of patients with PD. Furthermore, immunohistochemistry studies of the striatum have identified the degeneration of dopaminergic nerve terminals and inclusions of alpha-synuclein. An aggressive and early onset form of familial PD is caused by the G51D point mutation in alpha-synuclein (G51D/+). Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) technology has been used to generate a novel and precise rat model of PD which has the G51D mutation in rat alpha-synuclein. Wild-type (WT) and G51D/+ rats were analysed over the course of ageing (5, 10/11 and 16/17 months of age) using histological experiments and L-3,4-dihydroxy-6-18F-fluorophenylalanine (18FDOPA) PET imaging in order to determine if G51D/+ rats have abnormalities of histological staining and dopaminergic function analogous to those identified in patients with PD. Histological experiments were optimised using WT rat tissue and then used immunohistochemistry for tyrosine hydroxylase (an enzyme involved in the synthesis of dopamine) to evaluate dopamine nerve terminal integrity in the striatum of WT and G51D/+ rats. In addition, immunohistochemistry for alpha-synuclein was used to evaluate staining for alpha-synuclein in cell bodies and the neuropil within the striatum of WT and G51D/+ rats. 18F-DOPA is a well validated PET radiotracer and has been used to investigate dopaminergic function in the striatum of rats. The enzyme aromatic L-amino acid decarboxylase converts 18F-DOPA to 6-18F-fluorodopamine, which is in turn incorporated into presynaptic vesicles, and then released into the synaptic cleft following neuronal activation. PET imaging experiments were first optimised using phantoms and WT rats, then the optimised protocols were applied to studies of WT and G51D/+ rats. Results from tyrosine hydroxylase immunohistochemistry at Bregma 0.00 mm identified a trend for decreased optical density of tyrosine hydroxylase staining in the striatum of 5 month G51D/+ rats compared with age-matched WT controls (p=0.15), and in 17 month G51D/+ rats compared with age-matched WT controls (p=0.10). Semi-quantitative analysis of alpha-synuclein immunohistochemistry indicated an increased abundance of alpha-synuclein positive cell somata in the striatum, and decreased punctate terminal staining in the neuropil of G51D/+ rats compared with age-matched WT rats. 18F-DOPA PET imaging experiments indicated a trend for decreased influx rate constant (Ki) of 18F-DOPA in the striatum of 5 month old G51D/+ rats compared with age-matched WT controls (p=0.08), and a trend for decreased distribution volume ratio (DVR) of 18F-DOPA in the striatum relative to the cerebellum of 16 month old G51D/+ rats when compared with age-matched WT controls (p=0.09). 18F-DOPA PET imaging experiments also identified a trend for a decreased effective distribution volume ratio (EDVR) of 18F-DOPA in the striatum relative to the cerebellum (p=0.09) and in turn indicated increased effective dopamine turnover (EDT) (p=0.13) in the striatum of 16 month old G51D/+ rats compared with age-matched WT rats. Therefore, the results indicated abnormalities of dopaminergic function, as well as tyrosine hydroxylase and alpha-synuclein staining in G51D/+ rats compared with age-matched WT controls, and this appeared to have some features of PD in humans. Indices of EDT indicated compensatory changes in dopaminergic function in the striatum of 16 month old G51D/+ rats compared with age-matched WT rats. Additional compensatory changes in dopaminergic terminal function and tyrosine hydroxylase protein expression may be evident in 11 and 10 month old G51D/+ rats respectively compared with age-matched WT rats. The G51D/+ rat model represents an interesting model for further studies such as the underlying pathophysiology of PD. However, the phenotype observed in G51D/+ rats appeared to be less severe than that which has been observed in humans with G51D type PD.