Le modèle induit par injectionunilatérale intrahippocampique d’acide kaïniquechez la souris présente de grandes analogiesavec l’épilepsie mésio-temporale (EMT) chezl’homme caractérisée par la périoded’épileptogénèse et par une sclérosehippocampique (SH) typique.De récents travaux ex vivo ont révélé l’existencede processus neuroinflammatoires au niveau dela SH chez des patients épileptiques et dans desmodèles animaux. La protéine translocatrice de18kDa (TSPO), la plus étudiée actuellement aumoyen de différents traceurs, est considéréecomme une cible de référence pour visualiser etquantifier la neuroinflammation.Ma thèse a donc eu pour objectif de déterminerl’évolution de l’expression de TSPO au cours dela constitution de la SH à l’aide de laTomographie par émission de positons (TEP) au18F-DPA-714 dans une étude longitudinale chezce modèle d’EMT, et à identifier son origine àpartir d’analyses d’immunohistofluorescence.Nous avons démontré la faisabilité de la TEPpour suivre in vivo le processus inflammatoiremême dans de petites structures cérébrales à lafois par la mesure locale du pourcentaged’activité injectée et par l’estimation du volumede distribution.Le signal maximum a été observé durantl’épileptogénèse et correspondait aux microgliesactivées puis il diminuait mais persistait lorsquela SH était bien établie, et était alorsprincipalement lié aux astrocytes activés.Nos principaux résultats ont permis d’identifierles phases pendant lesquelles de nouvellesstratégies thérapeutiques ciblant différentescomposants de la neuroinflammationmériteraient d’être étudiés. / The model induced by unilateralinjection of kainic acid is considered as the bestreliable model for the mesial temporal lobeepilepsy (MTLE) and reproduces theepileptogenesis and the typical hippocampalsclerosis (HS).Recent ex vivo studies have revealed theexistence of neuroinflammation in the HS ofepileptic patients and animal models. The18kDa translocator protein (TSPO), which iscurrently the most widely studied with variousradiotracers, is considered as a reference targetto visualize and quantify theneuroinflammation.In that context, my thesis focused ondetermining the evolution of TSPO during theconstitution of HS using 18F-DPA-714positrons emission tomography (PET) in alongitudinal study in this mouse model, and toidentify its origin fromimmunohistofluorescence analysis.We demonstrated the feasibility of PET tomonitor in vivo the inflammatory process evenin small cerebral structures both by the localmeasurement of the percent injected dose or bythe measurement of the volume of distribution.The peak signal was found during theepileptogenesis and corresponded to activatedmicroglia, and then this signal decreased butpersisted after the HS was well established, andmainly originated from activated astrocytesduring this period.Our main results allowed us to identifydifferent phases during which potential antiepileptictreatment targeting differentcomponents of neuroinflammation could beinvestigated.

Introduction: The role of positron emission tomography (PET) with 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) is currently under evaluation in urologic oncology. The aim of the present study was to investigate the use of [18F]FDG positron emission tomography ([18F]FDG-PET) in the detection and treatment control of malignant germ cell tumors compared to computed tomography (CT). Materials and Methods: Thirty-two PET studies and CT scans were carried out in 23 patients with histologically proven germ cell tumors (10 seminomas, 12 non-seminomatous germ cell tumors (NSGCT), 1 unclassified serologic recurrent disease) Lugano stage I–III. The scans were done either after initial diagnosis (n = 21) and/or within 3–45 days after chemotherapy was completed (n = 11). PET and CT were validated either by histology (n = 7) or clinical follow-up of 6–11 months after the last PET study has been performed (n = 16). Sensitivity, specificity, accuracy, positive and negative predictive values were determined for PET and CT. Differences between PET and CT for parameters of diagnostic value were evaluated by =χ2 test. Results: Although not statistically significant, the sensitivity, accuracy and negative predictive value were higher for PET than for CT with respect to the detection of metastatic infradiaphragmatic and supradiaphragmatic lesions after initial diagnosis. The specificity and positive predictive value of PET and CT were comparable. After chemotherapy, PET was found to be significantly superior in specificity and accuracy compared to CT with respect to infradiaphragmatic lesions (p < 0.05). False-positive PET findings in supradiaphragmatic lesions after chemotherapy occurred in the case of inflammatory processes and resulted in a loss of specificity and accuracy compared to CT (p < 0.05). Conclusions: These preliminary results demonstrate [18F]FDG-PET to be a useful diagnostic tool for the initial staging and treatment control in patients with germ cell tumors. Possible advantages compared to CT, however, are as yet not clearly defined. The possibility of false-positive PET findings due to reactive supradiaphragmatic inflammatory processes early after chemotherapy have to be considered. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

L’implication des récepteurs 5-HT1A dans la physiopathologie de la schizophrénie a été suggérée par de nombreuses études post mortem et pharmacologiques. Le développement d’études exploratoires du système sérotoninergique 5-HT1A chez des patients schizophrènes permet de préciser le rôle des récepteurs 5-HT1A dans la physiopathologie de la maladie et d’envisager de nouvelles stratégies thérapeutiques. L'existence du p-[18F]MPPF, radioligand ayant une affinité spécifique pour les récepteurs 5-HT1A, nous a permis de réaliser une exploration du système sérotoninergique 5-HT1A in vivo en tomographie par émission de positons (TEP) chez 19 patients schizophrènes et de comparer les résultats obtenus aux images de 19 témoins issus de la banque de données du CERMEP (Lyon). Notre premier objectif a été de mettre en évidence d’éventuelles différences de répartition de potentiel de liaison (BP) entre les patients et les témoins. Une diminution significative du [18F]MPPF BPND au niveau des régions frontales et orbitofrontales a été retrouvée chez les patients schizophrènes par rapport aux témoins. Dans un second temps, la comparaison des images TEP obtenues chez les patients selon que le traitement antipsychotique reçu a une action agoniste 5-HT1A (aripiprazole) ou en soit dépourvu (olanzapine, rispéridone) a montré une diminution plus importante du [18F]MPPF BPND chez les patients traités par aripiprazole que chez les patients traités par d’autres antipsychotiques, soulignant ainsi l’impact in vivo de ce traitement sur le système sérotoninergique 5-HT1A. Notre étude est la première, à notre connaissance, à utiliser le p-[18F]MPPF chez des patients schizophrènes / Backgrounds: Multiple post-mortem and pharmacological studies suggest a key role of the serotonergic 1A (5-HT1A) system in the pathophysiology of schizophrenia. Materials and methods: The aim of our work was to assess the 5-HT1A receptors availability In patients suffering from schizophrenia treated with different antipsychotic drugs, compared to controls, using a new ligand antagonist of 5-HT1A receptors, the [18F]MPPF. The 5-HT1A binding potential of 19 schizophrenic patients (treated with either aripiprazole (a 5-HT1A partial agonist) or Second Generation Antipsychotic (olanzapine or risperidone) was compared with that of 19 age-matched healthy controls. This is the first report of a [18F]MPPF PET study in treated patients with schizophrenia. Results: A significant reduction of [18F]MPPF BPND was found in treated patients with schizophrenia compared to age- and gender-matched healthy subjects. These modifications were mainly localized in the frontal and orbitofrontal cortex and may reflect either the pathophysiology of schizophrenia or medication effects. In comparison to matched healthy subjects, the reduction of 5-HT1A receptor availability was more extensive in schizophrenic patients with aripiprazole treatment than in schizophrenic patients with SGA treatment. Conclusion: These results suggest that aripiprazole has a major impact on [18F]MPPF BPND, likely due to its partial agonist activity at 5-HT1A receptors. In order to distinguish the relative contributions of the disease itself versus medication effects, future [18F]MPPF studies should be performed in APD-naïve patients with schizophrenia

Positron emission tomography/computed tomography (PET/CT) is a method that quantitatively visualizes physiological processes. The most common indications for PET brain are early diagnosis of various dementia types with 18F-Fludeoxyglucose (18F-FDG). The hospital in Jonkoping installed a new PET/CT and brain examinations have not yet been performed. The aim of the study was to map how hospitals in Sweden performed seven selected brain examinations with PET/CT focusing on modality structure, examination method and reconstruction method, with a comparison of radiation dose between PET/CT and single photon emission computed tomography/CT (SPECT)/CT. Out of the nine university hospitals selected, two were excluded. The method was prospective with quantitative approach and data was collected through a protocol. Compilation was made on Excel and the statistics were processed using the Wilcoxon Signed Ranks Test. The result showed similarities, for example reconstruction method and differences, for example fasting time. Effective dose was higher on SPECT than PET in examination of Parkinson's disease, however no significant difference (p = 0,059) was detected. Higher effective doses on SPECT was due to longer half-lives and greater dosages of Ioflupane (123I-Datscan) than 18F-FDG. For further studies, more hospitals and parameters in the protocol can be included.

Chez un patient épileptique, aucun examen ne permet la délimitation exacte de la zone épileptogène (ZE) qui est définie par la zone corticale nécessaire à la genèse des crises. Dans les épilepsies du lobe temporal (ELT), près d'un tiers des patients ne sont pas libres de crises après la chirurgie en dépit d'un bilan préopératoire concluant. La tomographie par émission de positons (TEP) au [18F]MPPF permet la mise en évidence de zones d'hypofixation qui sont, à l'échelle du groupe, corrélées à l'épileptogénicité du parenchyme cérébral. Afin d'évaluer la validité de la TEP au [18F]MPPF pour identifier la ZE au plan individuel, tout d'abord nous avons comparé l'analyse visuelle et statistique par SPM de la TEP au [18F]FDG à la TEP au [18F]MPPF en termes de sensibilité et de spécificité chez 42 patients souffrant d'une ELT en cours de bilan préchirurgical. Dans une seconde étude nous avons développé une méthode d'analyse statistique d'un index d'asymétrie (IA) de la fixation du [18F]MPPF [BPND] et comparé les rendements de cette nouvelle approche à l'analyse standard SPM des images TEP en utilisant deux seuils statistiques différents (p< 0,05, corrigé au niveau du voxel et p< 0,05, corrigé au niveau du cluster) chez 24 patients opérés et guéris de leur ELT. Dans une troisième étude nous avons évalué, au niveau du groupe, l'influence d'un état dépressif sur le BPND du [18F]MPPF chez 24 patients souffrant d'une ELT. Ces trois études ont permis les conclusions suivantes : i) dans des conditions d'analyse identiques, La TEP au [18F]MPPF est supérieure au [18F]FDG pour identifier le lobe épileptogène chez des patients souffrant d'une ELT, ii) L'analyse de l'IA, avec un seuil à p< 0,05 corrigé au niveau du cluster, est la meilleure technique d'analyse de la TEP au [18F]MPPF et permet l'identification de la ZE avec une sensibilité de 96% et une spécificité de 88% dans l'ELT, iii) A l'échelle du groupe, un état dépressif est responsable d'une augmentation du BPND du [18F]MPPF dans les noyaux du raphé et l'insula controlatérale à la ZE.

Le [18F]Fluoro-éthoxybenzovesamicol ([18F]FEOBV) a été identifié comme étant un des agents radioactifs les plus prometteurs pour l'imagerie du transporteur vésiculaire de l'acétylcholine en utilisant la tomographie par émission de positrons (TEP). Nous rapportons ici que cette approche est en mesure de détecter de subtiles pertes de terminaux cholinergiques, comme celles associés avec le vieillissement ou suivant la lésion partielle du noyau basal de Meynert (NBM). Vingt-et-un rats adultes ont été distribués également en trois groupes : 1) Rats âgés (18 mois); 2) Jeunes rats (3 mois); et 3) Rats avec une lésion unilatérale du NBM induite par une infusion locale de saporine-IgG 192. Pour les rats normaux et ceux avec lésion, la plus haute valeur de liaison du [18F]FEOBV a été observée dans le striatum, suivi de valeurs similaires dans le cortex frontal et le thalamus, puis de valeurs plus faibles pour les hippocampes et le cortex temporo-pariétal. Les rats avec lésion du NBM ont démontré une liaison de [18F]FEOBV diminuée principalement dans la partie ventrale du cortex frontal. Cette perte est plus importante du côté de la lésion, mais également présente dans la région homologue de l'hémisphère controlatéral. Le vieillissement a entraîné une diminution de liaison de [18F]FEOBV localisée dans les hippocampes. Le [18F]FEOBV semble être une marqueur très prometteur pour la quantification in vivo du transporteur vésiculaire de l'acétylcholine dans le cerveau; l'imagerie TEP avec cet agent permet la détection de réductions physiologique et pathologique de la densité des terminaisons cholinergiques. ______________________________________________________________________________ MOTS-CLÉS DE L’AUTEUR : Tomographie par émission de positrons, transporteur vésiculaire de l'acétylcholine, neurodégénérescence, vieillissement, saporine-IgG 192, [18F]Fluoro-éthoxybenzovesamicol

Type 1 and 2 Diabetes Mellitus are a growing health problem throughout the world. There is an increasing  need for methodologies, which are both reliable and non-invasive to measure the amount of insulin-producing tissue (Beta-cell mass, or BCM), as well as rapidly quantify changes in the BCM due to the onset of disease, beta-cell replacement therapy, or other treatments. Positron Emission Tomography (PET) is a non-invasive, quantitative functional imaging technique which can be used to study dynamical or static processes inside the body. In this thesis, we present a study protocol for in vivo imaging of the most common form of beta- cell replacement therapy; islet transplantation. Islets were labeled with the PET tracer, 2-deoxy-2[18F]fluoro-D-glucose ([18F]FDG), and administered intra-portally, while the recipient was monitored by PET/CT. The hepatic distribution of the islets was highly heterogeneous, and around 25% (human) or 50% (porcine) of the administered islets could not be found in the liver after completed transplantation, confirming previous reports of considerable cell injury during the procedure leading to low hepatic engraftment. Native BCM in the pancreas can potentially be quantified using a PET tracer with sufficiently high specificity, but the major obstacle is the relative low amounts of insulin producing tissue (only 1-2% of the pancreatic volume). Two tetrabenazine analogues, [18F]FE-(+)-DTBZ and [18F]FE-(+)-DTBZ-d4, are ligands to VMAT2, which is expressed in islet tissue. Both analogues were investigated and characterized as potential BCM imaging agents both in vitro and in vivo.  Both tracers exhibited high preferential binding to islet tissue compared to exocrine pancreatic tissue. However, the specificity was not high enough to overcome the obscuring exocrine signal in vivo (7-10% of the signal originating from specific islet tracer uptake). This thesis demonstrates that it is possible to quantitatively assess islet transplantation by PET imaging. In vivo determination of native pancreatic BCM is, in theory, possible with both [18F]FE-(+)-DTBZ and [18F]FE-(+)-DTBZ-d4, but tracer analogues with higher islet specificity is needed for quantification of smaller BCM changes with physiological impact.

In this thesis new synthetic routes towards perfluorinated compounds are described, as well as their radiolabelling with fluorine-18, with the aim of application in pharmaceutically interesting targets. Part A investigates late-stage fluorination, i.e. retrosynthetic C–F bond disconnections. A silver catalysed electrophilic fluorodecarboxylation of fluorinated carboxylic acids for the formation of difluoromethyl-, trifluoromethyl-, and pentafluoroethylarenes is developed and transferred to a radiochemistry setting using [¹⁸F]Selectfluor bis(triflate). Part B explores late-stage perfluoroalkylation via cross-coupling strategies. The use of visible light-mediated ruthenium catalysis is investigated for the radical trifluoromethylation and pentafluoroethylation of vinyl- and alkynylsilanes and alkynes. Finally, the first generally applicable copper-mediated cross-coupling of Ruppert-Prakash-like aryl(tetrafluoroethyl)trimethylsilanes (ArCF2CF2SiMe3) is presented.

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.

Background: Breast cancer is the second most common cancer in adults and the most frequent cancer diagnosed in women. In South Africa, breast cancer accounts for 38.5% of cancers diagnosed in women. Since the presence, extent and location of distant metastases is one important prognostic factor in locally advanced breast cancer (LABC), accurate staging at diagnosis is crucial to ensure patients receive the appropriate treatment. Increasing evidence shows that the use of 18F-FDG PET/CT for disease staging of LABC may improve diagnostic sensitivity. Aim: To prospectively assess the difference in diagnostic accuracy between whole-body PET/PET-CT and conventional imagine (CI) for staging LABC. Methods: A total of 42 participants with clinical stage III and a select few stage II breast cancer underwent both 18F-FDG PET/CT and CI. Results: 18F-FDG PET/CT found significantly more (p=0.0077) distant metastatic sites than CI (36% vs. 21%). 18F-FDG PET/CT upstaged 9 (21.4%) of patients from clinical stage IIIa to stage IIIc, and changed management of 54% of patients. Thirty-eight percent (38%) of the patients had their clinical stage unchanged. One of 5 suspected metastatic sites 18F FDG PET/CT was positive for malignancy on biopsy. Conclusion: The 18F-FDG PET/CT is useful for staging locally advanced non-inflammatory infiltrating ductal carcinoma of the breast. Use of 18F-FDG PET/CT was superior to conventional imaging in assessing metastatic mediastinal lymphadenopathy, but with a poor specificity. The use of 18F-FDG PET/CT in LABC is useful, with the biopsy of isolated suspicious lesions for metastasis increasing its accuracy.