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Positron emission tomography (PET) is an important and powerful nuclear imaging modality and is essential in a range of medical fields. A suitable radiotracer must be identified in order for PET imaging to provide high quality and quantifiable data about the pathology. This includes the design and implementation of optimal radiochemistry that will reliably deliver the radiotracer that can answer the pertinent biological questions being asked. PET can be used to study the biological processes which are involved in pain perception and inflammatory responses that can occur in a number of chronic and acute conditions. This thesis aims to demonstrate how PET radiochemistry can enhance our knowledge of these biological processes and permits access to the underlying molecular mechanisms behind pain and inflammation. This thesis has been written in an alternative format, comprising the different areas which have been investigated. The work encompasses the study of the endogenous opioid system using the opioid receptor antagonist [11C]diprenorphine. This includes the design and automation of [11C]diprenorphine radiochemistry followed by the development of a method to reliably analyse its metabolism. Finally the application of [11C]diprenorphine in a clinical PET study, investigating opioid receptor occupancy by endogenous opioids as well as up-regulation of opioid receptors in the brain, is described. In the study of inflammation a pro-inflammatory cytokine, recombinant human interleukin-1 receptor antagonist (rhIL-1RA), was radiolabelled with novel 18F radiochemistry permitting pharmacokinetic study in pre-clinical models. This is followed by the design of a new technique to radiolabel white blood cells with 89Zr for quantifiable cell trafficking with PET. For this technique, chitosan nanoparticles are used to deliver the radio-metal cargo into white blood cells with a proposed application in inflammatory models. The process of chitosan nanoparticle construction is described alongside development of a procedure that is optimised for use in the proposed application. This thesis covers a variety of topics illustrating the contribution of PET radiochemistry in the area of pain and inflammation. The synergy between identification of new biological targets and development of radiotracers and radiolabelling strategies ensure PET radiochemistry will continue to contribute to our knowledge of pain and inflammation and aid understanding of its role in countless medical conditions.

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No description available.

<p>Compounds labelled with ¹¹C (<i>β</i>⁺, t_1/2 = 20.4 min) are used in positron emission tomography (PET), which is a quantitative non-invasive molecular imaging technique. It utilizes computerized reconstruction methods to produce time-resolved images of the radioactivity distribution in living subjects. </p><p>The feasibility of preparing [¹¹C]methyl iodide from [¹¹C]methane and iodine via a single pass through a non-thermal plasma reactor was explored. [¹¹C]Methyl iodide with a specific radioactivity of 412 ± 32 GBq/µmol was obtained in 13 ± 3% decay-corrected radiochemical yield within 6 min via catalytic hydrogenation of [¹¹C]carbon dioxide (24 GBq) and subsequent iodination, induced by electron impact. </p><p>Labelled ethyl-, propyl- and butyl iodide was synthesized, within 15 min, via palladium-mediated carbonylation using [¹¹C]carbon monoxide. The carbonylation products, labelled carboxylic acids, esters and aldehydes, were reduced to their corresponding alcohols and converted to alkyl iodides. [1-¹¹C]Ethyl iodide was obtained via palladium-mediated carbonylation of methyl iodide with a decay-corrected radiochemical yield of 55 ± 5%. [1-¹¹C]Propyl iodide and [1-¹¹C]butyl iodide were synthesized via the hydroformylation of ethene and propene with decay-corrected radiochemical yields of 58 ± 4% and 34 ± 2%, respectively. [1-¹¹C]Ethyl iodide was obtained with a specific radioactivity of 84 GBq/mmol from 10 GBq of [¹¹C]carbon monoxide. [1-¹¹C]Propyl iodide was synthesized with a specific radioactivity of 270 GBq/mmol from 12 GBq and [1-¹¹C]butyl iodide with 146 GBq/mmol from 8 GBq. </p><p>Palladium-mediated hydroxycarbonylation of acetylene was used in the synthesis of [1-¹¹C]acrylic acid. The labelled carboxylic acid was converted to its acid chloride and subsequently treated with amine to yield <i>N-</i>[<i>carbonyl</i>-¹¹C]benzylacrylamide. In an alternative method, [<i>carbonyl</i>-¹¹C]acrylamides were synthesized in decay-corrected radiochemical yields up to 81% via palladium-mediated carbonylative cross-coupling of vinyl halides and amines. Starting from 10 ± 0.5 GBq of [¹¹C]carbon monoxide, <i>N-</i>[<i>carbonyl</i>-¹¹C]benzylacrylamide was obtained in 4 min with a specific radioactivity of 330 ± 4 GBq/µmol. </p>

Compounds labelled with 11C (β+, t1/2 = 20.4 min) are used in positron emission tomography (PET), which is a quantitative non-invasive molecular imaging technique. It utilizes computerized reconstruction methods to produce time-resolved images of the radioactivity distribution in living subjects. The feasibility of preparing [11C]methyl iodide from [11C]methane and iodine via a single pass through a non-thermal plasma reactor was explored. [11C]Methyl iodide with a specific radioactivity of 412 ± 32 GBq/µmol was obtained in 13 ± 3% decay-corrected radiochemical yield within 6 min via catalytic hydrogenation of [11C]carbon dioxide (24 GBq) and subsequent iodination, induced by electron impact. Labelled ethyl-, propyl- and butyl iodide was synthesized, within 15 min, via palladium-mediated carbonylation using [11C]carbon monoxide. The carbonylation products, labelled carboxylic acids, esters and aldehydes, were reduced to their corresponding alcohols and converted to alkyl iodides. [1-11C]Ethyl iodide was obtained via palladium-mediated carbonylation of methyl iodide with a decay-corrected radiochemical yield of 55 ± 5%. [1-11C]Propyl iodide and [1-11C]butyl iodide were synthesized via the hydroformylation of ethene and propene with decay-corrected radiochemical yields of 58 ± 4% and 34 ± 2%, respectively. [1-11C]Ethyl iodide was obtained with a specific radioactivity of 84 GBq/mmol from 10 GBq of [11C]carbon monoxide. [1-11C]Propyl iodide was synthesized with a specific radioactivity of 270 GBq/mmol from 12 GBq and [1-11C]butyl iodide with 146 GBq/mmol from 8 GBq. Palladium-mediated hydroxycarbonylation of acetylene was used in the synthesis of [1-11C]acrylic acid. The labelled carboxylic acid was converted to its acid chloride and subsequently treated with amine to yield N-[carbonyl-11C]benzylacrylamide. In an alternative method, [carbonyl-11C]acrylamides were synthesized in decay-corrected radiochemical yields up to 81% via palladium-mediated carbonylative cross-coupling of vinyl halides and amines. Starting from 10 ± 0.5 GBq of [11C]carbon monoxide, N-[carbonyl-11C]benzylacrylamide was obtained in 4 min with a specific radioactivity of 330 ± 4 GBq/µmol.

Les transporteurs d’acides aminés sont très souvent surexprimés au niveau des cellules tumorales et représentent une cible moléculaire privilégiée pour l’imagerie TEP (Tomographie par Emission de Positons) des cancers. Dans le but d’accéder à des radiotraceurs spécifiques de ces transporteurs, les travaux de thèse ont consisté à mettre au point - dans une première partie, une nouvelle méthode de marquage au fluor-18 d’acides aminés fluorés basée sur la déoxyradiofluoration de précurseurs hydroxyaminoesters, via un intermédiaire aziridinium, - et dans une seconde partie, le marquage au carbone-11 de la sulfasalazine, un inhibiteur sélectif des transporteurs Xc-. La réaction de déoxyradiofluoration des hydroxyaminoesters de structure sérine, méthylsérine ou hydroxyphénylalanine, facilement accessibles et stables, a permis d’obtenir à température ambiante les [18F]fluoroaminoesters correspondants avec efficacité et reproductibilité. La régiosélectivité de la réaction a été trouvée dépendante des substituants du cycle aziridinium et de la fonction amine. La radiosynthèse de la [11C]-sulfasalazine a été réalisée avec succès par couplage d’un sel de diazonium approprié avec l’acide [11C]salicylique obtenu par réaction de [11C]carboxylation d’un précurseur bismagnésien issu du iodophénol. L’automatisation de cette radiosynthèse est en cours d’optimisation afin de produire la [11C]sulfasalazine en quantité suffisante pour réaliser les études in vivo. / Aminoacid transporters are often overexpressed in tumour cells and they represent molecular targets of choice for cancer imaging by Positron Emission Tomography (PET). In order to access to specific radiotracers of these transporters, the thesis project aimed at developing – in a first part, a new 18F-radiolabeling method of fluoroaminoacids based on deoxyradiofluorination of hydroxyaminoester precursors via an aziridinium intermediate – and in a second part, the radiolabelling with carbon-11 of sulfasalazine, an selective inhibiter of Xc- transporters. Deoxyradiofluorination reaction of stable and easily accessible hydroxyaminoesters possessing a serine, methylserine or hydroxyphenylalanine moiety, led to [18F]fluoroaminoesters at room temperature in high and reproducible radiochemical yields. Regioselectivity was function of the substituents on aziridinium ring and amine function. The radiosynthesis of [11C]sulfasalazine has been successfully achieved by coupling reaction of an appropriate diazonium salt with [11C]salicylic acid, obtained by [11C]carboxylation of a bismagnesium precursor from iodophenol. The automation of the radiosynthesis is in progress to produce [11C]sulfasalazine for in vivo studies.

L’essor de la chimie organométallique a permis de développer de nouvelles possibilités dans le domaine du diagnostic médical, en particulier pour la tomographie à émission de positrons (TEP). Ainsi, de nouvelles méthodologies ont été développées pour permettre la synthèse de bio-traceurs avec le marquage au 11C comme étape finale. Dans ce contexte, notre équipe a récemment développé une nouvelle méthodologie pour marquer une large variété de substrats dans des conditions standards de carbonylation et ces travaux de thèse présentent une nouvelle stratégie de synthèse impliquant la préformation de complexes palladiés supportées. Ainsi, leurs ancrages préalables sur une résine facilitent la réaction de carbonylation en simplifiant leur purification. De nouveaux complexes à base de palladium ont aussi été synthétisés et étudiés pour envisager de potentielles applications en catalyse photorédox. Enfin le développement de nouvelles stratégies de couplage impliquant des intermédiaires d’or (III) étant un domaine en plein expansion, notamment lorsqu’elles combinent catalyse à l’or et photorédox, il a été envisagé de synthétiser de nouveaux complexes d’or afin d’étudier les mécanismes réactionnels impliqués dans ces couplages et d’évaluer les possibilités de synthèse de composés biaryliques atropoisomériques. / The growth of organometallic chemistry has allowed numerous developments in the field of medical diagnosis, especially for Positron Emission Tomography (PET). Developing new methodologies for the synthesis of biological tracers by a last-step 11C labeling, our team has been recently able to take advantage of the great functional tolerance of palladium-catalyzed carbonylation to achieve this goal. A new synthetic strategy involving preformed palladium complexes is described in this manuscript. Their anchoring on a polystyrene resin allowed subsequently to facilitate the carbonylation process by simplifying the purification. New palladium complexes have also been investigated for their potential photoredox applications. Finally, new coupling strategies implying gold (III) intermediates and photoredox catalysis being a very attractive subject, new gold complexes have been synthetized in order to investigate the reaction mechanisms that could operate. Possibilities of asymmetric induction in the synthesis of atropoisomeric biaryl compounds were also studied.

In the first part of this thesis, palladium(0)-catalyzed and -mediated carbonylations are discussed. Paper I describes a new method for the safe, efficient use of a solid carbon monoxide source in the synthesis of primary and secondary benzamides. In total, 35 benzamides were synthesized from aryl iodides (20 examples, 69-97% yield) and aryl bromides (15 examples, 32-93% yield). Reduction-prone groups were used successfully in the reactions. In paper II, the same protocol was adopted for the palladium(0)-catalyzed synthesis of N-cyanobenzamides from aryl iodides/bromides, carbon monoxide and cyanamide. In total, 22 N-cyanobenzamides were synthesized (42-88% yield). The radiosynthesis of [11C]N-cyanobenzamides is discussed in paper III. In total, 22 compounds were synthesized from various aryl halides in 28-79% decay corrected radiochemical yield. The protocol was then applied to the radiosynthesis of [11C]N-cyanobenzamide analogs of flufenamic acid and dazoxibene. In the second part of this thesis, compounds of interest in relation to amyloid diseases are discussed. Paper IV describes the solid-phase synthesis of BACE-1 enzyme inhibitors containing secondary and tertiary hydroxyl as the transition state isostere. In total, 22 inhibitors were synthesized. The most potent compound (IC50= 0.19 µM) was co-crystallized at the active site of the enzyme to reveal a new binding mode. In paper V, the evaluation of a potent BACE-1 inhibitor as a potential radiotracer for use in PET is described. The radiolabeled [11C]BSI-IV was obtained in 29±12% decay corrected radiochemical yield by a three-component palladium(0)-mediated aminocarbonylation. Its properties as a potential PET tracer were investigated in vitro by autoradiography and in vivo in rats using small animal PET-CT. A new class of amyloid-binding PET ligands is described in paper VI. Three polythiophenes were labeled with carbon-11 or fluorine-18 (26-43% decay-corrected radiochemical yield). The in vitro studies showed that these ligands bind specifically to amyloid deposits. In vivo PET showed low uptake in the organs of interest in healthy rats and a monkey. These results suggest the labeled thiophenes derivatives could be useful as PET tracers for the study of amyloid diseases.

La Tomographie par émission de positons (TEP) constitue l’une des techniques d’imagerie médicale les plus novatrices pour la visualisation in vivo des processus biologiques. Elle intervient comme technique de choix pour le diagnostic dans de nombreux domaines notamment, en oncologie, cardiologie ou encore en neurologie. La conception et l’élaboration de nouveaux radiotraceurs sont en perpétuel développement. L’utilisationd’oligonucléotides (ODN) modifiés (aptamères) possédant une grande affinité et spécificité pour une cible (gène,protéine, principe actif), comme radiotraceur pour l’imagerie in vivo apparait comme une alternative intéressante. A ce jour, quelques rares exemples d’oligonucléotides marqués, par un radioisotope, ont été décrits dans la littérature.Dans ce contexte, il a été développé deux méthodologies d’introduction du radioisotope (11C ou 18F) en dernièreétape de synthèse par chimie ‘‘click’’ pour le marquage de nucléosides et d’oligonucléotides envisagés commeradiotraceurs pour la TEP. / Positron Emission Tomography (PET) is a powerful molecular-imaging technique for physiological and biologicalinvestigations in various areas, such as oncology, cardiology, and neurosciences, as well as for drug development.Due to the increasing need of this technique for in vivo applications, there is always a demand for the developmentof new tracers and radiolabeling strategies. Furthermore, because of their excellent targeting capacities and easysynthesis along with a high level of diversity, oligonucleotides are already extensively used in vitro as ligands fornucleic acids (antisense oligonucleotides), proteins, and small related molecules (aptamer oligonucleotides). Theuse of aptamers for in vivo imaging appears especially promising, because of the wide range of possibilitiesavailable to introduce variations in their structure through defined chemical modifications. However, only fewexamples of oligonucleotide labeling for PET have been reported. In this context, we have developed twomethodological ways to introduce the radioisotope (11C, 18F), by ‘‘click’’ chemistry, at the last radiosynthesis stepin order to label nucleoside and oligonucleotide as potential radiotracers for PET.