Ιnvestigatiοns of new radio-labeling strategies with iοdine isοtοpes

À l’heure actuelle, les isotopes de l’iode sont sous exploités par rapport au potentiel qu’offre leur emploi en imagerie médicale et en radio-thérapie. Le manque de méthodologies innovantes en accord avec les challenges d’une utilisation clinique est une des causes de ce désintéressement. Le développement de nouvelles stratégies de radio-marquage en employant des substrats bons marchés, peu toxiques, facilement synthétisables est légitimement devenu un enjeu crucial pour la médecine nucléaire de demain. Les projets et résultats inscrits dans cette thèse sont axés dans cette nouvelle optique et a permis l’exploration de trois nouvelles stratégies de radio-iodation. Une méthode de radio-iododésilylation, déjà décrite, a été ré-évaluée dans des conditions beaucoup plus douces, et, de surcroît, a été transposée à l’emploi de composés organo-germanylés comme substrat précurseur. Le développement d’une méthode de radio-iodation à partir de composés faciles d’accès, ici les acides benzoïques, a été mise au point par l’emploi d’un complexe d’or. Le dernier projet, quant à lui, a consisté à mettre au point une nouvelle voie d’accès aux molécules radio-iodées par activation C-H au cobalt.Currently, iodine isotopes are underexploited compared to the potential offered by their use in medical imaging and radio-therapy. The insuffiency of innovative methodologies in line with the challenges for clinical applications is one of the causes of this lack of interest. The development of new radio-labeling strategies using cheap, non-toxic, easily synthesized substrates has legitimately become a crucial issue for the tomorrow’s nuclear medicine. The projects and results included in this thesis are focused on this new challenge and described the exploration of three new radio-iodination’s strategies. The radio-iododesilylation method, already described, has been re-investigated in-depth under much milder conditions, and, moreover, has been transposed to the use of organo-germane compounds as precursors. The development of a radioiodination method from easily accessible compounds, benzoic acids, was developed using gold complexes. The last project was to develop a new access to radio-iodinated molecules by C-H activation with cobalt complexes

Gold(I)-Mediated Radioiododecarboxylation of Arenes

Abstract The 18 kDa translocator protein (TSPO) is a classical marker of neuroinflammation targeted for in vivo molecular imaging. Microglial cells were originally thought to be the only source of TSPO overexpression but astrocytes, neurons and endothelial cells can also up-regulate TSPO depending on the pathological context. This study aims to determine the cellular origin of TSPO overexpression in a simplified model of neuroinflammation and to identify the molecular pathways involved. This is essential to better interpret TSPO molecular imaging in preclinical and clinical settings. We used lentiviral vectors (LV) to overexpress the ciliary neurotrophic factor (CNTF) in the right striatum of 2-month-old Sprague Dawley rats. A LV encoding for β-Galactosidase (LV-LacZ) was used as control. One month later, TSPO expression was measured by single-photon emission computed tomography (SPECT) imaging using [ 125 I]CLINDE. The fluorescence-activated cell sorting to radioligand-treated tissue (FACS-RTT) method was used to quantify TSPO levels in acutely sorted astrocytes, microglia, neurons and endothelial cells. A second cohort was injected with LV-CNTF and a LV encoding suppressor of cytokine signaling 3 (SOCS3), to inhibit the JAK-STAT3 pathway specifically in astrocytes. GFAP and TSPO expressions were quantified by immunofluorescence. We measured a significant increase in TSPO signal in response to CNTF by SPECT imaging. Using FACS-RTT, we observed TSPO overexpression in reactive astrocytes (+ 153 ± 62%) but also in microglia (+ 2088 ± 500%) and neurons (+ 369 ± 117%), accompanied by an increase in TSPO binding sites per cell in those three cell populations. Endothelial cells did not contribute to TSPO signal increase. Importantly, LV-SOCS3 reduced CNTF-induced astrocyte reactivity and decreased global TSPO immunoreactivity (-71% ± 30%), suggesting that TSPO overexpression is primarily mediated by reactive astrocytes. Overall, this study reveals that CNTF induces TSPO in multiple cell types in the rat striatum, through the JAK2-STAT3 pathway in astrocytes, identifying this cell type as the primary mediator of CNTF effects neuroinflammatory processes. Our results highlight the difficulty to interpret TSPO imaging in term of cellular origin without addition cellular analysis by FACS-RTT or quantitative immunostainings. Consequently, TSPO should only be used as a global marker of neuroinflammation

Synthesis and emission properties of 1,1,4,4-tetracyanobutadienes derived from ynamides bearing fluorophores

A series of 1,1,4,4-tetracyanobutadienes (TCBD) bearing a large diversity of fluorophores was prepared following a multi-step synthesis. In a crucial last step, all compounds were obtained from the corresponding ynamides which were particularly suitable for the formation of the TCBDs in the presence of tetracyanoethylene via a [2+2] cycloaddition/retroelectrocyclization step (CA-RE). Fluorenyl derivatives including several variations on position 7 and 9, in addition to phenanthrenyl and terphenyl derivatives provided ynamide-based TCBD affording remarkable emission properties covering a large range of wavelengths. Those compounds emit both in solid state and in solution from the visible region to the NIR range, depending on the molecular structures. Quantum yields in cyclohexane reached unforeseen values for such derivatives, up to 7.8%. A huge sensitivity to the environment of the TCBDs has also been unraveled for most of the compounds since we observed a dramatic fall of the quantum yields when changing the solvent from cyclohexane to toluene, while they are almost non-emissive in dichloromethane

Synthesis and photophysical properties of 1,1,4,4-tetracyanobutadienes derived from ynamides bearing fluorophores

International audience1,1,4,4-Tetracyanobutadienes (TCBDs) bearing a large diversity of fluorophores were prepared following a multi-step synthesis. In a crucial last step, all compounds were obtained from the corresponding ynamides, which were particularly suitable for the formation of the TCBDs in the presence of tetracyanoethylene via a [2+2] cycloaddition/retroelectrocyclization step (CA-RE). Several fluorenyl derivatives in addition to phenanthrenyl and terphenyl ones provided ynamide-based TCBDs affording remarkable emission properties covering a large range of wavelengths. Those compounds emit both in solid state and in solution from the visible region to the NIR range, depending on the molecular structures. Quantum yields in cyclohexane reached unforeseen values for such derivatives, up to 7.8%. A huge sensitivity to the environment of the TCBDs has also been unraveled for most of the compounds since we observed a dramatic fall of the quantum yields when changing the solvent from cyclohexane to toluene, while they are almost non-emissive in dichloromethane