5 research outputs found
ÎnvestigatiÎżns of new radio-labeling strategies with iÎżdine isÎżtÎżpes
Ă lâheure actuelle, les isotopes de lâiode sont sous exploitĂ©s par rapport au potentiel quâoffre leur emploi en imagerie mĂ©dicale et en radio-thĂ©rapie. Le manque de mĂ©thodologies innovantes en accord avec les challenges dâune utilisation clinique est une des causes de ce dĂ©sintĂ©ressement. Le dĂ©veloppement de nouvelles stratĂ©gies de radio-marquage en employant des substrats bons marchĂ©s, peu toxiques, facilement synthĂ©tisables est lĂ©gitimement devenu un enjeu crucial pour la mĂ©decine nuclĂ©aire de demain. Les projets et rĂ©sultats inscrits dans cette thĂšse sont axĂ©s dans cette nouvelle optique et a permis lâexploration de trois nouvelles stratĂ©gies de radio-iodation. Une mĂ©thode de radio-iododĂ©silylation, dĂ©jĂ dĂ©crite, a Ă©tĂ© rĂ©-Ă©valuĂ©e dans des conditions beaucoup plus douces, et, de surcroĂźt, a Ă©tĂ© transposĂ©e Ă lâemploi de composĂ©s organo-germanylĂ©s comme substrat prĂ©curseur. Le dĂ©veloppement dâune mĂ©thode de radio-iodation Ă partir de composĂ©s faciles dâaccĂšs, ici les acides benzoĂŻques, a Ă©tĂ© mise au point par lâemploi dâun complexe dâor. Le dernier projet, quant Ă lui, a consistĂ© Ă mettre au point une nouvelle voie dâaccĂšs aux molĂ©cules radio-iodĂ©es 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 tomorrowâs nuclear medicine. The projects and results included in this thesis are focused on this new challenge and described the exploration of three new radio-iodinationâs 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
BaseâMediated RadioâIodination of Arenes by using Organosilane and Organogermane as Radiolabelling Precursors
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 ÎČ-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 (+â153 ± 62%) but also in microglia (+â2088 ± 500%) and neurons (+â369 ± 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