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Chevalier A.,CNRS Organic Chemistry, Bioorganic Chemistry: Reactivity and Analysis | Renault K.,CNRS Organic Chemistry, Bioorganic Chemistry: Reactivity and Analysis | Boschetti F.,CheMatech | Renard P.-Y.,CNRS Organic Chemistry, Bioorganic Chemistry: Reactivity and Analysis | And 2 more authors.
European Journal of Organic Chemistry | Year: 2015

A transition-metal-free method for the synthesis of N-substituted unsymmetrical sulforhodamine fluorophores from an unusual monobrominated sulfoxanthene dye and primary or secondary amines by direct SNAr-type reactions is presented. The simplicity and effectiveness of this "postamination" procedure were demonstrated through the rapid preparation of a library of multifunctional red-emitting rhodamine analogues. Some of these analogues are equipped with a reactive handle and retain the two water-solubilizing sulfonic acid moieties of the starting halogenated derivative; this makes them ideal candidates for biolabeling applications. The potential utility of this expeditious strategy to finely tune the photophysical (Stokes shift) and physicochemical properties (amphiphilic character and water solubility) of the sulforhodamine scaffold was also demonstrated through the appendage of a fluorescent amine to create a fluorescence resonance energy transfer (FRET) pair, a long-chain amine, and tetraazamacrocycles derived from cyclen © 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. Source

Heskamp S.,Radboud University Nijmegen | Laverman P.,Radboud University Nijmegen | Rosik D.,KTH Royal Institute of Technology | Boschetti F.,CheMatech | And 5 more authors.
Journal of Nuclear Medicine | Year: 2012

Affibody molecules are small (7 kDa) proteins with subnanomolar targeting affinity. Previous SPECT studies in xenografts have shown that the Affibody molecule 111In-DOTA-Z HER2:2395 can discriminate between high and low human epidermal growth factor receptor type 2 (HER2) - expressing tumors, indicating that radiolabeled Affibody molecules have potential for patient selection for HER2-targeted therapy. Compared with SPECT, PET with positron-emitting radionuclides, such as 18F, may improve imaging of HER2 expression because of higher sensitivity and improved quantification of PET. The aim of the present study was to determine whether the 18F-labeled NOTA-conjugated Affibody molecule Z HER2:2395 is a suitable agent for imaging of HER2 expression. The tumor-targeting properties of 18F-labeled Z HER2:2395 were compared with 111In- and 68Ga-labeled Z HER2:2395 in mice with HER2-expressing SK-OV-3 xenografts. Methods: Z HER2:2395 was conjugated with NOTA and radiolabeled with 18F, 68Ga, and 111In. Radiolabeling with 18F was based on the complexation of Al 18F by NOTA. The 50% inhibitory concentration values for NOTA-Z HER2:2395 labeled with 19F, 69Ga, and 115In were determined in a competitive cell-binding assay using SK-OV-3 cells. Mice bearing subcutaneous SK-OV-3 xenografts were injected intravenously with radiolabeled NOTA-Z HER2:2395. One and 4 h after injection, PET/CT or SPECT/CT images were acquired, and the biodistribution was determined by ex vivo measurement. Results: The 50% inhibitory concentration values for 19F-, 69Ga-, and 115In- NOTA-Z HER2:2395 were 5.0, 6.3, and 5.3 nM, respectively. One hour after injection, tumor uptake was 4.4 ± 0.8 percentage injected dose per gram (%ID/g), 5.6 ± 1.6%ID/g, and 7.1 ± 1.4%ID/g for 18F-, 68Ga-, and 111In-NOTA-Z HER2:2395, respectively, and the respective tumor-to-blood ratios were 7.4 ± 1.8, 8.0 ± 1.3, and 4.8 ± 1.3. Tumor uptake was specific, because uptake could be blocked efficiently by coinjection of an excess of unlabeled Z HER2:2395. PET/CT and SPECT/CT images clearly visualized HER2-expressing SK-OV-3 xenografts. Conclusion: This study showed that 18F-NOTA-Z HER2:2395 is a promising new imaging agent for HER2 expression in tumors. Affibody molecules were successfully labeled with 18F within 30 min, based on the complexation of Al 18F by NOTA. Further research is needed to determine whether this technique can be used for patient selection for HER2-targeted therapy. Copyright © 2012 by the Society of Nuclear Medicine, Inc. Source

Lux F.,University Claude Bernard Lyon 1 | Mignot A.,CNRS Laboratory for Materials: Engineering and Science | Mowat P.,University Claude Bernard Lyon 1 | Louis C.,Nano H S.A.S | And 24 more authors.
Angewandte Chemie - International Edition | Year: 2011

Ultrasmall but multifunctional: Rigid imaging particles that are smaller than 5 nm in size can be obtained in a top-down process starting from a core-shell structure (core=gadolinium oxide; shell=polysiloxane). They represent the first multifunctional silica-based particles that are sufficiently small to escape hepatic clearance and enable animal imaging by four complementary techniques. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source

Rousselin Y.,University of Burgundy | Sok N.,University of Burgundy | Boschetti F.,CheMatech | Guilard R.,University of Burgundy | Denat F.,University of Burgundy
European Journal of Organic Chemistry | Year: 2010

A powerful synthetic route for the preparation of new polyazamacrocycles, valuable precursors of afunctional chelating agents with applications in nuclear medicine, is reported. The desired functional group was introduced onto the macrocycle backbone during the cyclization step, thus avoiding the tedious preparation of a C-functionalized synthon. The regioselective reaction of macrocycles bearing an aminomethyl pendant arm with aldehydes is also described. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA. Source

Altai M.,Uppsala University | Perols A.,KTH Royal Institute of Technology | Karlstrom A.E.,KTH Royal Institute of Technology | Sandstrom M.,Uppsala University Hospital | And 3 more authors.
Nuclear Medicine and Biology | Year: 2012

Introduction: Affibody molecules have demonstrated potential for radionuclide molecular imaging. The aim of this study was to synthesize and evaluate a maleimido derivative of the 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid (NODAGA) for site-specific labeling of anti-HER2 Affibody molecule. Methods: The maleimidoethylmonoamide NODAGA (MMA-NODAGA) was synthesized and conjugated to ZHER2:2395 Affibody molecule having a C-terminal cysteine. Labeling efficiency, binding specificity to and cell internalization by HER2-expressing cells of [111In-MMA-NODAGA-Cys61]-ZHER2:2395 were studied. Biodistribution of [111In-MMA-NODAGA-Cys61]-ZHER2:2395 and [111In-MMA-DOTA-Cys61]-ZHER2:2395 was compared in mice. Results: The affinity of [MMA-NODAGA-Cys61]-ZHER2:2395 binding to HER2 was 67 pM. The 111In-labeling yield was 99.6%±0.5% after 30 min at 60°C. [111In-MMA-NODAGA-Cys61]-ZHER2:2395 bound specifically to HER2-expressing cells in vitro and in vivo. Tumor uptake of [111In-MMA-NODAGA-Cys61]-ZHER2:2395 in mice bearing DU-145 xenografts (4.7%±0.8% ID/g) was lower than uptake of [111In-MMA-DOTA-Cys61]-ZHER2:2395 (7.5%±1.6% ID/g). However, tumor-to-organ ratios were higher for [111In-MMA-NODAGA-Cys61]-ZHER2:2395 due to higher clearance rate from normal tissues. Conclusions: MMA-NODAGA is a promising chelator for site-specific labeling of targeting proteins containing unpaired cysteine. Appreciable influence of chelators on targeting properties of Affibody molecules was demonstrated. © 2012 Elsevier Inc. Source

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