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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.

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.

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.

Tolmachev V.,Uppsala University | Altai M.,Uppsala University | Sandstrom M.,Uppsala University Hospital | Perols A.,KTH Royal Institute of Technology | And 3 more authors.
Bioconjugate Chemistry | Year: 2011

Radionuclide molecular imaging has the potential to improve cancer treatment by selection of patients for targeted therapy. Affibody molecules are a class of small (7 kDa) high-affinity targeting proteins with appreciable potential as molecular imaging probes. The NOTA chelator forms stable complexes with a number of radionuclides suitable for SPECT or PET imaging. A maleimidoethylmonoamide NOTA (MMANOTA) has been prepared for site-specific labeling of Affibody molecules having a unique C-terminal cysteine. Coupling of the MMA-NOTA to the anti-HER2 Affibody molecule ZHER2:2395 resulted in a conjugate with an affinity (dissociation constant) to HER2 of 72 pM. Labeling of [MMA-NOTA-Cys61]-ZHER2:2395 with 111In gave a yield of >95% after 20 min at 60 °C. In vitro cell tests demonstrated specific binding of [111In-MMA-NOTA-Cys 61]-ZHER2:2395 to HER2-expressing cell lines. In mice bearing prostate cancer DU-145 xenografts, the tumor uptake of [ 111In-MMA-NOTA-Cys61]-ZHER2:2395 was 8.2 ( 0.9% IA/g and the tumor-to-blood ratio was 31 ( 1 (4 h postinjection). DU-145 xenografts were clearly visualized by a gamma camera. Direct in vivo comparison of [111In-MMA-NOTA-Cys61]-ZHER2:2395 and [ 111In-MMA-DOTA-Cys61]-ZHER2:2395 demonstrated that both conjugates provided equal radioactivity uptake in tumors, but the tumor-to-organ ratios were better for [111In-MMANOTA-Cys 61]-ZHER2:2395 due to more efficient clearance from normal tissues. In conclusion, coupling of MMA-NOTA to a cysteine-containing Affibody molecule resulted in a site-specifically labeled conjugate, which retains high affinity, can be efficiently labeled, and allows for high-contrast imaging. © 2011 American Chemical Society.

PubMed | TU Munich, University of Burgundy and Chematech
Type: Journal Article | Journal: ChemMedChem | Year: 2015

In the past few years, gallium-68 has demonstrated significant potential as a radioisotope for positron emission tomography (PET), and the optimization of chelators for gallium coordination is a major goal in the development of radiopharmaceuticals. Methylaminotriazacyclononane trimethylphosphinate (MA-NOTMP), a new C-functionalized triazacyclononane derivative with phosphinate pendant arms, presents excellent coordination properties for (68) Ga (low ligand concentration, labelling at low pH even at room temperature). A ready-to-be-grafted bifunctional chelating agent (p-NCS-Bz-MA-NOTMP) was prepared to allow (68) Ga labelling of sensitive biological vectors. Conjugation to a bombesin(7-14) derivative was performed, and preliminary in vitro experiments demonstrated the potential of MA-NOTMP in the development of radiopharmaceuticals. This new chelator is therefore of major interest for labelling sensitive biomolecules, and further in vivo experiments will soon be performed.

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.

Bernhard C.,CNRS Molecular Chemistry Institute of Burgundy University | Moreau M.,CNRS Molecular Chemistry Institute of Burgundy University | Lhenry D.,CNRS Molecular Chemistry Institute of Burgundy University | Goze C.,CNRS Molecular Chemistry Institute of Burgundy University | And 4 more authors.
Chemistry - A European Journal | Year: 2012

A DOTA derivative that contains an anhydride group was readily synthesized by reacting DOTAGA with acetic anhydride and its reactivity was investigated. Opening the anhydride with propylamine led to the selective formation of one of two possible regioisomers. The structure of the obtained isomer was unambiguously determined by 1D and 2D NMR experiments, including COSY, HMBC, and NOESY techniques. This bifunctional chelating agent offers a convenient and attractive approach for labeling biomolecules and, more generally, for the synthesis of a large range of DOTA derivatives. The scope of the reaction was extended to prepare DOTA-like compounds that contained various functional groups, such as isothiocyanate, thiol, ester, and amino acid moieties. This versatile building block was also used for the synthesis of a bimodal tag for SPECT or PET/optical imaging. © 2012 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim.

PubMed | CNRS Organic Chemistry, Bioorganic Chemistry: Reactivity and Analysis, CNRS Molecular Chemistry Institute of Burgundy University, CheMatech and CNRS The Institute of Chemistry and Processes for Energy, Environment and Health
Type: Journal Article | Journal: Chemistry (Weinheim an der Bergstrasse, Germany) | Year: 2015

Members of a series of boron difluoride complexes with 3-(heteroaryl)-2-iminocoumarin ligands bearing both a phenolic hydroxyl group (acting as a fluorogenic center) and an N-aryl substituent (acting as a stabilizing moiety) have been synthesized in good yields by applying a straightforward two-step method. These novel fluorogenic dyes belong to the family of Boricos (D. Frath etal., Chem. Commun.- 2013, 49, 4908-4910) and are the first examples of phenol-based fluorophores of which the photophysical properties in the green-yellow spectral range are dramatically improved by N,N-chelation of a boron atom. Modulation of their fluorescence properties through reversible chemical modification of their phenol moieties has been demonstrated by the preparation of the corresponding 2,4-dinitrophenyl (DNP) ethers, which led to a dramatic OFF-ON fluorescence response upon reaction with thiols. Additionally, to expand the scope of these 7-hydroxy-Borico derivatives, particularly in biolabeling, amine or carboxylic acid functionalities amenable to (bio)conjugation have been introduced within their scaffold. Their utility has been demonstrated in the preparation of fluorescent bovine serum albumin (BSA) conjugates and Borico-DOTA-like scaffolds in an effort to design novel monomolecular multimodal fluorescence- radioisotope imaging agents.

PubMed | CNRS Molecular Chemistry Institute of Burgundy University, German Cancer Consortium DKTK, CheMatech and University Hospital Freiburg
Type: Journal Article | Journal: Bioconjugate chemistry | Year: 2016

CXCR4 is a G protein-coupled receptor (GPCR), which is overexpressed in numerous diseases, particularly in multiple cancers. Therefore, this receptor represents a valuable target for imaging and therapeutic purposes. Among the different approaches, which were developed for CXCR4 imaging, a CXCR4 antagonist biscyclam system (AMD3100, also called Mozobil), currently used in the clinic for the mobilization of hematopoietic stem cells, was radiolabeled with different radiometals such as (62)Zn, (64)Cu, (67)Ga, or (99m)Tc. However, cyclam is not an ideal chelator for most of these radiometals, and could lead to the release of the radionuclide in vivo. In the current study, a new family of CXCR4 imaging agents is presented, in which AMD3100 is used as a carrier for specific delivery of an imaging reporter, i.e., a (68)Ga complex for PET imaging. AMD3100 was functionalized on the phenyl moiety with different linkers, either ethylenediamine or diamino-polyethylene glycol 3 (PEG3). The resulting AMD3100 analogues were further coupled with two different chelators, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or 1,4,7-triazacyclononane-1-glutaric acid-4,7-acetic acid (NODAGA). Five potential CXCR4 targeting agents were obtained. The derived AMD3100-based ligands were labeled with (68)Ga, highlighting the influence of the spacer nature on the (68)Ga-labeling yield. The lipophilic character of the different systems was also investigated, as well as their affinity for the CXCR4 receptor. The most promising compound was further evaluated in vivo in H69 tumor xenografts by biodistribution and PET imaging studies, validating the proof of principle of our concept.

According to the present invention an enantiopure chelating compound of general Formula 10A or 10B is provided:_(1) through R_(3) is independently selected hydrogen, substituted or unsubstituted C_(1)-C_(20) alkyl, substituted or unsubstituted C_(2)-C_(20) alkenyl, substituted or unsubstituted C_(2)-C_(20) alkynyl, substituted or unsubstituted C_(3)-C_(10) cycloalkyl, substituted or unsubstituted C_(6)-C_(60) aryl, or -Si(R_(4))(R_(5))(R_(6)), and each of R_(4) through R_(6) is independently selected a substituted or unsubstituted group consisting of C_(1)-C_(20) alkyl, C_(2)-C_(20) alkenyl, C_(2)-C_(20) alkynyl, C_(1)-C_(20) alkoxy, C_(3)-C_(10) cycloalkyl, C_(6)-C_(60) aryl, and C_(6)-C_(60) aryloxy. The present invention further refers to a corresponding preparation method of the chelating compound and chelator coupled pharmaceuticals including the same.

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