Towards Translational ImmunoPET/MR Imaging of Invasive Pulmonary Aspergillosis: The Humanised Monoclonal Antibody JF5 Detects Aspergillus Lung Infections In Vivo

Invasive pulmonary aspergillosis (IPA) is a life-threatening lung disease of hematological malignancy or bone marrow transplant patients caused by the ubiquitous environmental fungus Aspergillus fumigatus. Current diagnostic tests for the disease lack sensitivity as well as specificity, and culture of the fungus from invasive lung biopsy, considered the gold standard for IPA detection, is slow and often not possible in critically ill patients. In a previous study, we reported the development of a novel non-invasive procedure for IPA diagnosis based on antibody-guided positron emission tomography and magnetic resonance imaging (immunoPET/MRI) using a [64Cu] DOTA-labeled mouse monoclonal anti…

DOTAGA-Trastuzumab. A New Antibody Conjugate Targeting HER2/Neu Antigen for Diagnostic Purposes.

International audience; Improved bifunctional chelating agents (BFC) are required for indium-111 radiolabeling of monoclonal antibodies (mAbs) under mild conditions to yield stable, target-specific agents. 2,2',2″-(10-(2,6-Dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (DOTAGA-anhydride) was evaluated for mAb conjugation and labeling with indium-111. The DOTA analogue was synthesized and conjugated to trastuzumab-which targets the HER2/neu receptor-in mild conditions (PBS pH 7.4, 25 °C, 30 min) and gave a mean degree of conjugation of 2.6 macrocycle per antibody. Labeling of this immunoconjugate with indium-111 was performed in 75% yield after 1 h a…

Efficient Synthesis of Multifunctional Chelating Agents Based on Tetraazacycloalkanes

An efficient route has been developed for the synthesis of multifunctional tetraazacycloalkanes (in particular 1,4,7,10-tetraazacyclotridecane) incorporating an aminomethyl pendant arm on the carbon skeleton. Starting from the appropriate C-functionalized bisaminal-protected intermediate, the target macrocycles were easily obtained by means of a step-by-step introduction of the desired functional groups onto the free primary amine group, followed by deprotection of the bisaminal intermediates. This straightforward and versatile synthetic approach paves the way for the design of a new family of multifunctional chelators.

Rapid Synthesis of Unsymmetrical Sulforhodamines Through Nucleophilic Amination of a Monobrominated Sulfoxanthene Dye

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 …

A top-down synthesis route to ultrasmall multifunctional Gd-based Silica nanoparticles for theranostic applications

International audience; New, ultrasmall nanoparticles with sizes below 5 nm have been obtained. These small rigid platforms (SRP) are composed of a polysiloxane matrix with DOTAGA (1,4,7,10-tetraazacyclododecane-1-glutaric anhydride-4,7,10-triacetic acid)-Gd3+ chelates on their surface. They have been synthesised by an original top-down process: 1) formation of a gadolinium oxide Gd2O3 core, 2) encapsulation in a polysiloxane shell grafted with DOTAGA ligands, 3) dissolution of the gadolinium oxide core due to chelation of Gd3+ by DOTAGA ligands and 4) polysiloxane fragmentation. These nanoparticles have been fully characterised using photon correlation spectroscopy (PCS), transmission elec…

Minor changes in the macrocyclic ligands but major consequences on the efficiency of gold nanoparticles designed for radiosensitization

International audience; Many studies have been devoted to adapting the design of gold nanoparticles to efficiently exploit their promising capability to enhance the effects of radiotherapy. In particular, the addition of magnetic resonance imaging modality constitutes an attractive strategy for enhancing the selectivity of radiotherapy since it allows the determination of the most suited delay between the injection of nanoparticles and irradiation. This requires the functionalization of the gold core by an organic shell composed of thiolated gadolinium chelates. The risk of nephrogenic systemic fibrosis induced by the release of gadolinium ions should encourage the use of macrocyclic chelat…

Ultrasmall Rigid Particles as Multimodal Probes for Medical Applications

International audience; 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.

MANOTA: a promising bifunctional chelating agent for copper-64 immunoPET

International audience; Improved bifunctional chelating agents (BFC) are required for copper-64 radiolabelling of monoclonal antibodies (mAbs) under mild conditions to yield stable, target-specific imaging agents. Four different bifunctional chelating agents (BFC) were evaluated for Fab (Fragment antigen binding) conjugation and radiolabelling with copper-64. Two DOTA- (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and two NOTA- (1,4,7-triazacyclononane-1,4,7-triacetic acid) derivatives bearing a p-benzyl-isothiocyanate group were conjugated to Fab-trastuzumab - which targets the HER2/neu receptor - and the average number of chelators attached ranged from 2.4 to 4.3 macrocycles …

AGuIX® from bench to bedside-Transfer of an ultrasmall theranostic gadolinium-based nanoparticle to clinical medicine.

International audience; AGuIX® are sub-5 nm nanoparticles made of a polysiloxane matrix and gadolinium chelates. This nanoparticle has been recently accepted in clinical trials in association with radiotherapy. This review will summarize the principal preclinical results that have led to first in man administration. No evidence of toxicity has been observed during regulatory toxicity tests on two animal species (rodents and monkeys). Biodistributions on different animal models have shown passive uptake in tumours due to enhanced permeability and retention effect combined with renal elimination of the nanoparticles after intravenous administration. High radiosensitizing effect has been obser…

An Off-On-Off Fluorescent Sensor for pH Windows Based on the 13aneN4-Zn 2+ System

International audience; The new ligand L was prepared and features a 13-membered tetraaza macrocyclic ring with a 1,8-naphthalimide fluorophore appended to a C atom of its backbone. The protonation constants of L as well as its complexation constants with Zn2+ ions were determined in 1:1 water/methanol solutions by potentiometric titrations. Fluorimetric pH titrations were performed with L alone and L in the presence of Zn2+ ions (1:1), and the species distributions (%) versus pH were compared. A window-shaped fluorescence trend was observed with pH for the L/Zn2+ system, which behaves as an off-on-off pH sensor. The on window is centred in the 6.5-7.5 pH range, in correspondence with the f…

Efficient Synthesis of 1,4,7-Triazacyclononane and 1,4,7-Triazacyclononane-Based Bifunctional Chelators for Bioconjugation (Eur. J. Org. Chem. 35/2014)

Efficient synthesis of new C-functionalized macrocyclic polyamines

A powerful synthetic route for the preparation of new poly-azamacrocycles, valuable precursors of bifunctional chelating agents with applications in nuclear medicine, is reported. The desired functional group was introduced onto the macro-cycle 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.

Functionalization of theranostic AGuIX® nanoparticles for PET/MRI/optical imaging

International audience; A novel trifunctional imaging probe containing a chelator of radiometal for PET, a NIR heptamethine cyanine dye, and a bioconjugatable handle, has been grafted onto AGuIX® nanoparticles via a Michael addition reaction. The resulting functionalized nanoparticles have been fully characterized, radiolabelled with 64Cu, and evaluated in a mice TSA tumor model using multimodal (PET/MRI/optical) imaging.

Reinforced cyclam derivatives functionalized on the bridging unit

International audience; A new synthetic method has been developed for the preparation of reinforced cyclams (1,4,8,11-tetraazacyclotetradecane) C-functionalized on the bridging unit, by using a "one pot" reaction starting from the appropriate bis-aminal cyclam intermediate. The high reactivity of quaternized aminal moiety toward nucleophilic agent has been used to elaborate a new class of cross-bridged and side-bridged cyclam derivatives containing cyanide group on the ethylene bridge. Several chelators and corresponding copper(II) complexes have been prepared and characterized by X-ray diffraction. These new constrained polyazamacrocycles are valuable precursors of bifunctional chelating a…

Efficient Synthesis of 1,4,7-Triazacyclononane and 1,4,7-Triazacyclononane-Based Bifunctional Chelators for Bioconjugation

The reaction of diethylenetriamine with chloroacetaldehyde yielded a bicyclic aminal intermediate for the synthesis of 1,4,7-triazacyclononane (TACN), a macrocyclic polyamine the derivatives of which find applications as catalysts, bleaching agents, and chelators for medical imaging. This new synthetic protocol outperforms the synthetic methods described so far because it does not involve any cyclization step. Moreover, this aminal intermediate allowed access to a new family of TACN derivatives functionalized on the carbon skeleton, for example, C-aminomethyl-TACN. This novel compound is a precursor of valuable bifunctional chelating agents for nuclear medicine, in particular, for the prepa…

One-pot direct synthesis for multifunctional ultrasmall hybrid silica nanoparticles

International audience; Ultrasmall silica nanoparticles (NPs), having hydrodynamic diameters under 10 nm are promising inorganic platforms for imaging and therapeutic applications in medicine. Herein is described a new way for synthesizing such kind of NPs in a one-pot scalable protocol. These NPs bear DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) ligands on their surface that can chelate different metals suitable for a wide variety of biomedical applications. By varying the ratio of the precursors, the hydrodynamic diameters of the particles can be controlled over the range of 3 to 15 nm. The resulting NPs have been characterized extensively by complementary techniques li…

AMD3100: A Versatile Platform for CXCR4 Targeting 68 Ga-Based Radiopharmaceuticals

International audience; 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 62Zn, 64Cu, 67Ga, or 99mTc. 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 …

DOTAGA-anhydride: a valuable building block for the preparation of DOTA-like chelating agents.

International audience; 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 f…

Ultrasmall particles for Gd-MRI and68Ga-PET dual imaging

Nanoparticles made of a polysiloxane matrix and surrounded by 1,4,7,10-tetraazacyclododecane-1-glutaric anhydride-4,7,10-triacetic acid (DOTAGA)[Gd(3+) ] and 2,2'-(7-(1-carboxy-4-((2,5-dioxopyrrolidin-1-yl)oxy)-4-oxobutyl)-1,4,7-triazonane-1,4-diyl)diacetic acid) NODAGA[(68) Ga(3+) ] have been synthesized for positron emission tomography/magnetic resonance (PET/MRI) dual imaging. Characterizations were carried out in order to determine the nature of the ligands available for radiolabelling and to quantify them. High radiolabelling purity (>95%) after (68) Ga labelling was obtained. The MR and PET images demonstrate the possibility of using the nanoparticles for a combined PET/MR imaging sca…

CCDC 1583210: Experimental Crystal Structure Determination

Related Article: Nicolas Sok, Claire Bernhard, Pauline Désogère, Christine Goze, Yoann Rousselin, Frédéric Boschetti, Isabelle Baglin, Franck Denat|2018|Eur.J.Org.Chem.|2018|4762|doi:10.1002/ejoc.201800801

CCDC 1583212: Experimental Crystal Structure Determination

Related Article: Nicolas Sok, Claire Bernhard, Pauline Désogère, Christine Goze, Yoann Rousselin, Frédéric Boschetti, Isabelle Baglin, Franck Denat|2018|Eur.J.Org.Chem.|2018|4762|doi:10.1002/ejoc.201800801

CCDC 1583211: Experimental Crystal Structure Determination

Related Article: Nicolas Sok, Claire Bernhard, Pauline Désogère, Christine Goze, Yoann Rousselin, Frédéric Boschetti, Isabelle Baglin, Franck Denat|2018|Eur.J.Org.Chem.|2018|4762|doi:10.1002/ejoc.201800801

CCDC 1583209: Experimental Crystal Structure Determination

Related Article: Nicolas Sok, Claire Bernhard, Pauline Désogère, Christine Goze, Yoann Rousselin, Frédéric Boschetti, Isabelle Baglin, Franck Denat|2018|Eur.J.Org.Chem.|2018|4762|doi:10.1002/ejoc.201800801

CCDC 1476682: Experimental Crystal Structure Determination

Related Article: Nicolas Sok, Isabelle Baglin, Christelle Basset, Fatima Fakkor, Evelyne Kohli, Yoann Rousselin, Claire Bernhard, Frédéric Boschetti, Christine Goze, Franck Denat|2017|RSC Advances|7|28291|doi:10.1039/C7RA04218C

CCDC 1583208: Experimental Crystal Structure Determination

Related Article: Nicolas Sok, Claire Bernhard, Pauline Désogère, Christine Goze, Yoann Rousselin, Frédéric Boschetti, Isabelle Baglin, Franck Denat|2018|Eur.J.Org.Chem.|2018|4762|doi:10.1002/ejoc.201800801

CCDC 960361: Experimental Crystal Structure Determination

Related Article: Pauline Désogère, Yoann Rousselin, Sophie Poty, Claire Bernhard, Christine Goze, Frédéric Boschetti, Franck Denat|2014|Eur.J.Org.Chem.|2014|7831|doi:10.1002/ejoc.201402708

CCDC 1476683: Experimental Crystal Structure Determination

Related Article: Nicolas Sok, Isabelle Baglin, Christelle Basset, Fatima Fakkor, Evelyne Kohli, Yoann Rousselin, Claire Bernhard, Frédéric Boschetti, Christine Goze, Franck Denat|2017|RSC Advances|7|28291|doi:10.1039/C7RA04218C

CCDC 1476681: Experimental Crystal Structure Determination

Related Article: Nicolas Sok, Isabelle Baglin, Christelle Basset, Fatima Fakkor, Evelyne Kohli, Yoann Rousselin, Claire Bernhard, Frédéric Boschetti, Christine Goze, Franck Denat|2017|RSC Advances|7|28291|doi:10.1039/C7RA04218C

CCDC 960359: Experimental Crystal Structure Determination

Related Article: Pauline Désogère, Yoann Rousselin, Sophie Poty, Claire Bernhard, Christine Goze, Frédéric Boschetti, Franck Denat|2014|Eur.J.Org.Chem.|2014|7831|doi:10.1002/ejoc.201402708

CCDC 1583213: Experimental Crystal Structure Determination

Related Article: Nicolas Sok, Claire Bernhard, Pauline Désogère, Christine Goze, Yoann Rousselin, Frédéric Boschetti, Isabelle Baglin, Franck Denat|2018|Eur.J.Org.Chem.|2018|4762|doi:10.1002/ejoc.201800801

CCDC 960360: Experimental Crystal Structure Determination

Related Article: Pauline Désogère, Yoann Rousselin, Sophie Poty, Claire Bernhard, Christine Goze, Frédéric Boschetti, Franck Denat|2014|Eur.J.Org.Chem.|2014|7831|doi:10.1002/ejoc.201402708