Kinetics of Ga(NOTA) formation from weak Ga-citrate complexes.

International audienceGallium complexes are gaining increasing importance in biomedical imaging thanks to the practical advantages of the (68)Ga isotope in Positron Emission Tomography (PET) applications. (68)Ga has a short half-time (t(1/2) = 68 min); thus the (68)Ga complexes have to be prepared in a limited time frame. The acceleration of the formation reaction of gallium complexes with macrocyclic ligands for application in PET imaging represents a significant coordination chemistry challenge. Here we report a detailed kinetic study of the formation reaction of the highly stable Ga(NOTA) from the weak citrate complex (H(3)NOTA = 1,4,7-triazacyclononane-1,4,7- triacetic acid). The transmetalation has been studied using (71)Ga NMR over a large pH range (pH = 2.01-6.00). The formation of Ga(NOTA) is a two-step process. First, a monoprotonated intermediate containing coordinated citrate, GaHNOTA(citrate)*, forms in a rapid equilibrium step. The rate-determining step of the reaction is the deprotonation and slow rearrangement of the intermediate accompanied by the citrate release. The observed reaction rate shows an unusual pH dependency with a minimum at pH 5.17. In contrast to the typical formation reactions of poly(amino carboxylate) complexes, the Ga(NOTA) formation from the weak citrate complex becomes considerably faster with increasing proton concentration below pH 5.17. We explain this unexpected tendency by the role of protons in the decomposition of the GaHNOTA(citrate)* intermediate which proceeds via the protonation of the coordinated citrate ion and its subsequent decoordination to yield the final product Ga(NOTA). The stability constant of this intermediate, log K(GaHNOTA(citrate)*) = 15.6, is remarkably high compared to the corresponding values reported for the formation of macrocyclic lanthanide(III)-poly(amino carboxylates). These kinetic data do not only give mechanistic insight into the formation reaction of Ga(NOTA), but might also contribute to establish optimal experimental conditions for the rapid preparation of Ga(NOTA)-based radiopharmaceuticals for PET applications

Complexation du bismuth III par les macrocycles polyazotés en vue d'une application en alpha-radio-immunothérapie

Récemment, l alpha-radio-immunothérapie a connu un essor important. pour traiter les tumeurs difficilement opérables. Ce type de thérapie nécessite des émetteurs alpha comme le bismuth 213. Sa demi-vie de 46 minutes le rend très intéressant. Notre travail a eu pour but de préparer des ligands destinés à vectoriser ce métal en alpha-radio-immunothérapie et d étudier les différents aspects de la complexation du bismuth non-radioactif par les ligands synthétisés. Une élude préliminaire sur les 1.4.7, 10-tetrakis(pyridin-2-ylmethyl)-cyclen et son homologue cyclam a permis d envisager la synthèse de tétraazamacrocycles dérivés du cyclen et du, cyclam N-substitués par deux bras de type pyridinyle et deux bras amide polyoxygéné. Les travaux portant sur la stabilité thermodynamique et sur la vitesse de fomation des complexes de bismuth III des ligands préparés ont montré la nette supériorité du dérivé cyclen en niveau de la stabilité et de l inertie cinétique. Le complexe du dérivé cyclam présente un comportement labile. La cinétique de complexation, initialement lente, a été grandement améliorée en pré-engageant le métal dans un complexe plus faible (Binta), celui-ci permettant de maintenir le métal en solution à pH neutre. De ce fait ce ligand, associé au nta, présente les caractéristiques nécessaires en vue de tests in-vivo avec le bismuth 213 : bonne stabilisé thermodynamique, cinétique de complexation en adéquation avec la demi-vie du radioélément et inertie cinétique. Le greffage sur anticorps sera ainsi envisagé par la suite.Recently bismuth complexes have attracted much attention due to their potential applications in medicine: bismuth 213 is alpha-emitting show great promise in radio-immunotherapy grace to his attractive half time of 46 minutes. The purpose of our work was to prepare ligands intended for dispatch bismuth 213 for alpharadio-immunotherapy and to study the various aspects of the complexation of not-radioactive metal by the synthesized ligands. Preliminary studies on the 1 ,4,7, 10-tetrakis (pyridin-2-ylmethyl)-cyclen and its homologue cyclam made it possible to consider the synthesis of tétraazamacrobycicles derived from the cyclen and of the cyclam, N-substitute by two pyridyle arms and two polyoxygenated amid arms. The thermodynamic studies and formation rate of the bismuth III complexes with synthesized ligands clearly showed the superiority of cyclen derived for stability and kinetic inertia. The complex of cyclam derived has an unstable behavior. The complex formation rate, initially slow, was largely improved by pre-engaging metal in a weaker complex (Binta), this one making it possible to maintain metal in solution with neutral pH. Thus, this ligand associated the nta, shows the characteristics necessary for tests in-vivo with bismuth 213: high stability, kinetic of complexation in adequacy with the half-life of the radioelement and kinetic inertia.The grafting on antibody will be thus considered thereafter.BREST-BU Droit-Sciences-Sports (290192103) / SudocSudocFranceF

Agents de contraste pour l'IRM

International audienceL'imagerie par résonance magnétique (IRM) permet d'accéder à la structure interne des êtres vivants, de manière non invasive et atraumatique. Pour aller au-delà de la simple structuration de la matière vivante, des molécules aux propriétés très particulières ont été développées, les agents de contraste, qui permettent d'étendre le champ d'action et la spécificité de l'IRM. Ces agents de contraste ont permis d'augmenter le contraste des images IRM, ils sont maintenant destinés à visualiser des événements moléculaires au niveau cellulaire et à permettre une caractérisation physico-chimique des tissus

Gd3+ complexes conjugated to Pittsburgh compound B: potential MRI markers of b-amyloid plaques

In an effort towards the visualization of b-amyloid (Ab) plaques by T1-weighted magnetic resonance imaging for detection of Alzheimer’s disease, we report the synthesis and characterization of stable, noncharged Gd3? complexes of three different 1,4,7,10- tetraazacyclododecane-1,4,7-triacetic acid monoamide derivatives conjugated to Pittsburgh compound B, a wellestablished marker of Ab plaques. The ligands L1, L2, and L3 differ in the nature and size of the spacer linking the macrocyclic chelator and the Pittsburgh compound B targeting moiety, which affects their lipophilicity, the octanol– water partition coefficients of the complexes ranging from -0.15 to 0.32. Given their amphiphilic behavior, the complexes form micelles in aqueous solution (critical micellar concentration 1.00–1.49 mM). The parameters determining the relaxivity, including the water exchange rate and the rotational correlation times, were assessed for the monomeric and the micellar form by a combined 17O NMR and 1H nuclear magnetic relaxation dispersion (NMRD) study. They are largely influenced by the aggregation state and the hydrophobic character of the linkers. The analysis of the rotational dynamics for the aggregated state in terms of local and global motions using the Lipari– Szabo approach indicates highly flexible, large aggregates. On binding of the complexes to human serum albumin or to the amyloid peptide Ab1–40 in solution, they undergo a fourfold and a twofold relaxivity increase, respectively (40 MHz). Proton relaxation enhancement studies confirmed moderate interaction of Gd(L1) and Gd(L3) with human serum albumin, with KA values ranging between 250 and 910 M-1.This work was financially supported by Fundação para a Ciência e a Tecnologia, Portugal (PhD grant SFRH/BD/ 46370/2008 to AFM) and Rede Nacional de RMN (project REDE/ 1517/RMN/2005) for the acquisition of the Varian VNMRS 600 NMR spectrometer in Coimbra and the French-Portuguese PESSOA project. This work was carried out in the frame of the European Actions TD1004 ‘‘Theragnostics Imaging and Therapy’’ and TD1007 ‘‘PET-MRI’’

Metal complexes for the visualisation of amyloid peptides

International audienceAmyloid forms of many different proteins have been long identified as relevant biomarkers in important pathologies with high societal impact, including Aβ in Alzheimer's disease, amylin in type 2 diabetes, α-synuclein in Parkinson's disease, etc. With over eighty novel complexes reported in the last six years, metal-based agents designed for the detection of such amyloid fibrils represent a rapidly growing field in molecular imaging. While the majority of these examples are radiocomplexes for nuclear imaging and focus on the detection of Aβ in Alzheimer's disease, there is increasing interest in other peptides and pathologies, and few studies are also directed at magnetic resonance imaging probes. In this review, we survey the recent literature according to the chemical nature of the amyloid recognition moieties, most of which are derived from a few basic structures, including benzothiazole, benzofuran or stilbene. Relationships between chemical structure and amyloid binding properties and biodistribution, in particular brain delivery and brain clearance, are outlined in order to help further work in this emerging area of research

Bismuth(III) complexes with tetra-pyridylmethyl-cyclen

International audienceBimuth(III) complexes with 1,4,7,10-tetrakis(2-pyridylmethyl)-1,4,7,10-tetraazacyclododecane have been prepared in dichloromethane and ethanol and investigated. These complexes have been characterized structurally by X-ray diffraction and NMR-2D studies. They present different coordination scheme depending on the reaction conditions: according to the nature of solvent, bismuth coordinates from six to eight nitrogen atoms and forms in the solid state a chiral structure which is maintained in solution

Bismuth (III) coordination to cyclen and cyclam bearing four appended groups

International audienceThe synthesis of new cyclam and cyclen derivatives (respectively L1 and L2), able to efficiently coordinate to Bi(III) are presented here. The two ligands bearing two different pendant arms (two-pycolyl and two (2-(2-hydroxyethoxy)ethyl)-2-aminoacetamide in trans position) were synthesized in the aim to obtain stable and water soluble complexes. The thermodynamic and kinetic of the formation of the corresponding complexes in aqueous solution were studied by means of NMR and potentiometric investigations. The fast kinetic of complexation and the high stability of the complexes are encouraging for further application with the alpha-emitting 213Bi isotope

Zinc responsive contrast agents

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Smart MRI contrast agents for zinc detection

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