Towards highly efficient, intelligent and bimodal imaging probes: Novel approaches provided by lanthanide coordination chemistry

Bioinorganic chemistry; Lanthanides; Ligand design; Magnetic properties; Imaging agents; Gadolinium; MRI CONTRAST AGENTS; HIGH-FIELD RELAXIVITY; HIGH MAGNETIC-FIELD; FAST WATER EXCHANGE; GD-III COMPLEXES; IN-VIVO; PARACEST MRI; ENZYMATIC-ACTIVITY; METAL-COMPLEXES; RESONANCEInternational audienceGd3+ complexes are widely used as contrast enhancing agents in medical magnetic resonance imaging (MRI). In recent years, new fields have emerged in their development. The general tendency of using higher magnetic fields in biomedical and clinical MRI for a better signal to noise ratio calls for new contrast agents specifically optimized for such high field applications Molecular imaging, aiming at the non-invasive visualisation of expression and function of bioactive molecules, requires imaging probes that provide a specific magnetic response to a particular molecular event. Finally, bimodal imaging may allow for combining the excellent resolution of MRI with a good sensitivity of other imaging modalities, such as optical methods. It requires bimodal imaging probes that satisfy requirements for both modalities within a single molecule. Here we review our latest efforts to develop novel lanthanide-based contrast agents in these specific fields and demonstrate the possibilities offered by lanthanide coordination chemistry. (C) 2010 Academic des sciences Published by Elsevier Masson SAS. All rights reserved. RESUM

Thermodynamic stability and relaxation studies of small, triaza-macrocylic Mn(II) chelates

Due to its favorable relaxometric properties, Mn2+ is an appealing metal ion for magnetic resonance imaging (MRI) contrast agents. This paper reports the synthesis and characterization of three new triazadicarboxylate-type ligands and their Mn2+ chelates (NODAHep, 1,4,7-triazacyclononane-1,4-diacetate-7-heptanil; NODABA, 1,4,7-triazacyclononane-1,4-diacetate-7-benzoic acid; and NODAHA (1,4,7-triazacyclononane-1,4-diacetate-7-hexanoic acid). The protonation constants of the ligands and the stability constants of the chelates formed with Mn2+ and the endogenous Zn2+ ion have been determined by potentiometry. In overall, the thermodynamic stability of the chelates is lower than that of the corresponding NOTA analogues (NOTA = 1,4,7-triazacyclononane-1,4,7-triacetate), consistent with the decreased number of coordinating carboxylate groups. Variable temperature 1H NMRD and 17O NMR measurements have been performed on the paramagnetic chelates to provide information on the water exchange rates and the rotational dynamics. The values of the 17O chemical shifts are consistent with the presence of one water molecule in the first coordination sphere of Mn2+. The three complexes are in the slow to intermediate regime for the water exchange rate, and they all display relatively high rotational correlation times, which explain the relaxivity values between 4.7 and 5.8 mM-1.s-1 (20 MHz and 298 K). These relaxivities are higher than expected for Mn2+ chelates of such size and comparable to those of small monohydrated Gd3+ complexes. The amphiphilic [Mn(NODAHep)] forms micelles above 22 mM (its critical micellar concentration was determined by relaxometry and fluorescence), and interacts with HSA via its alkylic carbon chain providing a 60% relaxivity increase at 20 MHz due to a longer tumbling time.We thank the financial support from Fundacao para a Ciencia e a Tecnologia (F.C.T.), Portugal and Fundo Social Europeu (FSE) (PhD grant SFRH/BD/63639/2009 and Rede Nacional de RMN (REDE/1517/RMN/2005) for the acquisition of the Bruker Avance III 400 NMR spectrometer at the University of Minho), as well as financial support from La Ligue Contre le Cancer, France (E. T.). This work was carried out in the frame of the COST Actions D38 "Metal Based Systems for Molecular Imaging" and TD1004 "Theragnostics Imaging and Therapy"

pH-Responsive Relaxometric Behaviour of Coordination Polymer Nanoparticles Made of a Stable Macrocyclic Gadolinium Chelate

Lanthanide-containing nanoscale particles have been widely explored for various biomedical purposes, however, they are often prone to metal leaching. Here we have created a new coordination polymer (CP) by applying, for the first time, a stable Gdchelate as building block in order to prevent any fortuitous release of free lanthanide(III) ion. The use of the Gd-DOTA-4AmP complex as a design element in the CP allows not only for enhanced relaxometric properties (maximum r=16.4 mmsat 10 MHz), but also for a pH responsiveness (Δr=108 % between pH 4 and 6.5), beyond the values obtained for the low molecular weight Gd-DOTA-4AmP itself. The CP can be miniaturised to the nanoscale to form colloids that are stable in physiological saline solution and in cell culture media and does not show cytotoxicity

Responsive ParaCEST Contrast Agents

This article aimed at reviewing the advances on the development of paramagnetic complexes used as chemical exchange saturation transfer agents in magnetic resonance imaging. This relatively new type of contrast opens new avenues in the development of MRI probes for molecular imaging, and coordination chemistry lies at the center of such advances. Strategies to detect important biomarkers such as pH, cations, anions, metabolites, enzyme, and O2 were described. The current challenges, limitations, and opportunities in this field of research were discussed

Smart Contrast Agents for Magnetic Resonance Imaging

By visualizing bioactive molecules or biological parameters in vivo, molecular imaging is searching for information at the molecular level in living organisms. In addition to contributing to earlier and more personalized diagnosis in medicine, it also helps understand and rationalize the molecular factors underlying physiological and pathological processes. In magnetic resonance imaging (MRI), complexes of paramagnetic metal ions, mostly lanthanides, are commonly used to enhance the intrinsic image contrast. They rely either on the relaxation effect of these metal chelates (T1 agents), or on the phenomenon of paramagnetic chemical exchange saturation transfer (PARACEST agents). In both cases, responsive molecular magnetic resonance imaging probes can be designed to report on various biomarkers of biological interest. In this context, we review recent work in the literature and from our group on responsive T1 and PARACEST MRI agents for the detection of biogenic metal ions (such as calcium or zinc), enzymatic activities, or neurotransmitter release. These examples illustrate the general strategies that can be applied to create molecular imaging agents with an MRI detectable response to biologically relevant parameters

Luminescent lanthanide-binding peptides: sensitising the excited states of Eu(III) and Tb(III) with a 1,8-naphthalimide-based antenna.

International audienceThe investigation into the luminescence properties of a lanthanide-binding peptide, derived from the Ca-binding loop of the parvalbumin, and modified by incorporating a 1,8-naphthalimide (Naph) chromophore at the N-terminus is described. Here, the Naph is used as a sensitising antenna, which can be excited at lower energy than classical aromatic amino acids, such as tryptophan (the dodecapeptide of which was also synthesised and studied herein). The syntheses of the Naph antenna, its solid phase incorporation into the dodecapeptide, and the NMR investigation into the formation of the corresponding lanthanide complexes in solution is presented. We also show that this Naph antenna can be successfully employed to sensitize the excited states of both europium and terbium ions, the results of which was used to determined the stability constants of their formation complexes, and we demonstrated that our peptide 'loop' can selectively bind these lanthanide ions over Ca(II)

Particles Comprising Luminescent Lanthanide Complexes

The present invention relates to particles, useful for drug release detection, comprising: at least one luminescent metal complex of formula [Ln].[L], wherein: Ln is a lanthanide ion, L is an organic ligand comprising a hydrophilic unit with at least 6 chelating groups chosen from the group consisting of hydroxyl, carboxyl, optionally in the carboxylate form, carbonyl, ether, phosphonate, phosphinate, thiolate, amino and imino functions, and - at least one drug comprising a conjugated aromatic system, wherein said drug is not covalently bonded to the metal complex, said particle having a size comprised from 3 nm to 2 000 nm, and wherein the distribution of the metal complex and the drug within the particle is such that the mean distance between a drug molecule and a metal complex is less than 15 nm.L'invention concerne des particules utilisées pour détecter la libération d'un médicament et comprenant au moins un complexe métallique luminescent de formule [Ln].[L], où: Ln est un ion lanthanide, L un ligand organique comprenant une unité hydrophile contenant au moins 6 groupes de chélation choisis dans le groupe comprenant l'hydroxyle, le carboxyle, éventuellement sous forme de carboxylate, le carbonyle, l'éther, le phosphonate, le phosphinate, le thiolate, les fonctions amine et imine, et - au moins un médicament comprenant un système aromatique conjugué, ledit médicament n'étant pas lié par covalence au complexe métallique, ladite particule ayant une dimension comprise entre 3 nm et 2 000 nm, la répartition du complexe métallique et du médicament au sein des particules étant telle que la distance moyenne séparant une molécule de médicament et un complexe métallique soit inférieure à 15 nm

A phosphorylated zinc finger peptide bearing a gadolinium complex for zinc detection by MRI.

International audienceTwo zinc finger peptides, namely ZFQD(Ln) and ZFQE(Ln) (Ln = Tb or Gd), with an appended Ln(3+) chelate and a phosphoserine able to coordinate the Ln(3+) ion are presented. The two peptides differ by the amino acid anchorage of the chelate, either aspartate (D) or glutamate (E). Both peptides are able to bind Zn2+ and adopt the beta beta alpha fold. Interestingly, ZFQE(Tb) shows a decrease in sensitized Tb3+ luminescence upon Zn2+ binding whereas ZFQD(Tb) does not. The luminescence change upon Zn2+ binding is attributed to a change in hydration number (q) of the Tb3+ ion due to the decoordination of the phosphoserine from the Ln(3+) ion upon Zn2+ binding and peptide folding. This process is highly sensitive to the length of the linker between the Ln chelate and the peptidic backbone. The magnetic properties of the gadolinium analogue ZFQE(Gd) were studied. An impressive relaxivity increase of 140% is observed at 60 MHz and 25 degrees C upon Zn2+ binding. These changes can be attributed to a combined increase effect of the hydration number of Gd3+ and of the rigidity of the system upon Zn2+ binding. Phantom MR images at 9.4 T show a clear signal enhancement in the presence of Zn2+. These zinc finger peptides offer a unique platform to design such Zn-responsive probes