Synthetic Approaches to Heterocyclic Ligands for Gd-Based MRI Contrast Agents (original) (raw)
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ChemInform Abstract: Synthetic Approaches to Heterocyclic Ligands for Gd-Based MRI Contrast Agents
ChemInform, 2009
Magnetic Resonance Imaging (MRI) methods are currently used in the clinic for the non invasive detection and characterization of a wide variety of pathologies. Increases in the diagnostic efficiency of MRI have been helped by both the design of dedicated MR sequences revealing specific aspects of the pathology and by the development of more sensitive and selective Contrast Agents (CAs), capable of more precisely delineating the borderline regions. In the present review we focus on the synthetic strategies used to obtain MRI CAs containing heterocyclic rings.
[Gd-AAZTA] - : A New Structural Entry for an Improved Generation of MRI Contrast Agents
Inorganic Chemistry, 2004
An innovative MRI contrast agent based on the unprecedented and easily obtained ligand AAZTA is described. The simple and straightforward synthesis of the ligand, together with the potentiometric and relaxometric behavior of the corresponding Gd(III) chelate, is reported. The complex [Gd(AAZTA)]shows outstanding magnetic properties connected with high thermodynamic stability in aqueous solution and a nearly complete inertness toward the influence of bidentate endogenous anions, placing this compound as one of the most promising candidates for the development of high performance MRI contrast agents.
Synthesis and Evaluation of a Gd (III) Complex as T 1 -Weighted MRI Contrast Agent
https://ijshr.com/IJSHR\_Vol.4\_Issue.3\_July2019/IJSHR\_Abstract.0016.html, 2019
A hexadentate ligand, H4mum consisting of two phenyl moieties with four acetate arms was designed and synthesized. A water-soluble Gd(III) complex (1) was synthesized by reacting ligand H4mum with GdCl3·xH2O in 1:1 molar equivalent. Tb (III) congener (complex 2) of complex 1 was also synthesized and used for determining the number of coordinated water molecules present in the inner-coordination sphere of the complex by luminescence lifetime measurements. It was confirmed that the complex consisted of two directly coordinated-water molecules. At 25 °C and pH ~ 7.4 in HEPES buffer, the complex offered longitudinal relaxivity r1 value of 8.34 mM–1s–1 at a magnetic field of strength 1.41 T. However, with increasing filed strength to 14.1 T, the r1 relaxivity value slightly deceased to 7.62 mM–1s–1 at the same experimental conditions. The complex stability under physiological conditions was investigated by measuring r1 relaxivity in the presence of various physiological anions. In the presence of almost 100 equivalents (~ 50.0 mM) excess of these anions the r1 value remained almost constant, justified the complex stability under physiological conditions. Finally, phantom MR imaging under clinical scanner at 1.5 T showed positive contrast efficiency of the complex. Keywords: MRI, Contrast agents, Gadolinium (III) complex, Relaxivity, Hydration state, High field.
Synthesis and Development of Gd 3+ -ALGDG 2 -C595 as MR Imaging Contrast Agent
Magnetic Resonance imaging (MR imaging) as a powerful non-invasive modality is of high global interest for early cancer detection. The aim of this study was the synthesis of nanodendrimer and its conjugate with monoclonal antibody C595 against breast cancer cell, followed by its chelating with gadolinium for its magnetic property. First, anti-MUC-1 monoclonal antibody C595 was coupled to a biodegradable biocompatible Anionic Linear Globular Dendrimer G 2 (having polyethylene glycol core and citric acid shell). Then prepared nanocomplex loaded by gadolinium to make novel agent of functional MR imaging. Anticancer effects and MR imaging parameters of the prepared nanoconjugate was investigated under in vitro conditions doing performing several studies such as evaluation of monoclonal antibody C595 binding to mucine-1 (MUC-1) cell, its purification, size of nanoconjugate and relaxivity measurements. The obtained data showed a powerful relaxations as well as selective MUC-1 antigen binding to the cell. Based on the findings from the present research Gd 3+ -ALGDG 2 -C595 nano-probe may be a potential breast molecular imaging and therapeutic agent. However, further investigations by in vivo studies and clinical trials are in the pipeline.
Journal of the American Chemical Society, 2012
MR imaging at high magnetic fields benefits from an increased signal to noise ratio, however T 1 based MR contrast agents show decreasing relaxivity (r 1) at higher fields. High field, high relaxivity contrast agents can be designed by carefully controlling the rotational dynamics of the molecule. To this end, we investigated applications of the alanine analogue of Gd(DOTA), Gd(DOTAla). Fmoc protected DOTAla suitable for solid phase peptide synthesis was synthesized and integrated into polypeptide structures. Gd(III) coordination results in very rigid attachment of the metal chelate to the peptide backbone through both the amino acid sidechain and coordination of the amide carbonyl. Linear and cyclic monomers (GdL1, GdC1), dimers (Gd 2 L2, Gd 2 C2) and trimers (Gd 3 L3, Gd 3 C3) were prepared and relaxivities were determined at different field strengths ranging from 0.47T to 11.7T. Amide carbonyl coordination was indirectly confirmed by determination of the hydration number q for the EuL1 integrated into a peptide backbone, q = 0.96±0.09. The water residency time of GdL1 at 37 °C was optimal for relaxivity, τ M =17±2 ns. Increased molecular size leads to increased per Gd relaxivity (from r 1 = 7.5 for GdL1 to 12.9 mM −1 s −1 for Gd3L3 at 1.4T, 37 °C). The cyclic, multimeric derivatives exhibited slightly higher relaxivities than the corresponding linearized multimers (Gd2C2: r 1 = 10.5 mM −1 s −1 versus Gd 2 C2-red r 1 = 9 mM −1 s −1 at 1.4T, 37 °C). Overall, all six synthesized Gd complexes had higher relaxivities at low, intermediate and high fields than the clinically used small molecule contrast agent [Gd(HP-DO3A)(H 2 O)].
Chemistry – A European Journal, 2020
Herein, the synthesis and an extensive characterization of two novel Gd(AAZTA) (AAZTA = 6-amino-6-methylperhydro-1,4-diazepine tetra acetic acid) derivatives functionalized with short (C 2 and C 4) n-alkyl acid functions are reported. The carboxylate functionality is the site for further conjugations for the design of more specific contrast agents (CAs). Interestingly, it has been found that the synthesized complexes display enhanced properties for use as MRI contrast agents on their own. The stability constants determined by using potentiometric titration and UV/Vis spectrophotometry were slightly higher than the one reported for the parent Gd(AAZTA) complex. This observation might be accounted for by the larger sigma-electron donation of the acyl substituents with respect to the one provided by the methyl group in the parent complex. As far as concerns the kinetic stability, transmetallation experiments with endogenous ions (e.g., Cu 2 + , Zn 2 + and Ca 2 +) implied that the Gd 3 + ions present in these Gd(AAZTA) derivatives show somewhat smaller susceptibility to chemical exchange towards these ions at 25 8C, close to the physiological condition. The 1 H NMR spectra of the complexes with Eu III and Yb III displayed a set of signals consistent with half the number of methylene protons present on each ligand. The number of resonances was invariant over a large range of temperatures, suggesting the occurrence of a fast interconversion between structural isomers. The relaxivity values (298 K, 20 MHz) were consistent with q = 2 being equal to 8.8 mm À1 s À1 for the C 2 derivative and 9.4 mm À1 s À1 for the C 4 one, that is, sensibly larger than the one reported for Gd(AAZTA) (7.1 mm À1 s À1). Variable-temperature (VT)-T 2 17 O NMR measurements showed, for both complexes, the presence of two populations of coordinated water molecules, one in fast and one in slow exchange with the bulk water. As the high-resolution 1 H NMR spectra of the analogs with Eu III and Yb III did not show the occurrence of distinct isomers (as frequently observed in other macrocyclic lanthanide(III)-containing complexes), we surmised the presence of two fast-interconverting isomers in solution. The analysis of the 17 O NMR VT-T 2 profiles versus temperature allowed their relative molar fraction to be established as 35 % for the isomer with the fast exchanging water and 65 % for the isomer with the water molecules in slower exchange. Finally, 1 H NMRD profiles over an extended range of applied magnetic field strengths have been satisfactory fitted on the basis of the occurrence of the two interconverting species.
Rational Design of Protein-Based MRI Contrast Agents
Journal of the American Chemical Society, 2008
We describe the rational design of a novel class of magnetic resonance imaging (MRI) contrast agents with engineered proteins (CAi.CD2, i ) 1, 2,..., 9) chelated with gadolinium. The design of proteinbased contrast agents involves creating high-coordination Gd 3+ binding sites in a stable host protein using amino acid residues and water molecules as metal coordinating ligands. Designed proteins show strong selectivity for Gd 3+ over physiological metal ions such as Ca 2+ , Zn 2+ , and Mg 2+ . These agents exhibit a 20-fold increase in longitudinal and transverse relaxation rate values over the conventional small-molecule contrast agents, e.g., Gd-DTPA (diethylene triamine pentaacetic acid), used clinically. Furthermore, they exhibit much stronger contrast enhancement and much longer blood retention time than Gd-DTPA in mice. With good biocompatibility and potential functionalities, these protein contrast agents may be used as molecular imaging probes to target disease markers, thereby extending applications of MRI.