From monomers to micelles: investigation of the parameters influencing proton relaxivity

17O NMR and (1)H NMRD studies have been performed on a series of Gd(III) 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) derivatives as potential liver-specific magnetic resonance imaging (MRI) contrast agents. They bear aliphatic side chains which make them capable of micellar self-organization. The compounds differ in the length (C10-C18) and in the chemical nature (alkyl or monoamide-alkyl) of their lipophilic chain. We have established a convenient method to determine the critical micellar concentration (cmc) of paramagnetic surfactants by (1)H relaxivity measurements. This technique can be easily used over a large temperature range; thus, it can find wide application outside the field of MRI contrast agents. The knowledge of the cmc allowed us to determine the parameters governing the water proton relaxivity of the Gd(III) chelates in both nonaggregated and aggregated micellar forms. The relaxation data of the micellar complexes have been interpreted with the Lipari-Szabo approach. This model allows a local motion to be separated from the global tumbling of the whole micelle (modulated by a local, tau(l), and a global, tau(g), rotational correlation time, respectively). The aggregation substantially affects the rotational dynamics and thus increases the proton relaxivity of the Gd(III) chelates. The global rotational correlation times increase with increasing length of the side chain (500-2800 ps for C10-C18). Local motions are also influenced by the length and by the hydrophobicity of the side chain. The analysis of the relaxation data reveals considerable flexibility for these micellar aggregates. The rate of water exchange obtained for these chelates is identical to that for [Gd(DOTA)(H(2)O)](-) (k(ex)(298)= 4.8 x 10(6)s(-1))and is not sensitive either to micellization or to differences in the aliphatic chain. A relaxivity gain in such systems could be attained by simultaneously optimizing the water exchange by modifications of the chelate and increasing the micelle rigidity by using water-soluble surfactants with more hydrophobic side chains.     

Synthesis and characterization of new porphyrazine-Gd(III) conjugates as multimodal MR contrast agents

Magnetic resonance imaging (MRI) has long been used clinically and experimentally as a diagnostic tool to obtain three-dimensional, high-resolution images of deep tissues. These images are enhanced by the administration of contrast agents such as paramagnetic Gd(III) complexes. Herein, we describe the preparation of a series of multimodal imaging agents in which paramagnetic Gd(III) complexes are conjugated to a fluorescent tetrapyrrole, namely, a porphyrazine (pz). Zinc metalated pzs conjugated to one, four, or eight paramagnetic Gd(III) complexes are reported. Among these conjugates, Zn-Pz-8Gd(III) exhibits an ionic relaxivity four times that of the monomeric Gd(III) agent, presumably because of increased molecular weight and a molecular relaxivity that is approximately thirty times larger, while retaining the intense electronic absorption and emission of the unmodified pz. Unlike current clinical MR agents, Zn-Pz-1Gd(III) is taken up by cells. This probe demonstrates intracellular fluorescence by confocal microscopy and provides significant contrast enhancement in MR images, as well as marked phototoxicity in assays of cellular viability. These results suggest that pz agents possess a new potential for use in cancer imaging by both MRI and near-infrared (NIR) fluorescence, while acting as a platform for photodynamic therapy.     

Comparison of a tartaric acid derived polymeric MRI contrast agent to a small molecule model chelate

Contrast agents with high relaxivity are needed to increase the sensitivity of magnetic resonance imaging (MRI) for novel clinical and research applications. For this reason, polymeric structures containing multiple Gd(III) chelates are of current interest. Described in this communication are the syntheses and characterization of a glycopolymer derived from L-tartaric acid, Gd 4(H2O), as well as a low molecular weight compound, Gd 10(H2O), that models the Gd(III) chelate structure in the repeat unit of polymer Gd 4(H2O). Luminescence lifetime measurements in H2O and D2O for Eu(III) analogues of Gd 4(H2O) and Gd 10(H2O) [named Eu 4(H2O) and Eu 10(H2O)] reveal that the lanthanide in both structures likely has one water ligand in the primary coordination sphere. The relaxivity of the model chelate Gd 10(H 2O) at 400 MHz and 310 K was determined to be 4.7 mmol (-1).s (-1), representing a nearly 50% increase over Magnevist (3.2 mmol (-1).s (-1)). Relaxivity values on a per Gd basis for the polymeric structure Gd 4(H2O) prepared at two degrees of polymerization, n = 12 and 19, are similar, but slightly lower than Gd 10(H2O) (4.4 mmol (-1).s (-1) and 4.5 mmol (-1).s (-1), respectively). However, their molecular relaxivities of 51 mmol (-1).s (-1) and 80 mmol (-1).s (-1), respectively, provide a substantial increase over that of Magnevist.     

Novel paramagnetic macromolecular complexes derived from the linkage of a macrocyclic Gd(III) complex to polyamino acids through a squaric acid moiety

Macromolecular Gd(III) complexes may find useful application as contrast agents for magnetic resonance angiography (MRA). Herein two novel systems are reported, namely Gd(DO3ASQ)3-lys16 and Gd(DO3ASQ)30-orn114. Their syntheses are based on the ability of the squaric acid moiety to act as a linker between the DO3A (1,4,7, 10-tetraazacyclododecane-1,4,7-triacetic acid) chelate moiety and the polyamino acidic chain. Moreover, the squaric acid participates in the coordination cage of the Gd(III) ion. The investigation of 1H and 17O NMR relaxation processes of solvent water nuclei allowed a detailed characterization of the systems under study. Gd(DO3ASQ)30-orn114 displays a remarkable ability to enhance the water proton relaxation rate of its solutions, and it may be considered as potential contrast agent for MRA applications.     

New paramagnetic supramolecular adducts for MRI applications based on non-covalent interactions between Gd(III)-complexes and beta- or gamma-cyclodextrin units anchored to chitosan

Gd(III) complexes are used as magnetic resonance imaging (MRI) contrast agents because they greatly enhance the relaxation rate of water protons of tissues in which they distribute, an effect that is much more marked if the paramagnetic complex is part of a macromolecular system. Furthermore applications in molecular imaging, require that as many units of contrast agent as possible be directed to the site of interest. To this end we synthesised a polymer made of chitosan functionalized with beta- and gamma-cyclodextrins (CDs) that is able to form high-affinity adducts with suitably functionalized Gd(III) complexes. beta- and gamma-CDs were first treated with maleic anhydride to afford 6-monosubstituted derivatives that reacted regioselectively with the amino groups of chitosan. Reaction times and yields were markedly improved by carrying out these reactions under high-intensity ultrasound or microwave irradiation. Compared to the CD monomers, beta- and gamma-CD-chitosan adducts show large increases both in terms of their binding affinity towards Gd(III) complexes and in relaxivity values and they appear promising carriers for the in vivo vehiculation of Gd(III) complexes.     

Nuclear magnetic spin-lattice relaxation of water protons caused by metal cage compounds.

The nuclear magnetic spin-lattice relaxation rates of water protons are reported for solutions of manganese(II), copper(II), and chromium(III) cage complexes of the sarcophagine type. As simple aqueous solutions, the complexes are only modest magnetic relaxation agents, presumably because they lack protons on atoms in the first-coordination-sphere protons that are sufficiently labile to mix the large relaxation rate at the metal complex with that of the bulk solvent. The relaxation is approximately modeled using spectral density functions derived for translational diffusion of the interacting dipole moments with the modification that the electron spin relaxation rate is directly included as a contribution to the correlation time. In all cases studied, the electron spin relaxation rate is sufficiently large that it contributes directly to the water-proton spin relaxation process. The poor relaxation efficiency of the cage compound may, however, be improved dramatically by binding the complex to a protein. The efficiency is improved even further if the rotational motion of the protein is reduced drastically by an intermolecular cross-linking reaction. The relaxation efficiency of the cross-linked protein-cage complexes rivals that of the best first-coordination-sphere relaxation agents like [Gd(DTPA)(H2O)]2- and [Gd(DOTA)(H2O)]-.     

Synthesis and Relaxometric Characterization of New Poly[N,N‐bis(3‐aminopropyl)glycine] (PAPGly) Dendrons Gd‐Based Contrast Agents and Their in Vivo Study by Using the Dynamic Contrast‐Enhanced MRI Technique at Low Field (1 T)

The synthesis of poly[N,N‐bis(3‐aminopropyl)glycine] (PAPGly) dendrons Gd‐based contrast agents (GdCAs) via an orthogonal protection of the different functional groups and an activation/coupling strategy wherein a specific number of synthetic steps add a generation to the existing dendron has been described. The aim of this protocol is to build up two different generations of dendrons ( G‐0 or dendron's core, and G‐1 ) with peripheral NH₂ groups to conjugate a 1,4,7,10‐tetraazacyclododecane‐1,4,7‐triacetic acid (DO3A) derivative and afterwards to chelate with Gd³⁺ paramagnetic ions. These complexes, which have a well‐defined molecular weight, are of relevance to MRI as an attempt to gain higher ¹H relaxivity by slowing down the rotation of molecule compared to monomeric Gd(III) complexes used as contrast agents and to increase the number of paramagnetic centers present in one molecular structure. From the study of their water ¹H longitudinal relaxation rate at different magnetic fields (NMRD, Nuclear Magnetic Relaxation Dispersion) and by evaluating the variable temperature ¹⁷O‐NMR data we determined the parameters characterizing the water exchange rate and the rotational correlation time of each complex, both affecting ¹H relaxivity. Furthermore, these two novel PAPGly GdCAs were objects of i) an in vivo study to determine their biodistributions in healthy C57 mice at several time points, and ii) the Dynamic Contrast‐Enhanced MRI (DCE‐MRI) approach to assess their contrast efficiency measured in the tumor region of C57BL/6 mice transplanted subcutaneously with B16‐F10 melanoma cells. The aim of the comparison of these two dendrons GdCAs, having different molecular weights (MW), is to understand how MW and relaxivity may influence the contrast enhancement capabilities in vivo at low magnetic field (1 T). Significant contrast enhancement was observed in several organs (vessel, spleen and liver), already at 5 min post‐injection, for the investigated CAs. Moreover, these CAs induced a marked contrast enhancement in the tumor region, thanks to the enhanced permeability retention effect of those macromolecular structures.     

Synthesis and evaluation of nanoglobular macrocyclic Mn(II) chelate conjugates as non-gadolinium(III) MRI contrast agents

Because of the recent observation of the toxic side effects of Gd(III) based MRI contrast agents in patients with impaired renal function, there is strong interest on developing alternative contrast agents for MRI. In this study, macrocyclic Mn(II) chelates were conjugated to nanoglobular carriers, lysine dendrimers with a silsesquioxane core, to synthesize non-Gd(III) based MRI contrast agents. A generation 3 nanoglobular conjugate of Mn(II)-1,4,7-triaazacyclononane-1,4,7-triacetate-GA amide (G3-NOTA-Mn) was also synthesized and evaluated. The per ion T(1) and T(2) relaxivities of G2, G3, G4 nanoglobular Mn(II)-DOTA monoamide conjugates decreased with increasing generation of the carriers. The T(1) relaxivities of G2, G3, and G4 nanoglobular Mn(II)-DOTA conjugates were 3.3, 2.8, and 2.4 mM(-1) s(-1) per Mn(II) chelate at 3 T, respectively. The T(1) relaxivity of G3-NOTA-Mn was 3.80 mM(-1) s(-1) per Mn(II) chelate at 3 T. The nanoglobular macrocyclic Mn(II) chelate conjugates showed good in vivo stability and were readily excreted via renal filtration. The conjugates resulted in much less nonspecific liver enhancement than MnCl(2) and were effective for contrast-enhanced tumor imaging in nude mice bearing MDA-MB-231 breast tumor xenografts at a dose of 0.03 mmol Mn/kg. The nanoglobular macrocyclic Mn(II) chelate conjugates are promising nongadolinium based MRI contrast agents.     

A beta-cyclodextrin "click cluster" decorated with seven paramagnetic chelates containing two water exchange sites

The development of novel macromolecular contrast agents that offer enhanced relaxivity profiles at high magnetic fields have the potential to greatly improve the diagnosis, understanding, and treatment of disease. To this end, we have designed a monodiperse paramagnetic beta-cyclodextrin click cluster decorated with seven paramagnetic arms. A novel alkyne-functionalized diethylenetriaminetetraacetic acid (DTTA) chelate (6) has been created and coupled to a per-azido-beta-cyclodextrin core (7) to yield the precursor macromolecule (8). After removal of the protecting groups and titrating with Gd (3+), the final paramagnetic click cluster, Gd10, was obtained. Luminescence measurements were carried out in H 2O and D 2O on an analogous structure, Eu10, and indicated that at each lanthanide has an average of 1.8 water exchange sites, which is important for enhancing relaxivity and MRI resolution. This discrete paramagnetic click cluster yields a high relaxivity profile (43.4 mM (-1) s (-1) per molecule and 6.2 mM (-1) s (-1) per Gd (3+) at 9.4 T) and enhanced contrast on a human MRI scanner as compared to a commercial agent, Magnevist (3.2 mM (-1) s (-1) at 9.4 T). Moreover, the useful inclusion properties exhibited by beta-cyclodextrin also make this an excellent host scaffold to functionalize via noncovalent assembly with receptor specific targeting moieties for biomolecular imaging.     

Gd(III) complexes as contrast agents for magnetic resonance imaging: a proton relaxation enhancement study of the interaction with human serum albumin

 The non-covalent interaction between human serum albumin (HSA) and DOTA-like Gd(III) complexes containing hydrophobic benzyloxymethyl (BOM) substituents has been thoroughly investigated by measuring the solvent proton relaxation rates of their aqueous solutions. The binding association constants (K _A) to HSA are directly related to the number of hydrophobic substituents present on the surface of the complexes. Furthermore, an estimation of ΔH° and ΔS° has been obtained by the temperature dependence of K _A. Assays performed with the competitor probes warfarin and ibuprofen established that the complexes interact with HSA through two nearly equivalent binding sites located in the subdomains IIA and IIIA of the protein. Strong relaxation enhancements, promoted by the formation of slowly tumbling paramagnetic adducts, have been measured at 20 MHz for complexes containing two and three hydrophobic substituents. The macromolecular adduct with the latter species has a relaxivity of 53.2±0.7 mM^–1 s^–1, which represents the highest value so far reported for a Gd(III) complex. The temperature dependence of the relaxivity for the paramagnetic adducts with HSA indicates long exchange lifetimes for the water molecules dipolarly interacting with the paramagnetic centre. This is likely to be related to the formation, upon hydrophobic interaction of the complexes with HSA, of a clathrate-like, second-coordination-sphere arrangement of water molecules. Besides affecting the dissociative pathway of the coordinated water molecule, this water arrangement may itself significantly contribute to enhancement of the bulk solvent relaxation rate. Received: 6 November 1995 / Accepted: 17 April 1996     

N-2-(azol-1(2)-yl)ethyliminodiacetic acids: a novel series of Gd(III) chelators as T2 relaxation agents for magnetic resonance imaging

The synthesis, physicochemical properties, and toxicological implications of a novel series of N-2-(azol-1(2)-yl)ethyliminodiacetic acids, useful as contrast agents for magnetic resonance imaging are reported. Compounds were prepared by alkylation of methyl iminodiacetate with N-2-bromoethylazoles and subsequent hydrolysis. Stability constants of the corresponding Gd(III) complexes and T1 and T2 relaxivities were determined and interpreted in terms of optimized geometries obtained by semiempirical PM3 calculations. Compounds show increased T2 relaxivity and decreased toxicity in vitro as compared to EDTA-Gd(III) complexes.     

Influence of transition metal ions on NMR proton T1 relaxation times of serum, blood, and red cells

The spin-lattice relaxation rates (1/T1) of serum, whole blood, and red cells were measured vs several concentrations of transition metal ions. For comparative purposes, the similar experiments were repeated in water. The rates show a linear dependence on concentration of each ion for water, but nearly a linear dependence for blood and its constituents. The influence of each ion on 1/T1 in a sample was expressed by the slope (relaxivity) of the least-squares fitting of 1/T1 vs ion concentration. The relaxivities of Mn(II) in serum and of Fe(III) in serum and blood are greater than those in water, whereas the relaxivities of these ions in the other cases and of all the other ions in call cases are smaller than those in water. However, the relaxivity data show that Cr(III) in serum and blood affects the 1/T1 rates. The ratio of relaxivity of each sample to that of water is known as proton relaxation enhancement (PRR) factor (epsilon). The epsilon factors for present data suggest that the added ions are bound to proteins, and only Mn(II) in serum and Fe(III) in blood and serum are accessible to water.     

Synthesis and physicochemical characterization of a novel precursor for covalently bound macromolecular MRI contrast agents

 The ligand DOTASA was designed and synthesized in the aim of obtaining a kinetically and thermodynamically stable Gd(III) chelate which, through its uncoordinated carboxylate function, will provide an efficient pathway to couple the complex to bio- or macromolecules without affecting the coordination pattern of DOTA. Furthermore, it allows us to study the influence of an extra carboxylate arm on the parameters determining proton relaxivity in comparison to the commercial agent [Gd(DOTA)(H₂O)]^–. A combined variable-temperature ¹⁷O NMR, EPR and nuclear magnetic relaxation dispersion study on the Gd(III) chelate resulted in k ²⁹⁸ _ex=(6.3±0.2)×10⁶ s^–1 for the water exchange rate and τ²⁹⁸ _R=125±2 ps for the rotational correlation time. The slight increase in both k ²⁹⁸ _ex and τ²⁹⁸ _R, as compared to those for [Gd(DOTA)(H₂O)]^–, is attributed to the presence of the extra negative charge. The longer rotational correlation time results in a proton relaxivity of 5.03 mM^–1 s^–1 for [Gd(DOTASA)(H₂O)]^2–, which is approximately 30% higher than that for [Gd(DOTA)(H₂O)]^–. The increased water exchange rate of [Gd(DOTASA)(H₂O)]^2– has no consequence for proton relaxivity since this latter is exclusively limited by fast rotation for both complexes. However, for slowly rotating macromolecular agents, which contain a covalently coupled DOTASA unit instead of a coupled DOTA, this increased exchange rate will have a significant positive effect. Received: 31 December 1998 / Accepted: 4 March 1999     

Contrast agents for magnetic resonance angiographic applications: 1H and 17O NMR relaxometric investigations on two gadolinium(III) DTPA-like chelates endowed with high binding affinity to human serum albumin

N,N′,N″,N‴ -pentaacetic acid) bearing different substituents for binding to human serum albumin (HSA) are compared. In spite of the structural differences of the recognition synthon and of the residual electric charge, the two chelates display an analogous binding affinity for the serum protein. Upon formation of the adducts with HSA, the exchange rates of the coordinated water appear slowed down by an amount corresponding to ca. 50% of the rates found for the free complexes. The relaxivity of [Gd(BOM)₃DTPA (H₂O)]^2 − is significantly higher than that of MS-325 either in the free complex or in the macromolecular adduct. Finally, the effect of pH on the stability of the HSA adducts and on the values of their relaxivities has been investigated. Received: 11 June 1999 / Accepted: 15 September 1999     

Anti-oxidant, in vitro, in vivo anti-inflammatory activity and antiproliferative activity of mefenamic acid and its metal complexes with manganese(II), cobalt(II), nickel(II), copper(II) and zinc(II)

Some new complexes of mefenamic acid with potentially interesting biological activity are described. The complexes of mefenamic acid [Mn(mef)(2)(H(2)O)(2)], 1, [Co(mef)(2)(H(2)O)(2)], 2, [Ni(mef)(2)(H(2)O)(2)], 3, [Cu(mef)(2)(H(2)O)](2), 4 and [Zn(mef)(2)], 5, were prepared by the reaction of mefenamic acid, a potent anti-inflammatory drug with metal salts. Optical and infrared spectral data of these new complexes are reported. Monomeric six-coordinated species were isolated in the solid state for Mn(II), Ni(II) and Co(II), dimeric five-coordinated for Cu(II) and monomeric four-coordinated for Zn(II). In DMF or CHCl(3) solution the coordination number is retained and the coordinated molecules of water are replaced by solvent molecules. The anti-oxidant properties of the complexes were evaluated using the 1,1-diphenyl-2-picrylhydrazyl, DPPH, free radical scavenging assay. The scavenging activities of the complexes were measured and compared with those of the free drug and vitamin C. We have explored their ability to inhibit soybean lipoxygenase, beta-glucuronidase and trypsin- induced proteolysis. The complex [Mn(mef)(2)(H(2)O)(2)] exhibits the highest antioxidant activity and the highest inhibitory effect against the soybean lipogygenase (LOX), properties that are not demonstrated by mefenamic acid. Their inhibitory effects on rat paw edema induced by Carrageenan was studied and compared with those of mefenamic acid. The complex [Zn(mef)(2)] exhibited a strong inhibitory effect at 0.1 mmol/Kg B.W. (81.5 +/- 1.3% inhibition), superior to the inhibition induced by mefenamic acid at the same dose (61.5 +/- 2.3% inhibition). Mefenamic acid and its metal complexes have been evaluated for antiproliferative activity in vitro against the cells of three human cancer cell lines: MCF-7 (human breast cancer cell line), T24 (bladder cancer cell line), A-549 (non-small cell lung carcinoma) and a mouse fibroblast L-929 cell line. The copper(II) complex displays against T24, MCF-7 and L-929 cancer cell lines, IC(50) values in a microM range similar to that of the antitumor drug cis-platin and they are considered for further stages of screening in vitro and/or in vivo as agents with potential antitumor activity.     

Towards MRI contrast agents of improved efficacy. NMR relaxometric investigations of the binding interaction to HSA of a novel heptadentate macrocyclic triphosphonate Gd(III)-complex

 A novel heptacoordinating ligand consisting of a thirteen-membered tetraazamacrocycle containing the pyridine ring and bearing three methylenephosphonate groups (PCTP-[13]) has been synthesized. Its Gd(III) complex displays a remarkably high longitudinal water proton relaxivity (7.7 mM^–1 s^–1 at 25  °C, 20 MHz and pH 7.5) which has been accounted for in terms of contributions arising from (1) one water molecule bound to the metal ion, (2) hydrogen-bonded water molecules in the second coordination sphere, or (3) water molecules diffusing near the paramagnetic chelate. Variable-temperature ¹⁷O-NMR transverse relaxation data indicate that the residence lifetime of the metal-bound water molecule is very short (8.0 ns at 25  °C) with respect to the Gd(III) complexes currently considered as contrast agents for magnetic resonance imaging. Furthermore, GdPCTP-[13] interacts with human serum albumin (HSA), likely through electrostatic forces. By comparing water proton relaxivity data for the GdPCTP-[13]-HSA adduct, measured as a function of temperature and magnetic field strength, with those for the analogous adduct with GdDOTP (a twelve-membered tetraaza macrocyclic tetramethylenephosphonate complex lacking a metal-bound water molecule), it has been possible to propose a general picture accounting for the main determinants of the relaxation enhancement observed when a paramagnetic Gd(III) complex is bound to HSA. Basically, the relaxation enhancement in these systems arises from (1) water molecules in the hydration shell of the macromolecule and protein exchangeable protons which lie close to the interaction site of the paramagnetic complex and (2) the metal bound water molecule(s). As far as the latter contribution is concerned, the interaction with the protein causes an elongation of the residence lifetime of the metal-bound water molecule, which limits, to some extent, the potential relaxivity enhancement expected upon the binding of the paramagnetic complex to HSA. Received: 27 January 1997 / Accepted: 12 May 1997     

Bridging-type changes facilitate successive oxidation steps at about 1 V in two binuclear manganese complexes--implications for photosynthetic water-oxidation

The redox behavior of two synthetic manganese complexes illustrates a mechanistic aspect of importance for light-driven water oxidation in Photosystem II (PSII) and design of biomimetic systems (artificial photosynthesis). The coupling between changes in oxidation state and structural changes was investigated for two binuclear manganese complexes (1 and 2), which differ in the set of first sphere ligands to Mn (N(3)O(3) in 1, N(2)O(4) in 2). Both complexes were studied by electron paramagnetic resonance (EPR) and X-ray absorption spectroscopy (XAS) in three oxidation states which had been previously prepared either electro- or photochemically. The following bridging-type changes are suggested. In 1: Mn(II)-(mu-OR)(mu-OCO)(2)-Mn(II)<-->Mn(II)-(mu-OR)(mu-OCO)(2)-Mn(III)-->Mn(III)-(mu-OR)(mu-OCO)(mu-O)-Mn(III). In 2: Mn(II)-(mu-OR)(mu-OCO)(2)-Mn(III)<-->Mn(III)-(mu-OR)(mu-OCO)(2)-Mn(III)-->Mn(III)-(mu-OR)(mu-OCO)(mu-O)-Mn(IV). In both complexes, the first one-electron oxidation proceeds without bridging-type change, but involves a redox-potential increase by 0.5-1V. The second one-electron oxidation likely is coupled to mu-oxo-bridge (or mu-OH) formation which seems to counteract a further potential increase. In both complexes, mu-O(H) bridge formation is associated with a redox transition proceeding at approximately 1V, but the mu-O(H) bridge is observed at the Mn(2)(III,III) level in 1 and at the Mn(III,IV) level in 2, demonstrating modulation of the redox behavior by the terminal ligands. It is proposed that also in PSII bridging-type changes facilitate successive oxidation steps at approximately the same potential.     

Synthesis and characterization of a new bioactivated paramagnetic gadolinium(III) complex [Gd(DOTA-FPG)(H2O)] for tracing gene expression

A smart contrast agent for magnetic resonance imaging (MRI) can be used to exploit an enzymatic activity specific to the tissue or disease state signified by converting an MRI-inactivated agent to an activated MRI agent. In this study, a beta-galactopyranose-containing gadolinium(III) complex [Gd(DOTA-FPG)(H 2O)] was designed, synthesized, and characterized as being potentially suitable for a bioactivated MRI contrast agent. The (17)O NMR experiments were conducted to estimate the water exchange rate k e x 298 and rotational correlation time tau R 298 . The k ex 298 value of [Gd(DOTA-FPG)(H 2O)] is similar to that of [Gd(DO3A-bz-NO 2)(H 2O)]. The rotational correlation time value of [Gd(DOTA-FPG)(H 2O)] is dramatically longer than that of [Gd(DOTA)(H 2O)] (-) Relaxometric studies show that the percentage change in the T 1 value of [Gd(DOTA-FPG)(H 2O)] decreases dramatically in the presence of beta-galactosidase and human serum albumin. The T(1) change percentage of [Gd(DOTA-FPG)(H 2O)] (60%) is significantly higher than those of Egad and gadolinium(III)-1-(4-(2-(1-(4,7,10-triscarboxymethyl-(1,4,7,10-tetraazacyclododecyl)))-ethylcarbamoyloxymethyl)-2-nitrophenyl)-beta- d-glucopyronuronate. The signal intensity of the MR image for [Gd(DOTA-FPG)(H 2O)] in the presence of human serum albumin and beta-galactosidase (2670 +/- 210) is significantly higher than that of [Gd(DOTA-FPG)(H 2O)] in the sodium phosphate buffer solution (1490 +/- 160). In addition, the MR images show a higher-intensity enhancement in CT26/beta-gal tumor with beta-galactosidase gene expression but not for the CT26 tumor without beta-galactosidase gene expression. We conclude that [Gd(DOTA-FPG)(H 2O)] is a suitable candidate for a bioactivated MRI contrast agent in tracing gene expression.     

Polydisulfide Gd(III) chelates as biodegradable macromolecular magnetic resonance imaging contrast agents

Macromolecular gadolinium (Gd)(III) complexes have a prolonged blood circulation time and can preferentially accumulate in solid tumors, depending on the tumor blood vessel hyperpermeability, resulting in superior contrast enhancement in magnetic resonance (MR) cardiovascular imaging and cancer imaging as shown in animal models. Unfortunately, safety concerns related to these agents' slow elimination from the body impede their clinical development. Polydisulfide Gd(III) complexes have been designed and developed as biodegradable macromolecular magnetic resonance imaging (MRI) contrast agents to facilitate the clearance of Gd(III) complexes from the body after MRI examinations. These novel agents can act as macromolecular contrast agents for in vivo imaging and excrete rapidly as low-molecular-weight agents. The rationale and recent development of the novel biodegradable contrast agents are reviewed here. Polydisulfide Gd(III) complexes have relatively long blood circulation time and gradually degrade into small Gd(III) complexes, which are rapidly excreted via renal filtration. These agents result in effective and prolonged in vivo contrast enhancement in the blood pool and tumor tissue in animal models, yet demonstrate minimal Gd(III) tissue retention as the clinically used low-molecular-weight agents. Structural modification of the agents can readily alter the contrast-enhancement kinetics. Polydisulfide Gd(III) complexes are promising for further clinical development as safe, effective, biodegradable macromolecular MRI contrast agents for cardiovascular and cancer imaging, and for evaluation of therapeutic response.     

Innovative magnetic resonance imaging diagnostic agents based on paramagnetic Gd(III) complexes

Gd(III) complexes are under intense scrutiny as contrast agents for magnetic resonance imaging (MRI). They act by enhancing tissutal proton relaxation rates. Much has already been done in order to get an in-depth understanding of the relationships between structure, dynamics, and contrastographic ability of these paramagnetic complexes. Their potential in the assessment of flow, perfusion, and capillary permeability has already been established. The next challenges are in the field of molecular imaging applications, which would allow the attainment of early diagnosis based on the recognition of specific reporters of the onset of the pathological state. To this end, Gd(III) complexes have to be endowed with improved targeting capabilities by conjugating suitable recognition synthons on their surfaces. Small peptides are candidates of choice for the attainment of this goal. Moreover, the intrinsic low sensitivity of the NMR techniques implies the need to deliver large amounts of contrast agents to the target in order to get its visualization in the resulting images. Highly efficient delivery systems have been identified, which bring a great promise for the development of innovative diagnostic agents based on Gd(III) complexes.