Jean F. Desreux

New Classes of MRI Contrast Agents

A very high spatial resolution and a so far unsurpassed ability in distinguishing soft tissues characterize magnetic resonance imaging (MRI). This imaging technique has therefore become one of the most important diagnosis tools available in medicine. Insufficient contrast is nevertheless a drawback of the technique in many instances, hence the need for contrast agents. A number of such substances have been developed and enjoy widespread use in hospitals around the globe. However, there remains a need for new and more selective contrast media that would allow a better delineation of diseases thus helping the radiologist in giving a more precise diagnosis. This chapter is devoted to these new types of contrast agents and provides an overview of new ideas and their applications as they appear in the recent literature. Examples are given of new blood-pool agents mostly based on macromolecular derivatives. Linking contrast agents to antibodies or other biologically relevant macromolecules may provide a way of highlighting regions of interest. Such compounds are also discussed. Very recent examples of in vitro and in vivo contrast agents for imaging gene expression will also be presented, as this appears to be of utmost importance for assessing gene delivery and gene expression in gene therapy applications and for studying developmental stages in embryology. Finally, MRI contrast agents are presented that react to variables in their environment. Temperature, pH, ions, enzymes are just a few of the parameters that may influence the response of these so-called smart contrast agents.

DESIGNING NEW MRI CONTRAST AGENTS : A COORDINATION CHEMISTRY CHALLENGE

Abstract Gadolinium(III) polyacetic macrocyclic complexes featuring cycloalkyl groups directly grafted onto 1,4,7,10-tetra-azacyclododecane feature interesting properties such as higher rigidity, better kinetic inertness and faster water exchange times. The solution structures of the paramagnetic Yb(III) complexes are deduced from the NMR spectra and the effect of the Gd(III) chelates on the T 1 relaxation times of water is interpreted by measuring independently parameters such as the water exchange times and the diffusion coefficients. Substituting the tetra-aza ring with a coordinating unit such as 1,10-phenanthroline leads to ditopic ligands that spontaneously form heteropolymetallic Gd(III)-Fe(II) complexes of well-defined stoichiometry with a marked effect on relaxivity.

Regioselective synthesis of 1,7-diprotected 1,4,7,10-tetraazacyclododecane and preparation of a dialcohol dicarboxylic macrocyclic ligand

The reaction of 1,4,7,10-tetraazacyclododecane with p-toluenesulfonyl chloride in pyridine or with diethyl phosphite and CCl4 in a water/CH2Cl2 mixture yields selectively the 1,7-diprotected regioisomer. The 1,7-diprotected tetraaza cycles are interesting starting materials, for instance for the preparation of 4,10-bis(2′-hydroxyethyl)-1,7-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane.

Modification of calix[4]arenes with CMPO-functions at the wide rim. Synthesis, solution behavior, and separation of actinides from lanthanides.

Two calix[4]arene tetraethers (Y = C5H11, C14H29) bearing on their wide rim four -N(Me)-CO-CH2-P(O)Ph2 residues were synthesized for the first time. Their ability to extract lanthanides and actinides from an acidic aqueous phase to organic phases (CH2Cl2, NPHE) was studied. In comparison to the corresponding -NH-analogs, they are less efficient extractants, the selectivity for the light over the heavy lanthanides is less pronounced, while there is still an interesting selectivity of Am3+ over Eu3+. Stability constants for selected lanthanide salts were determined also in homogenous phase (methanol, acetonitrile) but do not account for the different extraction results. The complexation of Gd3+ was also followed by relaxivity (NM RD) measurements, which suggest an even stronger aggregation for the N-methyl compound while the 1:1 complex is reached for a smaller ratio [L]/[Gd3+] compared to the NH analog. The formation of aggregates is also supported by dynamic light scattering measurements. A single crystal X-ray structure of the pentyl ether reveals a C2-symmetrical pinched cone conformation for the free ligand.

Behaviour of bidentate amines in the synergic extraction of lanthanides by thenoylfluoroacetone (HTTA)

Abstract Synergic extraction of europium (III) by thenoyltrifluoroacetone (HTTA) in the presence of 2,2′-dipyridyl, or 1,10-phenanthroline and its 2,9-dimethyl derivative was performed from aqueous 2 M NaClO4+0.01 Na acetate buffer at pH equal to 4.33 and at 25°C. The organic solvents considered were cyclohexane, benzene, carbon tetrachloride and chloroform. It has been shown by using the slope analysis method of the distribution curves that in this synergic system only 1:1 mixed complexes, e.g. Ln(TTA)3·B, where B is any of the above cited amines, are involved irrespective of the organic solvent used. The extraction constants Kex of Eu(TTA)3B as well as the formation constants of the extractable synertic adduct are given for the various solvents.

New Synthons for the Synthesis of Lanthanide Containing Macrocyclic Schiff Bases Featuring Substituents Available for Tethering

Abstract 2,6-Diacetylpyridine substituted with amine or alcohol groups in the 4-position have been prepared from chelidamic acid. The key 4-chloro derivative was synthesized in high yield via a diazo intermediate and was protected as a bis-1,3-dioxane before substitution with various amino alcohol groups. Lanthanide macrocyclic tetra–imine complexes were obtained by a template procedure that leads to stable paramagnetic and/or fluorescent derivatives with anchor groups available for linkage to macromolecules.

On the complexation of alkaline earth metal cations in propylene carbonate by macrocyclic crown ethers featuring from four to ten coordinating sites

Abstract The complexation of the alkaline earth ions by four crown ethers in anhydrous propylene carbonate has been investigated by a competitive potentiometric method using lead(II) as an auxiliary ion. The ligand-12-crown-4 forms bis-adducts with all the alkaline earths, the maximum stability being exhibited by the calcium complex. A fifteen-membered macrocycle, 4-tert-butylbenzo-15-crown-5 also forms 1:2 complexes but only with Sr2+ and Ba2+. The larger ligands 4,4′(5′)-di-tert-butylbenzo-18-crown-6 and dibenzo-30-crown-10 bind strongly the alkaline earths, especially Sr2+ and Ba2+. Moreover, the stability of the 1:1 adducts with dibenzo-30-crown-10 decreases regularly from Ba2+ to Mg2+. The complexation trends are interpreted by taking into account the known structures of macrocyclic complexes in the solid. Finally, the stability of the adducts with the alkali metals, the alkaline earths and the di- and trivalent lanthanides are compared.

Imaging apolipoprotein AI in vivo

Coronary disease risk increases inversely with high‐density lipoprotein (HDL) level. The measurement of the biodistribution and clearance of HDL in vivo, however, has posed a technical challenge. This study presents an approach to the development of a lipoprotein MRI agent by linking gadolinium methanethiosulfonate (Gd[MTS‐ADO3A]) to a selective cysteine mutation in position 55 of apo AI, the major protein of HDL. The contrast agent targets both liver and kidney, the sites of HDL catabolism, whereas the standard MRI contrast agent, gadolinium‐diethylenetriaminepentaacetic acid‐bismethylamide (GdDTPA‐BMA, gadodiamide), enhances only the kidney image. Using a modified apolipoprotein AI to create an HDL contrast agent provides a new approach to investigate HDL biodistribution, metabolism and regulation in vivo. Copyright

A proton nuclear magnetic resonance study of the synergic extraction of paramagnetic rare earths

Abstract The anhydrous paramagnetic complex tris(thenoyltrifluoroacetonato) Eu(III), Eu(TTA)3, induces NMR shifts in the spectra of a variety of substrates S currently used in solvent extraction. Eu(TTA)3 as a shift reagent, is a new tool with which to investigate the synergic extraction of rare earths. The analysis of the concentration dependence of the induced shifts yields the stoichiometry and stability constant of the adducts formed with Eu(TTA)3 in CDCl3. It is shown that the association between Eu(TTA)3 and 4-methyl-2-pentanone, triphenylphosphine oxide or 2-methylpyridine proceeds via the formation of 1:1 and 1:2 adducts. The compound 2-methylpyridine also forms a very stable ion-pair complex Eu(TTA)4−HS+. Similar ion-pair complexes are reported for ammonium salts such as methyl tridodecylammonium chloride. Dipyridyl is found to form 1:1 adducts only. All NMR data are compared with some times conflicting extraction measurements. Some deficiencies of the NMR approach are also discussed.

EPR assessment of protein sites for incorporation of Gd(III) MRI contrast labels

We have engineered apolipoprotein A-I (apoA-I), a major protein constituent of high-density lipoprotein (HDL), to contain DOTA-chelated Gd(III) as an MRI contrast agent for the purpose of imaging reconstituted HDL (rHDL) biodistribution, metabolism and regulation in vivo. This protein contrast agent was obtained by attaching the thiol-reactive Gd[MTS-ADO3A] label at Cys residues replaced at four distinct positions (52, 55, 76 and 80) in apoA-I. MRI of infused mice previously showed that the Gd-labeled apoA-I migrates to both the liver and the kidney, the organs responsible for HDL catabolism; however, the contrast properties of apoA-I are superior when the ADO3A moiety is located at position 55, compared with the protein labeled at positions 52, 76 or 80. It is shown here that continuous wave X-band (9 GHz) electron paramagnetic resonance (EPR) spectroscopy is capable of detecting differences in the Gd(III) signal when comparing the labeled protein in the lipid-free with the rHDL state. Furthermore, the values of NMR relaxivity obtained for labeled variants in both the lipid-free and rHDL states correlate to the product of the X-band Gd(III) spectral width and the collision frequency between a nitroxide spin label and a polar relaxation agent. Consistent with its superior relaxivity measured by NMR, the rHDL-associated apoA-I containing the Gd[MTS-ADO3A] probe attached to position 55 displays favorable dynamic and water accessibility properties as determined by X-band EPR. While room temperature EPR requires >1 m m Gd(III)-labeled and only >10 µ m nitroxide-labeled protein to resolve the spectrum, the volume requirement is exceptionally low (~5 µl). Thus, X-band EPR provides a practical assessment for the suitability of imaging candidates containing the site-directed ADO3A contrast probe.