Luciano Milone

Ln(III)-DOTAMGly complexes: a versatile series to assess the determinants of the efficacy of paramagnetic chemical exchange saturation transfer agents for magnetic resonance imaging applications.

Rationale and Objectives:Paramagnetic Ln-DOTAMGly complexes (Ln ≠ La, Lu, and Gd) are the prototypes of a novel class of contrast agents for magnetic resonance imaging based on chemical exchange saturation transfer (CEST). Their ability to reduce the water signal intensity depends on the interplay of several physico-chemical properties of the agent and instrumental parameters. This study aims to identify possible routes for their optimization Methods:Saturation transfer (ST) has been measured in vitro at 7.05 T as a function of pH, temperature, and concentration of the agent. Results:Large saturation transfer effects have been observed upon irradiating the coordinated water protons (for Ln = Pr, Nd, Eu, and Tb). The comparison of the results obtained by irradiating water versus amide protons allows the set-up of ratiometric methods through which the ST response can be made independent on the concentration of the agent. Conclusions:The modulation of the magnetic properties along the lanthanide series allows an in-depth understanding of the determinants of ST effect and provides useful insights for the design of more efficient agents.

Reactions of Ru3(CO)12 with asymmetrically substituted acetylenes. A new type of interaction between acetylenes and a metal-atom cluster

Abstract The compounds Ru 3 (CO) 9 X (where XC 2 (t-Bu)H and C 2 (Ph)H) have been obtaned from the reactions of Ru 3 (CO) 12 with t-BuCCH and PhCCH. Their IR, NMR and mass spectra are reported and discussed. A hydrido signal in the NMR spectrum and other evidence point to a new type of structure, different from that proposed by Blount and his coworkers for Fe 3 (CO) 9 C 2 Ph 2 .

Determination of water permeability of paramagnetic liposomes of interest in MRI field.

The water permeability of various liposome membranes has been determined at 298K by measuring the NMR longitudinal water proton relaxation rate of vesicles encapsulating the clinically approved Gd-HPDO3A complex (HPDO3A=10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid). Two basic formulations based on DPPC (dipalmitoylphosphatidylcholine) and POPC (palmitoyl-oleylphosphatidylcholine) phospholipids were selected and investigated. Furthermore, the permeability changes caused by the membrane incorporation of amphiphiles like cholesterol and/or metal complexes of interest for designing improved liposome-based MRI contrast agents, were also investigated. The incorporation of cholesterol and metal complexes bearing C18 saturated chains in POPC-based liposomes reduces the water diffusivity across the membrane bilayer. On the contrary, the incorporation of a macrocyclic metal complex bearing four C12 alkylic chains, one for each coordination arm of the ligand, considerably enhances the water permeability in DPPC-based liposomes. Finally, it is reported that the permeability of POPC-based bilayer is increased when the liposomes are subjected to an osmotic stress.

ELECTRONIC INTERACTIONS IN ORGANOMETALLIC DIMERS. AN ELECTROCHEMICAL APPROACH

Abstract A simple electrochemical criterion is employed for an approximate evaluation of the electronic interaction between redox centres in π-conjugated organometallic dimers. This approach allows one to predict the results of the use of such organometallic complexes (and related polymers) as precursors of mixed-valence compounds (in solution) and low-dimensional conducting or non-linear optical materials (in the solid state). Chemical complications following the redox processes often alter the electrochemical response. In such cases, this approach is only useful if the experimental conditions (measurements at high scan rates or sub-ambient temperatures) are chosen carefully.

Stereochemically nonrigid carbonyl complexes of group VIII B metal clusters

Abstract The variable temperature 13 C-nmr of M 3 (CO) 12 (M = Fe, Ru, Os) have been studied. Fe3(CO)12 and Ru 3 (CO) 12 give one sharp resonance down to −100° C. Os 3 (CO) 12 shows two resonances at room temperature which coalesce to a single resonance at +150 C. Possible mechanisms for carbonyl averaging are considered. The 13C-nmr of the acetylenic complexes HM3(CO)9C2C(CH3)3 (M = Ru, Os) were examined and shown to be stereochemically nonrigid. Both the osmium and ruthenium compounds show axial equatorial exchange on the metal atom which is sigmabonded to one of the acetylenic carbons. Only the ruthenium compound shows exchange between metal atoms in the temperature range examined. The importance of bridging intermediates in this exchange process is discussed.

1H and 13C NMR studies of acetylenic complexes of Co2(CO)8

Abstract 1H and 13 Cnmr spectra of the acetylenic complexesCo 2 (CO) 6 (RC 2 R′) show downfield shifts of the ligand resonance upon complexation. The slight dependence of the chemical shift of C from the substitution on C′ is discussed in terms of the metal-alkyne bonding. Upfield shifts are observed for the acetylenic carbons when L (P- or As-ligand) substitutes one CO. Variable temperature 13 Cnmr spectra show that the carbonyl are rapidly interchanging and that the rate of exchange depends on R and R′.

Methods for an improved detection of the MRI-CEST effect

CEST imaging is a recently introduced MRI contrast modality based on the use of endogenous or exogenous molecules whose exchangeable proton pools transfer saturated magnetization to bulk water, thus creating negative contrast. One of the critical issues for further development of these agents is represented by their limited sensitivity in vivo. The aim of this work is to improve the detection of CEST agents by exploring new approaches through which the saturation transfer (ST) effect can be enhanced. The performance of the proposed methods has been tested in vitro and in vivo using highly sensitive and highly shifted lipoCEST agents, and the results were compared with the standard ST evaluation mode. The acquired Z-spectra were interpolated locally and voxel-by-voxel by smoothing splines. Besides expressing the ST in the standard mode, we explore two methods, enhanced and integral ST, which better exploit all the information contained in the Z-spectrum. By combining different modes for ST assessment a significant improvement in the detection of the lipoCEST agents, both in vitro and in vivo, has been found. The results obtained from the application of the proposed methods outline the importance of post-processing analysis for highlighting the CEST-MRI contrast.

Dynamic properties of the trinuclear carbonyl cluster FeCo2(CO)9S and its Derivatives

Abstract 13C.-n.m.r. spectra show that the replacement of CO by a group V ligand in FeCo2(CO)9S is at one cobalt atom in the monosubstituted derivative, at the two cobalt atoms in the bisubstituted derivative and at the two cobalt and at the iron atom in the tri-substituted derivative. The substitution is at an equatorial position in each case. Multistage exchange of the carbonyls is a common feature of these complexes. The activation energies for the localised scrambling at the unique iron atom have been evaluated and shown to be influenced by the nature and the number of the substitents at the cobalt atoms. Localised scrambling of the CO of any M(CO)2L moiety is not observed to take place prior of internuclear scrambling.

First ex‐vivo MRI co‐localization of two LIPOCEST agents

One of the major advantages of the CEST methodology deals with the possibility of visualizing more probes in the same MR image voxels. This is a unique property within the contrast media that act on the (1)H-NMR signal of water protons, and it might considerably improve the potential of the technique. In addition to displaying sufficiently different resonance frequencies of their mobile protons, it is also important that the CEST agents designed for this application are highly sensitive. LIPOCEST agents represent the most sensitive class of CEST systems developed so far. On this basis, two LIPOCEST samples, a spherical one and an osmotically shrunken nonspherical one, endowed with markedly different resonance frequencies of their intraliposomal water protons, 3 ppm and 15 ppm, respectively, were prepared and tested both in vitro and in ex-vivo on a bovine muscle used as tissue-surrogate. The response of the two agents did not interfere each other, thus allowing the multiple visualization of the two agents present at nanomolar concentrations in the same image voxels.

13C NMR study of methynyltricobalt enneacarbonyls

Abstract The 13 C NMR apical carbon resonances for a series of Co 3 (CO) 9 CY complexes have been observed to be in the lowfiedl region (310–230 ppm). Variable temperature spectra have shown “thermal decoupling” of carbon from cobalt and scrambling of the carbonyls.