Pier Lucio Anelli

Relaxometric evaluation of novel manganese(II) complexes for application as contrast agents in magnetic resonance imaging

Abstract. Three novel Mn(II) complexes bearing benzyloxymethyl functionalities are reported and their ability to enhance water (1H and 17O) relaxation times is investigated in detail. Two of them contain one coordinated water molecule and display relaxivity values only slightly smaller than those shown by the most clinically used contrast agents (e.g. [Gd(DTPA)(H2O)]2–). Moreover, in these Mn(II) chelates the exchange rate of the coordinated water is ca. one order of magnitude higher if compared to the exchange rates previously reported for Gd(III) complexes with octadentate ligands. The occurrence of such fast exchange rates of the coordinated water is exploited in the formation of macromolecular adducts with human serum albumin to attain systems displaying relaxivity values in the upper range of those so far reported for analogous Gd(III) systems. These results strongly support the view that Mn(II) complexes, in spite of the lower effective magnetic moment, can be considered as viable alternatives to the currently used Gd(III) complexes as contrast agents for MRI applications.

Mixed micelles containing lipophilic gadolinium complexes as MRA contrast agents.

Mixed micelles for MRA are multicomponent systems containing a phospholipid, a biocompatible non-ionic surfactant (e.g. Synporonic(k) F-108) and a lipophilic gadolinium complex. A variety of lipophilic gadolinium complexes were designed taking into account features such as: (i) nature of ligand (cyclic versus acyclic); (ii) lipophilic moiety; (iii) global charge of the complex; and (iv) nature of bond connecting the complex to the lipophilic moiety. All the lipophilic gadolinium complexes after formulation as mixed micelles show high relaxivities in water and in blood (rat). Mixed micelles containing gadolinium complexes bearing only one aliphatic chain cannot be used as MRA contrast agents because they have a high haemolytic effect. Furthermore, in rats they are quickly eliminated from the blood stream. These drawbacks are completely circumvented using gadolinium complexes bearing two aliphatic chains. Mixed micelles containing such complexes show high relaxivities. no haemolytic effect and long blood permanence. This makes them promising candidates as MRA contrast agents. However, elimination, which occurs exclusively through the liver, is not complete, even after 7 days. Complexes containing labile (e.g. ester) bonds between the lipophilic moieties and the chelate subunit are eliminated through both the liver and the kidneys. However, elimination is stiil not complete after 7 days.

Magnetic resonance contrast agents : From the bench to the patient

Magnetic Resonance Imaging is gaining a prominent role in the routine clinical investigation. To further improve this technique it is crucial that contrast agents are developed with more optimal organ specificity. This will not only result in a better diagnostic efficiency but also in a reduction of the amount of the agent administered. A combination of techniques has been employed to increase the target selectivity of the contrast agent and thereby the feasibility to visualize different organs. The organ targeting is based on the understanding of the mechanisms involved in the interaction of the agent with plasma proteins (albumin in particular) as well as the different membrane transporters involved in the uptake and in the excretion of the agent from the organ. The physicochemical properties of the contrast agents play a major role in the interaction with these various proteins. In this review we address the relationship between the structure of the contrast agents and their binding to different plasma proteins and membrane transporters in different organs, with special reference to the liver and kidney. The present and potentially future applications of these concepts in the clinical setting are also discussed.

MILD CONVERSION OF PRIMARY CARBOXAMIDES INTO CARBOXYLIC ESTERS

Abstract Primary carboxamides are converted into the corresponding alkyl carboxylates by treatment with dimethylformamide dimethylacetal in the appropriate alcohol at 25–45 °C. Yields are very good to excellent.

ONE-POT MITSUNOBU-STAUDINGER PREPARATION OF 3-AMINOCHOLAN-24-OIC ACID ESTERS FROM 3-HYDROXYCHOLAN-24-OIC ACID ESTERS

Abstract 3-Hydroxycholan-24-oic acid esters are easily converted into the corresponding 3-amino derivatives via Mitsunobu reaction with diphenylphosphoryl azide (DPPA) and Staudinger reduction with PPh3/H2O of the intermediate azido compound in THF.

Smiles rearrangement as a tool for the preparation of 5-[(2-hydroxyacyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamides: Main pathway and side reactions

Abstract In the preparation of 5-[(2-hydroxyacyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamides 1a-h from 2a-h two conditions using stoichiometric amounts of base (method A - aq NaOH at 50°C; method B - MeONa in DMF at r. t.) were used. Yields are good to excellent provided that the right conditions are chosen. Primary amides 2a,b give 1a,b with method B only, whereas with method A extensive hydrolysis of the CONH2 moiety is observed. N-Methyl derivatives 2c,d afford 1c,d with either method. However, with method B long reaction times lead to the formation of large amounts of benzoxazinones, 4c,d. Under the same conditions, the pattern of side products which are formed from N-(hrmhydroxyalkyl)phenoxyacetamides 2e-g is furtherly complicated by: i) intramolecular cyclizations leading to bicyclic (7f,g) and tricyclic structures (5) ii) N-deacylation; iii) double Smiles rearrangement reactions.

Macrocyclic chelants, their chelates and uses thereof in the diagnostic field

This invention relates to novel compounds able to chelate paramagnetic bi- or trivalent metal ions, their chelates with said metal ions and their use as contrast agents in magnetic resonance imaging (MRI).

Spectral Discrimination of Chiral Macrocyclic Paramagnetic Metal Complexes by NMR Techniques

Axially symmetric macrocyclic polyaza complexes of lanthanide(III) ions are present in aqueous solution as a racemic mixture of two enantiomers in slow exchange at room temperature. Chiral resolution of an anionic paramagnetic complex has been achieved by exploiting multisite electrostatic and hydrogen-bonding interactions with an optically active organic base, and revealed by NMR techniques as illustrated. The bonding of the optically active substrate to the complex has been elucidated.

High-resolution NMR and relaxometric studies of Ln(III) complexes of relevance to MRI

Abstract The solution structure and dynamics and the relaxation properties of the lanthanide(III) complexes with ethylenebis(oxyethylenenitrilo)tetraacetic acid (EGTA) are studied by NMR techniques. The longitudinal water proton relaxation rates as a function of the magnetic field in a solution of Gd(EGTA) − are investigated and analysed. The experimental results are compared with existing data for other linear and macrocyclic complexes and interpreted as indicative of the presence of a single coordinated water molecule and of an unusual symmetry and stereochemical rigidity of the coordination cage. Variable temperature high resolution 1 H and 13 C NMR spectra for the Eu(III), Ho(III) and Yb(III) complexes confirm the above hypothesis and suggest a dodecahedral geometry for the complexes as well as a marked increase of rigidity along the lanthanide series.

Diazadibenzo-30-crown-10 derivatives as receptors for diquat

Abstract In acetone-d6 solution, 1H n.m.r. spectroscopy reveals that receptors 4–9, prepared from the readily-synthesised diazadibenzo-30-crown-10 derivative 1, form strong 1:1 molecular inclusion complexes with Diquat, which, although present mainly as the dication, is accompanied by trace amounts of the radical cation.