Gadolinium(III) Complexes of dota‐Derived N‐Sulfonylacetamides (H4(dota‐NHSO2R)=10‐{2‐[(R)sulfonylamino]‐2‐oxoethyl}‐1,4,7,10‐tetraazacyclododecane‐1,4,7‐triacetic Acid): A New Class of Relaxation Agents for Magnetic Resonance Imaging Applications

Four new ligands for lanthanide ions based on the H₃do3a (=1,4,7,10‐tetraazacyclododecane‐1,4,7‐triacetic acid) structure and bearing one N‐sulfonylacetamide arm were synthesized, i.e., H₄dota‐NHSO₂R=10‐{2‐[(R)sulfonylamino]‐2‐oxoethyl}‐1,4,7,10‐tetraazacyclododecane‐1,4,7‐triacetic acids 1a – e . A ¹⁵N‐NMR study of the ¹⁵N‐labelled Eu³⁺ complex of one such ligands, 1d , showed that the coordination of the N‐sulfonylacetamide arm involves the carbonyl O‐atom rather than the N‐atom. The relaxometric properties of the corresponding Gd³⁺ complexes were investigated as a function of pH and temperature. These complexes have relaxivities in the range 4.5–5.3 mM ^?1 s^?1, at 20 MHz and 25°, and are characterized by a single H₂O molecule in their inner coordination sphere. The mean residence lifetime of this molecule is relatively long (500–700 ns) compared to other anionic complexes. The slow rate of H₂O exchange can be justified by the extensive delocalization of the negative charge on the N‐sulfonylacetamide arm. The long residence time of the coordinated H₂O allowed the observation of the effect of the prototropic exchange on the relaxivity. The study of the interaction between the complex [Gd( 1e )]‐ and HSA revealed a weak affinity constant highlighting the importance of a localized negative charge on the complex to promote a strong interaction with the protein.     

A Practical Synthesis of 1,4,7,10-Tetraaza-Cyclododecane,A Pivotal Precursor for MRI Contrast Agents

A practical preparation of the versatile macrocycle 1,4,7,10-tetraazacyclododecane (cyclen) was developed starting from cheap and easily available starting materials as ethylenediamine and glyoxal.     

Synthesis of bifunctional chelating agents based on mono and diphosphonic derivatives of diethylenetriaminepentaacetic acid

Bifunctional chelating agents (BFCAs) are small molecules containing a chelating unit, able to strongly coordinate a metal ion, and a reactive functional group, devised to form a stable covalent bond with another molecule. BFCAs are widely employed since their conjugation to a suitable biomolecule (e.g., a peptide or an antibody) allows the synthesis of diagnostic or therapeutic agents that specifically target diseased tissue with metals or radiometals. For this reason, BFCAs find application in diagnostic imaging, molecular imaging, and radiotherapy of cancer. The synthesis of new BFCAs based on a diethylenetriaminepentaacetic acid (DTPA) structure in which one or two carboxylic groups are replaced with phosphonic units is described. The phosphonic group, aside from being a classical isostere of the carboxylic acid in coordination chemistry, allows to modulate the physico-chemical properties of the ligands and of the corresponding complexes.     

Gd-AAZTA]-: a new structural entry for an improved generation of MRI contrast agents

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.     

The synthesis and application of polyamino polycarboxylic bifunctional chelating agents

Bifunctional chelating agents (BFCAs) are molecules which contain two different moieties: a strong metal chelating unit and a reactive functional group. The latter is directed to react with amines, thiols, alcohols or other reactive molecules to form stable covalent bonds while the chelating moiety is able to strongly coordinate a metal ion. In this way, it is possible to label a molecule of interest (e.g. an antibody or a peptide) with a metal or a radioactive metal ion. Of all the ligands reported so far, those based on a polyamino polycarboxylic structure are most efficient and are widely employed for the chelation of metal ions. The resulting metal complexes have found a broad range of applications in chemistry, biology and medicine. Diagnostic imaging (MRI, SPECT, PET), molecular imaging, tumour therapy and luminescent materials are only a few examples. The present critical review gives an overview of the syntheses and most important applications of polyamino polycarboxylic BFCAs (334 references).     

Novel functionalized pyridine-containing DTPA-like ligand. Synthesis, computational studies and characterization of the corresponding Gd(III) complex

A novel pyridine-containing DTPA-like ligand, carrying additional hydroxymethyl groups on the pyridine side-arms, was synthesized in 5 steps. The corresponding Gd(III) complex, potentially useful as an MRI contrast agent, was prepared and characterized in detail by relaxometric methods and its structure modeled by computational methods.     

Equilibrium and NMR relaxometric studies on the s-triazine-based heptadentate ligand PTDITA showing high selectivity for Gd3+ ions

A complete potentiometric and NMR relaxometric solution study on the heptadentate 2,2',2″,2'″-[(6-piperidinyl-1,3,5-triazine-2,4-diyl)dihydrazin-2-yl-1-ylidene]tetraacetic acid (PTDITA) ligand has been carried out. This ligand is based on the 1,3,5-triazine ring with two hydrazine-N,N-diacetate groups in positions 2 and 4 and a piperidine moiety in position 6. The introduction of the triazine ring into the ligand backbone is expected to modify its flexibility and then to affect the stability of the corresponding complexes with transition-metal and lanthanide ions. Thermodynamic stabilities have been determined by pH potentiometry, UV spectrophotometry, and (1)H NMR spectroscopy for formation of the complexes with Mg(2+), Ca(2+), Cu(2+), Zn(2+), La(3+), Gd(3+), and Lu(3+) ions. PTDITA shows a good binding affinity for Gd(3+) (logK = 18.49, pGd = 18.6) and an optimal selectivity for Gd(3+) over the endogenous Ca(2+), Zn(2+), and Cu(2+) (K(sel) = 6.78 × 10(7)), which is 3 orders of magnitude higher that that reported for Gd(DTPA) (K(sel) = 2.85 × 10(4)). This is mainly due to the lower stability of the Cu(II)- and Zn(II)(PTDITA) complexes compared to the corresponding DTPA complexes, which suggests an important role of the triazine ring on the selectivity for the Gd(3+) ion. The relaxometric properties of Gd(PTDITA) have been investigated in aqueous solution by measuring the (1)H relaxivity as a function of the pH, temperature, and magnetic field strength (nuclear magnetic relaxation dispersion profile). Variable-temperature (17)O NMR data have provided direct information on the kinetic parameters for exchange of the coordinated water molecules. A simultaneous fit of the data suggests that the high relaxivity value (r(1) = 10.2 mM(-1) s(-1)) is a result of the presence of two inner-sphere water molecules along with the occurrence of relatively slow rotation and electronic relaxation. The water residence lifetime, (298)τ(M) = 299 ns, is quite comparable to that of clinically approved magnetic resonance imaging contrast agents. The displacement of the inner-sphere water molecules by bidentate endogeneous anions (citrate, phosphate, and carbonate) has also been evaluated by (1)H relaxometry. In general, the binding interaction is markedly weak, and only in the case of citrate, a ca. 35% decrease in relaxivity was observed in the presence of 60 equiv of the anion. Phosphate and carbonate also interact with the paramagnetic ion, likely as monodentate ligands, but formation of the ternary complex is accompanied by a modest increase of r(1) due to the contribution of second-sphere water molecules.     

Designing Novel Contrast Agents for Magnetic Resonance Imaging. Synthesis and Relaxometric Characterization of three Gadolinium(III) Complexes Based on Functionalized Pyridine‐Containing Macrocyclic Ligands

The three novel pyridine‐containing 12‐membered macrocyclic ligands 1 – 3 were synthesized. The coordinating arms are represented by three acetate moieties in 1 and 3 and by one acetate and two phosphonate moieties in 2 . In all three ligands, the acetate arm in the distal position is substituted, with a benzyl group in 1 and 2 and with an arylmethyl moiety in 3 . The relaxivities r_1p (20 MHz, 25°) of Gd^III complexes are: GD?1 , r_1p=8.3 mM ^?1 s^?1; GD?2 , r_1p8.1 mM ^?1 s^?1; Gd?3 , r_1p10.5 mM ^?1 s^?1. ¹H‐NMRD and ¹⁷O‐NMR T₂ data show that Gd?1 and Gd?3 contain two H₂O molecules in the inner sphere, whereas the presence of two phosphonate arms allows the coordination of only one H₂O molecule in Gd?2 . Interestingly, the exchange lifetime of coordinated H₂O in the three complexes is similar in spite of the difference in the coordination number of the Gd^III ion (i.e., 9 in Gd?1 and Gd?3 , and 8 in Gd?2 ). ¹H‐Relaxometric measurements at different pH and in the presence of lactate and oxalate were carried out to get some insight into the formation of ternary complexes from Gd?1 and Gd?3 . Finally, it was found that binding to human‐serum albumin (HSA) of Gd?1 and Gd?2 , though weak, yields limited relaxivity enhancements, likely as a consequence of effects on the hydration sphere caused by donor atoms on the surface of the protein.     

New functionalized, differently fluorinated building-blocks via Michael addition to γ-fluoro-α-nitroalkenes

The Michael addition of ketone-derived enamines, metalated methylene active compounds and N-methyl pyrroles to γ-fluoro-α-nitroalkenes provided in moderate to good isolated yields the corresponding β-fluoroalkyl nitro compounds, which represent new interesting, highly functionalized building blocks in organofluorine chemistry.     

A concise entry into nonsymmetrical alkyl polyamines

The synthesis of nonsymmetrical polyamines (PAs) has, up to now, been problematic due to lengthy synthetic procedures, lack of regioselectivity, and very poor atom economy. An innovative synthetic protocol for nonsymmetrical PAs using a modified Ugi reaction ( N-split Ugi) which simplifies the synthesis of these tricky compounds is described. We believe that this new synthesis may open the door for the generation of new and pharmacologically active PAs.