Alessandro Barge

Paramagnetic lanthanide(III) complexes as pH-sensitive chemical exchange saturation transfer (CEST) contrast agents for MRI applications

The recently introduced new class of contrast agents (CAs) based on chemical exchange saturation transfer (CEST) may have a huge potential for the development of novel applications in the field of MRI. In this work we explored the CEST properties of a series of Lanthanide(III) complexes (Ln = Eu, Dy, Ho, Er, Tm, Yb) with the macrocyclic DOTAM‐Gly ligand, which is the tetraglycineamide derivative of DOTA (1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid). These complexes possess two pools of exchangeable protons represented by the coordinated water and the amide protons. Yb‐DOTAM‐Gly displays the most interesting CEST properties when its amide N‐H resonance (16 ppm upfield H2O signal) is irradiated. Up to 70% suppression of the water signal is obtained at pH 8. As the exchange rate of amide protons is base‐catalyzed, Yb‐DOTAM‐Gly results to be an efficient pH‐responsive probe in the 5.5–8.1 pH range. Moreover, a ratiometric method has been set up in order to remove the dependence of the observed pH responsiveness from the absolute concentration of the paramagnetic agent. In fact, the use of a mixture of Eu‐DOTAM‐Gly and Yb‐DOTAM‐Gly, whose exchangeable proton pools are represented by the coordinated water (ca. 40 ppm downfield H2O signal at 312K) and amide protons, respectively, produces a pH‐dependent CEST effect which is the function of the concentration ratio of the two complexes. Magn Reson Med 47:639–648, 2002.

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).

Crystal structure and solution dynamics of the lutetium(III) chelate of DOTA

Abstract The X-ray structure of Na[Lu(DOTA)(H 2 O)]·4H 2 O consists of (−1) complex anions balanced by sodium cations. The ninecoordinate Lu(III) is linked to the four nitrogen and to four oxygen atoms of the macrocyclic ligand DOTA in a square antiprismatic arrangement with a coordinated water molecule in capping position. In aqueous solution the complex is present under two isomeric forms in the relative ratio of 10:1, as evaluated from the low temperature limiting 13C NMR spectrum. The variable temperature behavior is consistent with the presence of two dynamic processes. One exchanges enantiomeric pairs for both isomers and involves concerted conformational changes of the ethylenic groups of the macrocyclic ring and rotation of the acetate arms. The other corresponds to the interconversion between the two isomers. Complete line-shape analysis of the variable-temperature 13C NMR spectra of Lu-DOTA allowed a quantitative evaluation of the two processes. The enantiomerization is slower than the isomerization: the corresponding calculated free energies of activation are 65.9 ± 1.2, 62.7 ± 2.0 (exchange major ⇌ minor) and 58.7 ± 2.I kJ mol −1 (exchange minor ⇌ major), respectively.

Ultrasound-Promoted Copper-Catalyzed Azide-Alkyne Cycloaddition

†Dipartimento di Scienza e Tecnologia del Farmaco, Universita di Torino, Via Giuria 9, 10125Torino, Italy, and Department of Chemistry, The Scripps Research Institute, 10550 North TorreyPines Road, La Jolla, California 92037The 1,3-dipolar cycloaddition reaction of azides and alkynes has been known for over 100years and was studied extensively by Huisgen and co-workers in the 1960s.

Magnetic resonance imaging visualization of targeted cells by the internalization of supramolecular adducts formed between avidin and biotinylated Gd3+ chelates

The high binding affinity between avidin and biotin has been exploited to develop a procedure for magnetic resonance imaging (MRI) visualization of target cells. SHIN3 and PANC1 tumor cell lines have been used as target cells because they possess on their membranes galactosyl receptors able to bind avidin molecules. Avidin–Gd chelate adducts have been built by using two Gd complexes containing one (Gd-I) and two (Gd-II) biotin residues, respectively. The relaxivities of such supramolecular adducts are significantly higher than those shown by free Gd-I and Gd-II. There is evidence of the occurrence of multilayered adducts in which the bis-biotinylated Gd3+ complex acts as a bridge between adjacent avidin molecules. MRI differentiation of labeled versus unlabeled cells has been attained when approximately 6×108 Gd units were internalized in each cell. Furthermore, there is a marked decrease in the measured intracellular T1 relaxivity as the number of internalized Gd complexes increases, probably owing to too short relaxation times of endosomic water protons with respect to their diffusion lifetime.

MRI-guided neutron capture therapy by use of a dual gadolinium/boron agent targeted at tumour cells through upregulated low-density lipoprotein transporters.

The upregulation of low-density lipoprotein (LDL) transporters in tumour cells has been exploited to deliver a sufficient amount of gadolinium/boron/ligand (Gd/B/L) probes for neutron capture therapy, a binary chemio-radiotherapy for cancer treatment. The Gd/B/L probe consists of a carborane unit (ten B atoms) bearing an aliphatic chain on one side (to bind LDL particles), and a Gd(III)/1,4,7,10-tetraazacyclododecane monoamide complex on the other (for detection by magnetic resonance imaging (MRI)). Up to 190 Gd/B/L probes were loaded per LDL particle. The uptake from tumour cells was initially assessed on cell cultures of human hepatoma (HepG2), murine melanoma (B16), and human glioblastoma (U87). The MRI assessment of the amount of Gd/B/L taken up by tumour cells was validated by inductively coupled plasma-mass-spectrometric measurements of the Gd and B content. Measurements were undertaken in vivo on mice bearing tumours in which B16 tumour cells were inoculated at the base of the neck. From the acquisition of magnetic resonance images, it was established that after 4-6 hours from the administration of the Gd/B/L-LDL particles (0.1 and 1 mmol kg(-1) of Gd and (10)B, respectively) the amount of boron taken up in the tumour region is above the threshold required for successful NCT treatment. After neutron irradiation, tumour growth was followed for 20 days by MRI. The group of treated mice showed markedly lower tumour growth with respect to the control group.

DEPENDENCE OF THE RELAXIVITY AND LUMINESCENCE OF GADOLINIUM AND EUROPIUM AMINO-ACID COMPLEXES ON HYDROGENCARBONATE AND PH

Reversible binding of hydrogencarbonate to a chiral di-aqua lanthanide complex occurs in the pH range 6.5–8.5, limiting the measured relaxivity in the gadolinium complex and enhancing the metal-based emission in the europium analogue.

UAE, MAE, SFE-CO2 and classical methods for the extraction of Mitragyna speciosa leaves

Mitragyna speciosa, a tropical plant indigenous to Southeast Asia, is well known for its psychoactive properties. Its leaves are traditionally chewed by Thai and Malaysian farmers and manual labourers as it causes a numbing, stimulating effect. The present study aims to evaluate alkaloid yield and composition in the leaf extracts. For this purpose we have compared several non-conventional extraction techniques with classic procedures (room temperature or under heating). Dried M. speciosa leaves belonging to three batches of different origin (from Thailand, Malaysia and Indonesia) were extracted using ultrasound-assisted extraction (UAE), microwave-assisted extraction (MAE) and supercritical carbon dioxide extraction SFE-CO(2), using methanol, ethanol, water and binary mixtures. The extracts were compared using an HPLC/ESI-MS analysis of mitragynine and four other related alkaloids which were present in the alkaloid fraction. The extraction technique influences both the raw product yield and the relative alkaloid content of M. speciosa leaves. Of the several methods tested, MAE in a closed vessel at 110 °C (60 W, methanol/water 1:1) gave the highest alkaloid fraction amount, while UAE with an immersion horn at 25 °C (21.4 kHz, 50 W, methanol) showed the best yield for mitragynine. This work may prove to be a useful contribution to forensic, toxicological and pharmacognosy studies. Although the potential applications of M. speciosa alkaloids clearly need further investigation, these results may facilitate the scaling-up of their extraction.

Click Chemistry Under Microwave or Ultrasound Irradiation

The copper-catalyzed azide-alkyne cycloaddition (CuAAC) is generally recognized as the most striking example of “click reaction”. CuAAC fit so well into Sharpless’ definition that it became almost synonymous with “click chemistry” itself. The most common catalyst systems employ Cu(II) salt in the presence of a reducing agent (i.e. sodium ascorbate) to generate the required Cu(I) catalyst in situ or as an alternative the comproportionation of Cu(II)/Cu(0) species. Although, Cu(I) catalyzes the reaction with a rate enhancement of 10 7 even in the absence of ligands and provides a clean and selective conversion to the 1,4-substituted triazoles, some bulky and scantily reactive substrates still require long reaction times and often few side products are formed. Outstanding results have been achieved by performing CuAAC under microwave (MW) irradiation. Several authors described excellent yields, high purity and short reaction times. In few cases also power ultrasound (US) accelerated the reaction, especially when heterogeneous catalysts or metallic copper are employed. The aim of this review is to summarize and highlight the huge advantages offered by MWand US-promoted CuAAC. In the growing scenario of innovative synthetic strategies, we intend to emphasize the complementary role played by these nonconventional energy sources and click chemistry to achieve process intensification in organic synthesis.

Fast, Solvent-Free, Microwave-Promoted Friedländer Annulation with a Reusable Solid Catalyst

A fast, solvent-free method is described for the synthesis of substituted quinoline derivatives via Friedländer cyclization, employing a reusable solid catalyst (silica-propylsulfonic acid). Although it worked best under microwave irradiation (with generally more than 90% isolated yields in 30 min), the reaction was also feasible under conventional heating (with fair to good yields in about 5 h).