Tetraamine‐Derived Bifunctional Chelators for Technetium‐99m Labelling: Synthesis,Bioconjugation and Evaluation as Targeted SPECT Imaging Probes for GRP‐Receptor‐Positive Tumours

Owing to its optimal nuclear properties, ready availability, low cost and favourable dosimetry, ^99mTc continues to be the ideal radioisotope for medical‐imaging applications. Bifunctional chelators based on a tetraamine framework exhibit facile complexation with Tc(V)O₂ to form monocationic species with high in vivo stability and significant hydrophilicity, which leads to favourable pharmacokinetics. The synthesis of a series of 1,4,8,11‐tetraazaundecane derivatives ( 01 – 06 ) containing different functional groups at the 6‐position for the conjugation of biomolecules and subsequent labelling with ^99mTc is described herein. The chelator 01 was used as a starting material for the facile synthesis of chelators functionalised with OH ( 02 ), N₃ ( 04 ) and O‐succinyl ester ( 05 ) groups. A straightforward and easy synthesis of carboxyl‐functionalised tetraamine‐based chelator 06 was achieved by using inexpensive and commercially available starting materials. Conjugation of 06 to a potent bombesin‐antagonist peptide and subsequent labelling with ^99mTc afforded the radiotracer ^99mTc‐N4‐BB‐ANT, with radiolabelling yields of >97 % at a specific activity of 37 GBq μmol^?1. An IC₅₀ value of (3.7±1.3) nM was obtained, which confirmed the high affinity of the conjugate to the gastrin‐releasing‐peptide receptor (GRPr). Immunofluorescence and calcium mobilisation assays confirmed the strong antagonist properties of the conjugate. In vivo pharmacokinetic studies of ^99mTc‐N4‐BB‐ANT showed high and specific uptake in PC3 xenografts and in other GRPr‐positive organs. The tumour uptake was (22.5±2.6) % injected activity per gram (% IA g^?1) at 1 h post injection (p.i.). and increased to (29.9±4.0) % IA g^?1 at 4 h p.i. The SPECT/computed tomography (CT) images showed high tumour uptake, clear background and negligible radioactivity in the abdomen. The promising preclinical results of ^99mTc‐N4‐BB‐ANT warrant its potential candidature for clinical translation.     

Random serial dictatorship and ordinally efficient contracts

For any preference profile at which the random serial dictatorship allocation is ordinally inefficient there exists an ordering exchange contract inducing an ordinally efficient random allocation that ordinally dominates the random serial dictatorship allocation.     

Fluid-fluid and fluid-solid transitions in the Kern-Frenkel model from Barker-Henderson thermodynamic perturbation theory

We study the Kern-Frenkel model for patchy colloids using Barker-Henderson second-order thermodynamic perturbation theory. The model describes a fluid where hard sphere particles are decorated with one patch, so that they interact via a square-well potential if they are sufficiently close one another, and if patches on each particle are properly aligned. Both the gas-liquid and fluid-solid phase coexistences are computed and contrasted against corresponding Monte Carlo simulations results. We find that the perturbation theory describes rather accurately numerical simulations all the way from a fully covered square-well potential down to the Janus limit (half coverage). In the region where numerical data are not available (from Janus to hard-spheres), the method provides estimates of the location of the critical lines that could serve as a guideline for further efficient numerical work at these low coverages. A comparison with other techniques, such as integral equation theory, highlights the important aspect of this methodology in the present context.     

The low level laser therapy effect on the remodeling of bone extracellular matrix

The low level laser therapy (LLLT) has been used as an option to accelerate the regeneration of bone tissue. In this study, both femurs of male Wistar rats (30 animals) were injured with a drill and the effect of LLLT using a laser diode (100 mW at 660 nm) in the bone matrix on the left paw measured. LLLT effect on the healing bone tissue matrix was evaluated by a combination of immunohistochemical histomorphometry, confocal immunofluorescence microscopy and isolation and characterization of glycosaminoglycans. Histomorphometric analysis showed that LLLT increased bone matrix and showing more organized. Alcian Blue and PAS staining seems to suggest differential glycosaminoglycans and glycoproteins. The data showed increased expression of chondroitin sulfate and hyaluronic acid, after reduction as the LLLT and mature bone, resembling the expression of osteonectin and biglycan. The difference in expression of siblings (DMP‐1, OPN and BSP) is in accordance with the repair accelerated bone formation after the application of LLLT as compared with control. The expression of osteonectin and osteocalcin supports their role in bone mineralization protein, indicating that LLLT accelerates this process. The overall data show that LLLT bone changes dynamic array, shortening the time period involved in the bone repair.     

The electrocatalytic activity of a supramolecular assembly of CoTsPc/FeT4MPyP on multi-walled carbon nanotubes towards L-glutathione, and its determination in human erythrocytes

The electrocatalytic activity of a supramolecular complex based on cobalt(II) phthalocyanine tetrasulfonate and iron(III) tetra-(N-methyl-4-pyridyl)-porphyrin adsorbed on multi-walled carbon nanotubes for the oxidation of L-glutathione (GSH) was investigated at pH 7.4. Scanning electron microscopy and energy dispersive X-ray spectrometry were used to characterize the morphologies and composition of the materials. The modified electrode displayed efficient electrocatalytic activity in terms of oxidation of GSH at an oxidation potential of 0 V (versus Ag/AgCl). Cyclic voltammetry and amperometry indicated that the oxidation involves 2-electrons, with a heterogeneous rate constant of 4.9?×?10⁵ mol^?1 L s^?1. The response is linear from 2 to 210 μmol ?L^-1, the sensitivity is 1570 μA L mmol^?1, the detection limit is 0.03 μmol L^?1, and the relative standard deviation of 110 μmol L^?1 GSH was 2.6% (n?=?10). The modified electrode was applied to the determination of GSH in erythrocytes and the results were in agreement with those obtained by a method reported in the literature.     

Simultaneous electrochemical determination of nitrate and nitrite in aqueous solution using Ag-doped zeolite-expanded graphite-epoxy electrode

In this work a new electrochemical sensor based on an Ag-doped zeolite-expanded graphite-epoxy composite electrode (AgZEGE) was evaluated as a novel alternative for the simultaneous quantitative determination of nitrate and nitrite in aqueous solutions. Cyclic voltammetry was used to characterize the electrochemical behavior of the electrode in the presence of individual or mixtures of nitrate and nitrite anions in 0.1 M Na₂SO₄ supporting electrolyte. Linear dependences of current versus nitrate and nitrite concentrations were obtained for the concentration ranges of 1-10 mM for nitrate and 0.1-1 mM for nitrite using cyclic voltammetry (CV), chronoamperometry (CA), and multiple-pulsed amperometry (MPA) procedures. The comparative assessment of the electrochemical behavior of the individual anions and mixtures of anions on this modified electrode allowed determining the working conditions for the simultaneous detection of the nitrite and nitrate anions. Applying MPA allowed enhancement of the sensitivity for direct and indirect nitrate detection and also for nitrite detection. The proposed sensor was applied in tap water samples spiked with known nitrate and nitrite concentrations and the results were in agreement with those obtained by a comparative spectrophotometric method. This work demonstrates that using multiple-pulse amperometry with the Ag-doped zeolite-expanded graphite-epoxy composite electrode provides a real opportunity for the simultaneous detection of nitrite and nitrate in aqueous solutions.     

Pneumatically assisted desorption/ionization: 1. Some thoughts on the possible ionization mechanism(s)

We have observed that spraying solvent droplets on a zopiclone tablet produced MH⁺ ions also in the absence of any electrical field and without the addition of organic acids to the sprayed solvent. The choice of a drug tablet as test bench has been done for the signal stability, higher than that observed when the drug is directly placed on a stainless steel surface. This behavior indicates that the formation of MH⁺ ions is mainly due to pneumatical effects and the results are discussed with respect to those obtained by other research groups. Different mechanisms contributing to MH⁺ production under these conditions are proposed and discussed. The local heating of the solvent thin layer present on the surface has been calculated and the small temperature increase (and the consequent small decrease of pK_a value) suggests that this effect can play only a minor role. However, different solvents have been employed for studying this aspect and, quite surprisingly, the best results have been obtained with acetonitrile (ACN). Experiments performed by spraying CD₃CN showed again the formation of MH⁺ and not MD⁺, and this excludes the role of ACN as protonating medium. A further thought was stimulated by the behavior observed by varying the sheath gas (N₂) flow, showing that the MH⁺ ion intensity increases by increasing the flow. Side effects related to the highest kinetic energy of the spraying droplets can be considered, but an active role of N₂ in the MH⁺ formation could be taken into account, by considering the possible ionization of N₂ by collisional phenomena. The N₂^+? ions could undergo a charge–exchange reaction with analyte molecules leading to a short‐lived odd electron ion which behaves as protonating media for neutral molecules. The above‐described mechanism does not require either the presence of electrical fields nor the addition of organic acid to the sprayer solvent and can give a rationale for what was observed when only pneumatical conditions are employed. Copyright © 2010 John Wiley & Sons, Ltd.