Julia Torres

New Tris(hydroxypyridinone) Bifunctional Chelators Containing Isothiocyanate Groups Provide a Versatile Platform for Rapid One-Step Labeling and PET Imaging with 68Ga3+

Two new bifunctional tris(hydroxypyridinone) (THP) chelators designed specifically for rapid labeling with 68Ga have been synthesized, each with pendant isothiocyanate groups and three 1,6-dimethyl-3-hydroxypyridin-4-one groups. Both compounds have been conjugated with the primary amine group of a cyclic integrin targeting peptide, RGD. Each conjugate can be radiolabeled and formulated by treatment with generator-produced 68Ga3+ in over 95% radiochemical yield under ambient conditions in less than 5 min, with specific activities of 60–80 MBq nmol–1. Competitive binding assays and in vivo biodistribution in mice bearing U87MG tumors demonstrate that the new 68Ga3+-labeled THP peptide conjugates retain affinity for the αvβ3 integrin receptor, clear within 1–2 h from circulation, and undergo receptor-mediated tumor uptake in vivo. We conclude that bifunctional THP chelators can be used for simple, efficient labeling of 68Ga biomolecules under mild conditions suitable for peptides and proteins.

PET Imaging of Copper Trafficking in a Mouse Model of Alzheimer Disease

Alzheimer disease (AD) is a fatal neurodegenerative disorder characterized by progressive neuronal loss and cognitive decline. The lack of reliable and objective diagnostic markers for AD hampers early disease detection and treatment. Growing evidence supports the existence of a dysregulation in brain copper trafficking in AD. The aim of this study was to investigate brain copper trafficking in a transgenic mouse model of AD by PET imaging with 64Cu, to determine its potential as a diagnostic biomarker of the disorder. Methods: Brain copper trafficking was evaluated in 6- to 8-mo-old TASTPM transgenic mice and age-matched wild-type controls using the 64Cu bis(thiosemicarbazone) complex 64Cu-GTSM (glyoxalbis(N4-methyl-3-thiosemicarbazonato) copper(II)), which crosses the blood–brain barrier and releases 64Cu bioreductively into cells. Animals were intravenously injected with 64Cu-GTSM and imaged at 0–30 min and 24–25 h after injection. The images were analyzed by atlas-based quantification and texture analysis. Regional distribution of 64Cu in the brain 24 h after injection was also evaluated via ex vivo autoradiography and compared with amyloid-β plaque deposition in TASTPM mice. Results: Compared with controls, in TASTPM mice PET image analysis demonstrated significantly increased (by a factor of ∼1.3) brain concentration of 64Cu at 30 min (P < 0.01) and 24 h (P < 0.05) after injection of the tracer and faster (by a factor of ∼5) 64Cu clearance from the brain (P < 0.01). Atlas-based quantification and texture analysis revealed significant differences in regional brain uptake of 64Cu and PET image heterogeneity between the 2 groups of mice. Ex vivo autoradiography showed that regional brain distribution of 64Cu at 24 h after injection did not correlate with amyloid-β plaque distribution in TASTPM mice. Conclusion: The trafficking of 64Cu in the brain after administration of 64Cu-GTSM is significantly altered by AD-like pathology in the TASTPM mouse model, suggesting that 64Cu-GTSM PET imaging warrants clinical evaluation as a diagnostic tool for AD and possibly other neurodegenerative disorders.

Inframolecular acid-base and coordination properties towards Na + and Mg 2+ of myo-inositol 1,3,4,5,6-pentakisphosphate: a structural approach to biologically relevant species†

We present the chemical and structural study of the inframolecular aspects of Ins(1,3,4,5,6)P 5 protonation and complexation equilibria with biological cations.The myo-inositol phosphates (InsPs) are specific signalling metabolites ubiquitous in eukaryotic cells. Although Ins(1,3,4,5,6)P(5) is the second most abundant member of the InsPs family, its certain biological roles are far from being elucidated, in part due to the large number of species formed by Ins(1,3,4,5,6)P(5) in the presence of metal ions. In light of this, we have strived in the past to make a complete and at the same time biological-user-friendly description of the Ins(1,3,4,5,6)P(5) chemistry with mono and multivalent cations. In this work we expand these studies focusing on the inframolecular aspects of its protonation equilibria and the microscopic details of its coordination behaviour towards biologically relevant metal ions. We present here a systematic study of the Ins(1,3,4,5,6)P(5) intrinsic acid-base processes, in a non-interacting medium, and over a wide pH range, analyzing the (31)P NMR curves by means of a model based on the Cluster Expansion Method. In addition, we have used a computational approach to analyse the energetic and structural features of the protonation and conformational changes of Ins(1,3,4,5,6)P(5), and how they are influenced by the presence of two physiologically relevant cations, Na(+) and Mg(2+).

Interactions of W(VI) and Mo(VI) Oxyanions with Metal Cations in Natural Waters

AbstractnThe association of tungsten(VI) and molybdenum(VI) oxyanions with metal cations was investigated under conditions simulating those prevailing in most natural waters. Potentiometric titrations were carried out for the systems containing tungsten(VI) or molybdenum(VI) anions and metal cations. The selection includes the major metal cations and some other ions of high environmental relevance. At neutral and basic pH values, in the presence of the most abundant metal cations, ionic pair species such as [Ca(WO4)] or [Ca(MoO4)] are formed to high extents. For the acidic pH range, polyoxoanion associations with cations are also found but are only relevant for tungsten(VI) in the conditions of the natural aquatic systems. The present results provide the basis for studying W(VI) and Mo(VI) speciation in natural aquatic systems, on which the environmental fate, bioavailability and toxicity of the elements depend.

[18F]tetrafluoroborate as a PET tracer for the sodium/iodide symporter: the importance of specific activity

Background[18F]BF4−, the first 18F-labelled PET imaging agent for the sodium/iodide symporter (NIS), was produced by isotopic exchange yielding a product with limited specific activity (SA, ca. 1xa0GBq/μmol) posing a risk of sub-optimal target-to-background ratios (TBR) in PET images due to saturation of NIS in vivo. We sought to quantify this risk and to develop a method of production of [18F]BF4− with higher SA.MethodsA new radiosynthesis of [18F]BF4− was developed, involving reaction of [18F]F− with boron trifluoride diethyl etherate under anhydrous conditions, guided by 11B and 19F NMR studies of equilibria involving BF4− and BF3. The SA of the product was determined by ion chromatography. The IC50 of [19F]BF4− as an inhibitor of [18F]BF4− uptake was determined in vitro using HCT116-C19 human colon cancer cells expressing the human form of NIS (hNIS). The influence of [19F]BF4− dose on biodistribution in vivo was evaluated in normal mice by nanoPET imaging and ex vivo tissue counting.ResultsAn IC50 of 4.8xa0μΜ was found in vitro indicating a significant risk of in vivo NIS saturation at SA achieved by the isotopic exchange labelling method. In vivo thyroid and salivary gland uptake decreased significantly with [19F]BF4− doses above ca. 10xa0μg/kg. The new radiosynthesis gave high radiochemical purity (>99xa0%) and moderate yield (15xa0%) and improved SA (>5xa0GBq/μmol) from a starting activity of only 1.5xa0GBq.Conclusions[18F]BF4− produced at previously reported levels of SA (1xa0GBq/μmol) can lead to reduced uptake in NIS-expressing tissues in mice. This is much less likely in humans. The synthetic approach described provides an alternative for production of [18F]BF4− at higher SA with sufficient yield and without need for unusually high starting activity of [18F]fluoride, removing the risk of NIS saturation in vivo even in mice.Trial registrationISRCTN75827286.

Interaction of Molybdenum(VI) Oxyanions with +2 Metal Cations

AbstractnThe association of molybdenum(VI) oxyanions with metal cations was investigated in solutions of low ionic strength, such as those prevailing in most natural waters. Potentiometric titrations were carried out for the systems containing molybdenum(VI) anions and divalent metal cations (Mxa0=xa0Mg, Ca, Sr, Ba, Mn, Fe, Co, Ni, Cu, Zn, Cd, Hg and Pb). This selection includes the major cations and some other cations of high environmental relevance. The interaction of iron(III) with Mo(VI) anions was also studied. At neutral and basic pH values and for those systems where the solubility of the molybdate salt is high enough, ionic species pairs such as [M(MoO4)] predominate. At acidic pH values, [M(HMoO4)]+ and [M(Mo7O24)]4– are formed, the latter species are only relevant for total molybdenum concentrations higher than 1xa0mmol·L−1. These results provide the basis for molybdenum speciation in natural aquatic systems, on which the environmental fate, bioavailability and toxicity of the element depend.

Fucoidan Prolongs the Circulation Time of Dextran-Coated Iron Oxide Nanoparticles

The magnetic properties and safety of dextran-coated superparamagnetic iron oxide nanoparticles (SPIONs) have facilitated their clinical use as MRI contrast agents and stimulated research on applications for SPIONs in particle imaging and magnetic hyperthermia. The wider clinical potential of SPIONs, however, has been limited by their rapid removal from circulation via the reticuloendothelial system (RES). We explored the possibility of extending SPION circulatory time using fucoidan, a seaweed-derived food supplement, to inhibit RES uptake. The effects of fucoidan on SPION biodistribution were evaluated using ferucarbotran, which in its pharmaceutical formulation (Resovist) targets the RES. Ferucarbotran was radiolabeled at the iron oxide core with technetium-99m (99mTc; t1/2 = 6 h) or zirconium-89 (89Zr; t1/2 = 3.3 days). Results obtained with 99mTc-ferucarbotran demonstrated that administration of fucoidan led to a 4-fold increase in the circulatory half-life (t1/2 slow) from 37.4 to 150 min (n = 4; P < 0.0001). To investigate whether a longer circulatory half-life could lead to concomitant increased tumor uptake, the effects of fucoidan were tested with 89Zr-ferucarbotran in mice bearing syngeneic subcutaneous (GL261) tumors. In this model, the longer circulatory half-life achieved with fucoidan was associated with a doubling in tumor SPION uptake (n = 5; P < 0.001). Fucoidan was also effective in significantly increasing the circulatory half-life of perimag-COOH, a commercially available SPION with a larger hydrodynamic size (130 nm) than ferucarbotran (65 nm). These findings indicate successful diversion of SPIONs away from the hepatic RES and show realistic potential for future clinical applications.

New polynuclear compounds based on N-benzyliminodipropionic acid: solution studies, synthesis, and X-ray crystal structures

Abstract Three new polynuclear compounds based on a dicarboxylic acid ligand are reported. In particular, two Cu(II) coordination compounds, [Cu2(H2O)6(Hbzlidp)2](CF3SO3)2·2H2O (1) and [Cu(NO3)(Hbzlidp)]∞ (2) (bzlidp2− = N-benzyliminodipropionate anion), and a Ni(II) dinuclear compound, [Ni2(H2O)4(bzlidp)2] (3), were synthesized and characterized by IR spectroscopy, elemental analysis and single crystal X-ray diffraction. Different structures were obtained depending on the reaction conditions. The structural analyses reveal that 1 was formed by dinuclear [Cu2(H2O)6(Hbzlidp)2]2+ units built by two copper(II) ions joined through two Hbzlidp− ligands, while 2 was formed by pairs of Cu(II) centers bridged by four syn,syn carboxylate groups to generate “paddle wheel” units. The dinuclear copper units are arranged in a rhombus type grid, in a 2-D layer structure. In both cases, the N was protonated and not coordinated to the metal center. Compound 3 was formed by [Ni2(H2O)4(bzlidp)2] neutral dinuclear units, with octahedral Ni(II) centers. Solution studies of the ligand–M(II) systems (M(II) = Mn, Co, Ni, Cu, Zn, Cd, and Pb) were also carried out.

Polymorphism and luminescence properties of heteropolynuclear metal–organic frameworks containing oxydiacetate as linker

Using the flexible ligand oxydiacetic acid (H2oda), ten new heteropolynuclear compounds with general formula [Ln2Zn3(oda)6]·xH2O (Ln = lanthanide ion, oda = oxydiacetate) were synthesized and structurally characterized. They were prepared by the direct reaction of oda in aqueous solution with stoichiometric amounts of Zn and Ln salts, followed by slow organic solvent diffusion. Two different structures were obtained: the larger lanthanides Pr, Nd, Eu and Tb gave compounds belonging to the hexagonal system, space group P6/mcc; whereas, the smaller ones, Ho, Er, Yb and Y formed cubic systems, space group Fdc. In the case of Dy, the two polymorphs were obtained by slight variations in the synthetic conditions. The phase change observed is discussed in comparison with previously reported [Ln2M3(oda)6]·xH2O compounds (M = bivalent metal ion). Luminescence studies were also carried out. Compounds containing Eu and Tb showed the most intense luminescence, also bearing relatively long lifetimes for the excited state deactivation. The luminescence profiles of both Dy systems are independent of the hexagonal or cubic arrangements, due to the similar environment of the Ln having the same point symmetry.

Author Correction: Non-Invasive whole-body detection of complement activation using radionuclide imaging in a mouse model of myocardial ischaemia-reperfusion injury

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