Prospects of molybdenum and rhenium octahedral cluster complexes as X-ray contrast agents

doi:10.1016/j.jinorgbio.2014.12.016

Journal of Inorganic Biochemistry

Volume 144, March 2015, Pages 13-17

https://doi.org/10.1016/j.jinorgbio.2014.12.016 Get rights and content

Highlights

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The radiopacity of different cluster compounds was shown.
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The applicability of the clusters as agents for X-ray contrast media was demonstrated.
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Complex 8 excretes through the kidneys rapidly.

Abstract

Investigation of new X-ray contrast media for radiography is an important field of science since discovering of X-rays in 1895. Despite the wide diversity of available X-ray contrast media the toxicity, especially nephrotoxicity, is still a big problem to be solved. The octahedral metal-cluster complexes of the general formula [{M₆Q₈}L₆] can be considered as quite promising candidates for the role of new radiocontrast media due to the high local concentration of heavy elements, high tuning ability of ligand environment and low toxicity. To exemplify this, the X-ray computed tomography experiments for the first time were carried out on some octahedral cluster complexes of molybdenum and rhenium. Based on the obtained data it was proposed to investigate the toxicological proprieties of cluster complex Na₂H₈[{Re₆Se₈}(P(CH₂CH₂CONH₂)(CH₂CH₂COO)₂)₆]. Observed low cytotoxic and acute toxic effects along with rapid renal excretion of the cluster complex evidence its perspective as an X-ray contrast media for radiography.

Graphical abstract

The applicability of the hexanuclear metal cluster complexes as agents for X-ray contrast media was demonstrated. The highly radiopaque cluster cores {M₆Q₈} along with high tuning ability of the outer ligand environment allow creating a complex with low toxicity and rapid renal excretion.

Introduction

Since discovering of X-ray radiation in 1895 by Wilhelm C. Röentgen scientists attempted to use this new tool in medicine diagnostics [1]. To better delineate soft tissue regions the X-ray contrast agents based on heavy elements such as a silver, bismuth, barium, iodine, etc. were used [2], [3]. To date, iodinated X-ray contrast media based on 1,3,5-triiodobenzene core are among the mostly utilized pharmaceuticals for intravascular administration. However, the iodinated contrast agents have some significant disadvantages, among which cardiovascular, allergic and pain reactions [4], [5]. Also iodinated contrast media are contraindicated to patients with a history of renal insufficiency, diabetes and heart failure and with the tendency to thyroid dysfunction [6], [7], [8]. In such cases it is better to use not-iodinated X-ray contrast media containing electron-dense heavy elements like silver, tin, gadolinium, gold, thorium etc. [3], [9]. These metals can be used in different forms such as metal oxides (SnO₂, ThO₂, Ta₂O₅), nanoparticles (Ag, Au), salts (CaWO₄, CsCl) and as metal chelate complexes (Gd, Yb with diethylenetriaminepentacetate (DTPA), 1,4,7-tris(carboxymethylaza)cyclododecane-10-azaacetylamide (DO3A)). Despite the rather wide variety of X-ray contrast agents, intensive investigations of new compounds with a potential to be applied as contrast agents are carrying out. The two main factors contributing to a radiopacity are electron density of a contrast agent in whole and/or atomic number of chemical elements within the agent. According to these the octahedral metal-cluster complexes [{M₆Q₈}L₆] (M – Mo, W or Re; Q – inner halide or chalcogenide ligand; L – outer organic or inorganic ligand) are quite promising candidates for this role due to the high local concentration of heavy elements within the relatively small and very robust cluster core {M₆Q₈}. Unfortunately, the most of such complexes with organic outer ligands are insoluble in water that limits their use in medical applications. However, creation of appropriate outer ligand environment, for example, by ligation of the cluster core by organic molecules with polar (hydrophilic) groups, can provide water solubility of the complex.

In this contribution, preliminary comparative study of X-ray computed tomography contrast of stable water-soluble potassium salts of hexarhenium and hexamolybdenum anionic octahedral cluster complexes, namely K₄[{Re₆S₈}(CN)₆] (1), K₄[{Re₆Se₈}(CN)₆] (2), K₄[{Re₆Te₈}(CN)₆] (3), K₆[{Mo₆S₈}(CN)₆] (4), K₆[{Mo₆Se₈}(CN)₆] (5) and K₂[{Mo₆Br₈}(CN)₆] (6), K₂[{Mo₆I₈}(CN)₆] (7) is described. The cluster core {Re₆Se₈}²⁺ was selected as the most promising for creation of a new X-ray contrast agent by synthesis of a complex with outer organic ligand environment providing its solubility in water. Thus, the cytotoxicity and acute toxicity of the highly hydrophilic complex Na₂H₈[{Re₆Se₈}(P(CH₂CH₂CONH₂)(CH₂CH₂COO)₂)₆] (8) were evaluated. In addition, a computed tomography (CT) scan experiments were carried out.

Section snippets

Materials and methods

Potassium salts of the octahedral hexarhenium cluster complexes 1–3 and hexamolybdenum cluster complexes 4 and 5 were prepared by the high-temperature reactions of the corresponding polymers Re₆S₈Br₂, Re₆Se₈Br₂, Re₆Te₁₅, ZnMo₆S₈ or Mo₆Se₈ with molten KCN [10], [11], [12], [13], [14].

The cluster complexes 6 and 7 were prepared according to reported methodic [15] by reactions of (Bu₄N)₂[{Mo₆X₈}(NO₃)₆] (X—Br or I) [16], [17] with KCN in acetone solutions.

Na₄[{Re₆Se₈}(OH)₆] was obtained by

CT-scan experiment on molybdenum and rhenium hexacyanide cluster complexes

Octahedral metal-cluster complexes with the general formula [{M₆Q₈}L₆]^n– (M—Mo, Q—halogen or chalcogen; M—Re, Q—chalcogen; L—outer ligand) contain cluster core {M₆Q₈}ⁿ⁺ with nearly regular M₆ octahedron residing inside a Q₈ cube. In addition, all metal atoms are coordinated by outer L ligands (Fig. 1). The cluster core consists of locally concentrated heavy elements—six metal atoms (Mo or Re) and eight inner ligands (S, Se, Te or Br, I), provide a radiopacity of octahedral metal-clusters [3].

Conclusion

To summarize, we have demonstrated the radiopacity of different cluster compounds based on {M₆Q₈}-cluster core (M—Mo or Re; Q—halide or chalcogenide) by the X-ray computed tomography in vitro. Despite of the highest radiopacity of the complex with {Re₆Te₈}-cluster core revealed, the most perspective radiocontrast agents are the {Re₆Se₈}-based compounds since their outer ligands can be purposefully modified allowing us to create various compounds with necessary properties. The cellular uptake

Acknowledgments

This work was supported by the Russian Science Foundation (Grant no. 14-14-00192).

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Prospects of molybdenum and rhenium octahedral cluster complexes as X-ray contrast agents

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Materials and methods

CT-scan experiment on molybdenum and rhenium hexacyanide cluster complexes

Conclusion

Acknowledgments

J. Am. Pharm. Assoc.

Kidney Int.

Int. J. Cardiol.

Kidney Int.

Eur. J. Radiol.

J. Struct. Biol.

J. Inorg. Biochem.

Eur. J. Radiol.

Sitzungsber

Phys. Med. Ges. Wurzburg

Chem. Rev.

Radiology

J. Am. Soc. Nephrol.

Am. J. Roentgenol.

Arch. Intern. Med.

Phys. Chem. Chem. Phys.

J. Struct. Chem.

J. Struct. Chem.

Ukr. Khim. Zh.

Chem. Eur. J.