Synthesis and biological characterisation of novel dithiocarbamate containing 5-nitroimidazole 99mTc-complexes as potential agents for targeting hypoxia

Giglio, Javier; Fernández, Soledad; Rey, Ana; Cerecetto, Hugo

doi:10.1016/j.bmcl.2010.10.130

Cited by 34 publications

(18 citation statements)

References 19 publications

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“…99m TcN-NOET has the advantage of having a high first pass extraction coefficient as compared to some related reagents, but is only slowly cleared from the liver and this has hampered its development as a commercial product. Attempts are on-going to develop technetium-nitridedithiocarbamate complexes as radioactive tracers [111][112][113][114], for example the fluoroquinoline derivative (Fig. 11b) shows promise as a bacteria-specific infection imaging agent [111].…”

Section: Technetium Chemistry 99mmentioning

confidence: 99%

Metal-dithiocarbamate complexes: chemistry and biological activity

Hogarth¹

2012

MRMC

240

157

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Dithiocarbamates are highly versatile mono-anionic chelating ligands which form stable complexes with all the transition elements and also the majority of main group, lanthanide and actinide elements. They are easily prepared from primary or secondary amines and depending upon the nature of the cation can show good solubility in water or organic solvents. They are related to the thiuram disulfides by a one-electron redox process (followed by dimerisation via sulfur-sulfur bond formation) which is easily carried out upon addition of iodide or ferric salts. Dithiocarbamates are lipophilic and generally bind to metals in a symmetrical chelate fashion but examples of other coordination modes are known, the monodentate and anisobidentate modes being most prevalent. They are planar sterically non-demanding ligands which can be electronically tuned by judicious choice of substituents. They stabilize metals in a wide range of oxidation states, this being attributed to the existence of soft dithiocarbamate and hard thioureide resonance forms, the latter formally resulting from delocalization of the nitrogen lone pair onto the sulfurs, and consequently their complexes tend to have a rich electrochemistry. Tetraethyl thiuramdisulfide (disulfiram or antabuse) has been used as a drug since the 1950s but it is only recently that dithiocarbamate complexes have been explored within the medicinal domain. Over the past two decades anti-cancer activity has been noted for gold and copper complexes, technetium and copper complexes have been used in PET-imaging, dithiocarbamates have been used to treat acute cadmium poisoning and copper complexes also have been investigated as SOD inhibitors.

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Section: Technetium Chemistry 99mmentioning

confidence: 99%

Metal-dithiocarbamate complexes: chemistry and biological activity

Hogarth¹

2012

MRMC

240

157

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“…In the development of hypoxia imaging agents, nitroimidazole derivatives are enzymatically reduced and 25 accumulated in hypoxic regions, therefore labeled nitroimidazole analogues have received great attention. [4][5][6][7][8][9][10][11][12][13] However, there exist some limitations for these complexes, such as the relative lower tumor uptakes or slow clearance from blood. [2][3] However, the short half life, high cost and limited availability of the [ 18 F] isotope are realistic 30 limitations.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biodistribution of novel ^99mTc labeled 4-nitroimidazole dithiocarbamate complexes as potential agents to target tumor hypoxia

Zhang

et al. 2015

Med. Chem. Commun.

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The sodium 3-(4-nitro-1H-imidazolyl)propyl dithiocarbamate (N4IPDTC) was synthesized and radiolabelled with [ 99m TcO] 3+ , [ 99m Tc≡N] 2+ and [ 99m Tc(CO) 3 ] + cores to produce 99m TcO-N4IPDTC , 99m TcN-N4IPDTC and 99m Tc(CO) 3 -N4IPDTC, respectively. All of the three complexes were prepared with high radiochemical purity and had good in vitro stability over a period of 6 h. The partition coefficient results showed that 99m TcO-N4IPDTC and 99m TcN-N4IPDTC were lipophilic, while 10 99m Tc(CO) 3 -N4IPDTC was hydrophilic. The tumor cell experiments and the biodistribution in mice bearing S 180 tumor showed that all of the complexes exhibited good hypoxic selectivity and accumulation in the tumor. Among them, 99m TcO-N4IPDTC had advantages of higher tumor uptake, tumor/blood and tumor/muscle ratios. Planar scintigraphic imaging studies showed there was a visible accumulation in tumor sites, suggesting its potential usefulness as a tumor hypoxia imaging agent.

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“…[12][13][14][15] Metronidazole should be attached to adequate chelating groups to enable coordination of 99m Tc without losing the biological activity. As part of our ongoing research on potential radiopharmaceuticals for imaging tumour hypoxia, [9][10][11][16][17][18][19] we have designed and synthesised the novel metronidazole derivative 2-amine-3-[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethylthio] propanoic acid (L) (Figure 1). Chemical modifications were performed in order to introduce a cysteine-like donor-atom set (carboxylate, amine and thiol group), which acts as tridentate ligand towards the Tc(I)-tricarbonyl core.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and evaluation of a new ^99mTc(I)‐tricarbonyl complex bearing the 5‐nitroimidazol‐1‐yl moiety as potential hypoxia imaging agent

Giglio

Dematteis

Fernández

et al. 2014

Labelled Comp Radiopharmac

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The objective of this work was to develop a novel (99m) Tc complex bearing the 5-nitroimidazol-1-yl moiety with recognised selectivity towards hypoxic tissue, as a potential radiopharmaceutical for imaging tumour hypoxia. The new metronidazole derivative (2-amine-3-[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethylthio]propanoic acid) (L) containing adequate groups to coordinate technetium through the formation of a Tc(I)-tricarbonyl complex was synthesised with adequate yield (33%) and characterised by spectroscopy. Labelling was performed by substitution of three labile water molecules of the technetium tricarbonyl precursor, fac-[(99m)Tc(CO)3 (H2O)3](+) with the ligand. A radiochemical purity higher than 90% was achieved and remained unchanged for more than 4 h. The complex has a high stability in plasma, a moderate plasma protein binding and a moderate hydrophilicity. In vitro cell uptake studies showed a ratio between the activity taken up by cells in hypoxia/normoxia of 1.6 ± 0.4 (p < 0.5). Biodistribution in normal mice showed rapid depuration and low uptake in all organs and tissues except liver. Biodistribution in mice bearing induced tumours showed a low tumour uptake, but tumour/muscle ratio was favourable thanks to depuration. Comparison with biological results of other metronidazole derivatives clearly shows that modifications of the chelator are very important and contribute to improve the biological behaviour.

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Synthesis and biological characterisation of novel dithiocarbamate containing 5-nitroimidazole 99mTc-complexes as potential agents for targeting hypoxia

Cited by 34 publications

References 19 publications

Metal-dithiocarbamate complexes: chemistry and biological activity

Metal-dithiocarbamate complexes: chemistry and biological activity

Synthesis and biodistribution of novel ^99mTc labeled 4-nitroimidazole dithiocarbamate complexes as potential agents to target tumor hypoxia

Synthesis and evaluation of a new ^99mTc(I)‐tricarbonyl complex bearing the 5‐nitroimidazol‐1‐yl moiety as potential hypoxia imaging agent

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Synthesis and biological characterisation of novel dithiocarbamate containing 5-nitroimidazole 99mTc-complexes as potential agents for targeting hypoxia

Cited by 34 publications

References 19 publications

Metal-dithiocarbamate complexes: chemistry and biological activity

Metal-dithiocarbamate complexes: chemistry and biological activity

Synthesis and biodistribution of novel 99mTc labeled 4-nitroimidazole dithiocarbamate complexes as potential agents to target tumor hypoxia

Synthesis and evaluation of a new 99mTc(I)‐tricarbonyl complex bearing the 5‐nitroimidazol‐1‐yl moiety as potential hypoxia imaging agent

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Synthesis and biodistribution of novel ^99mTc labeled 4-nitroimidazole dithiocarbamate complexes as potential agents to target tumor hypoxia

Synthesis and evaluation of a new ^99mTc(I)‐tricarbonyl complex bearing the 5‐nitroimidazol‐1‐yl moiety as potential hypoxia imaging agent