Synthesis, in vitro and in vivo characterization of novel 99mTc-‘4+1’-labeled 5-nitroimidazole derivatives as potential agents for imaging hypoxia

Giglio, Javier; Fernández, Soledad; Pietzsch, Hans‐Jürgen; Dematteis, Sylvia; Moreno, Marı́a; Pacheco, José Emilio; Cerecetto, Hugo; Rey, Ana

doi:10.1016/j.nucmedbio.2011.12.012

Cited by 37 publications

(20 citation statements)

References 23 publications

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“…Finally, cells were separated from supernatant and activity measured in order to compare the percentage taken up in normoxic and hypoxic conditions. This study has been previously validated by our group and used successfully in the evaluation of other [ 99m Tc]‐complexes . Results for [ 99m Tc(CO) 3 ( L )] showed that the ratio between hypoxic and normoxic uptake was 1.6 ± 0.4.…”

Section: Resultsmentioning

confidence: 81%

“…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, we have designed and synthesised the novel metronidazole derivative 2‐amine‐3‐[2‐(2‐methyl‐5‐nitro‐1 H ‐imidazol‐1‐yl)ethylthio]propanoic acid ( L ) (Figure ). 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%

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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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Section: Resultsmentioning

confidence: 81%

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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“…Another characteristic of the ReO-MAMA complexes was the downfield shift of carbon atoms in the 13 C NMR spectrum. HPLC analysis for each Re analogue showed one major peak with a retention time similar to that of the corresponding Tc-NS3-M2) [46].…”

Section: Rhenium Nitroimidazole Compoundsmentioning

confidence: 86%

“…Elemental microanalyses (C, H, N) of the peaks isolated from HPLC were consistent with the proposed structures. Furthermore, mass spectra indicated the presence of m/z fragments corresponding to the expected molecular ions with isotopic distribution of the two rhenium isotopes [46].…”

Section: Rhenium Nitroimidazole Compoundsmentioning

confidence: 99%

“…Tc-based mixed ligand radiopharmaceuticals (59, 60; Figure 21) have a coordination sphere that consists of the metal centre, a tetradentate 2',2"-nitrilotris(ethanethiol) and a monodentate isocyanidemetronidazole derivative, forming a trigonal bipyramidal geometry [46]. The isocyanide-metronidazole derivatives such as 4-isocyano-N-[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl]butanamide (M1) and 1-(4-isocyanobutanoyl)-4-[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl]piperazine (M2) (Figure 21) were obtained by the reaction between the corresponding amino-functionalized metronidazole and the succinamide derivative of 4-isocyanobutanoic acid.…”

Section: The 99mmentioning

confidence: 99%

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Bifunctional Metal – Nitroimidazole Complexes for Hypoxia Theranosis in Cancer

Ricardo¹,

Kumar²,

Wiebe³

2015

J Diagn Imaging Ther

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Oxygen supply -demand imbalances can render proliferating cells acutely or chronically hypoxic. In cancer cells, hypoxia-induced pathophysiological changes give rise to genetic changes that lead to treatment-resistant, aggressive phenotypes. The reduced curability of hypoxic tumours by radiotherapy is one of consequent challenges, but their hypoxia also offers unique, exploitable properties. Nitroimidazoles, for example, capitalize on oxygen-sensitive reductive activation to achieve hypoxiaselective localization for theranostic consequence. The discovery of 2-nitroimidazole (azomycin) heralded the development of many drugs, including effective radiosensitizers of hypoxic cells. These electron-affinic, reductively bioactivated nitroheterocyclics undergo initial oxygen-reversible, enzymatic one-electron reductions that lead to the formation of molecular adducts that impair vital

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A thiourea‐bridged ^99mTc(CO)₃‐dipicolylamine‐2‐nitroimidazole complex for targeting tumor hypoxia: Utilizing metabolizable thiourea‐bridge to improve pharmacokinetics

Mittal,

Kumar,

Jha

et al. 2024

Drug Development Research

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The 2‐nitroimidazole based 99mTc‐radiopharmaceuticals are widely explored for imaging tumor hypoxia. Radiopharmaceuticals for targeting hypoxia are often lipophilic and therefore, show significant uptake in liver and other vital organs. In this context, lipophilic radiopharmaceuticals with design features enabling faster clearance from liver may be more desirable. A dipicolylamine‐NCS bifunctional chelator that could generate a thiourea‐bridge up on conjugation to primary amine bearing molecule was used to synthesize a 2‐nitroimidazole‐dipicolyl amine ligand for radiolabeling with 99mTc(CO)3 core. Corresponding Re(CO)3‐analogue was prepared to establish the structure of 2‐nitroimidazole‐99mTc(CO)3 complex prepared in trace level. The 2‐nitroimidazole‐99mTc(CO)3 complex showed a hypoxic to normoxic ratio of ~2.5 in CHO cells at 3 h. In vivo, the complex showed accumulation and retention in tumor with high tumor to blood and tumor to muscle ratio. The study demonstrated the utility of metabolizable thiourea‐bridge in 2‐nitroimidazole‐99mTc(CO)3 complex in inducing faster clearance of the radiotracer from liver. The dipicolylamine‐NCS bifunctional chelator reported herein can also be used for radiolabeling other class of target specific molecules with 99mTc(CO)3 core.

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Synthesis, in vitro and in vivo characterization of novel 99mTc-‘4+1’-labeled 5-nitroimidazole derivatives as potential agents for imaging hypoxia

Cited by 37 publications

References 23 publications

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

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

Bifunctional Metal – Nitroimidazole Complexes for Hypoxia Theranosis in Cancer

A thiourea‐bridged ^99mTc(CO)₃‐dipicolylamine‐2‐nitroimidazole complex for targeting tumor hypoxia: Utilizing metabolizable thiourea‐bridge to improve pharmacokinetics

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Synthesis, in vitro and in vivo characterization of novel 99mTc-‘4+1’-labeled 5-nitroimidazole derivatives as potential agents for imaging hypoxia

Cited by 37 publications

References 23 publications

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

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

Bifunctional Metal – Nitroimidazole Complexes for Hypoxia Theranosis in Cancer

A thiourea‐bridged 99mTc(CO)3‐dipicolylamine‐2‐nitroimidazole complex for targeting tumor hypoxia: Utilizing metabolizable thiourea‐bridge to improve pharmacokinetics

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

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

A thiourea‐bridged ^99mTc(CO)₃‐dipicolylamine‐2‐nitroimidazole complex for targeting tumor hypoxia: Utilizing metabolizable thiourea‐bridge to improve pharmacokinetics