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

Abstract

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.

99mTc Labelling Strategies for the Development of Potential Nitroimidazolic Hypoxia Imaging Agents

“…Although 2-nitroimidazoles have been preferred as redox centres in Tc complexes targeting hypoxia, 5-nitroimidazoles derived from metronidazole have also demonstrated high affinity for hypoxic tumours "in vitro" and "in vivo" and have been labelled by the formation of [ 99m Tc]Tc-(CO) 3 complexes. Giglio et al [41] have prepared a cysteine-derivative that bears an NSO type-chelator unit in which the donor atom system consists of an N-primary amine, an S-thioether and an O-carboxylate. The Tc complex was neutral but the log P o/w was −0.75 since the incorporation of a cysteine moiety reduced the lipophilicity.…”

“…Structure of imidazole derivatives used in the preparation of [ 99m Tc]Tc-tricarbonyl complexes[37][38][39][40][41][42].…”

Neutral 99mTc(CO)3 complexes of “clicked” nitroimidazoles for the detection of tumor hypoxia

“…IR (KBr, cm The rhenium analogue of 4-nitroimidazole-triazole-[ 99m Tc(CO) 3 ] was prepared by refluxing a mixture of 4-nitroimidazole-triazole (0.17 g, 0.55 mmol) and bis(tetraethylammonium)-fac-tribromotricarbonylrhenate (0.42 g, 0.55 mmol) in 5 mL water for 15 h [27]. The compound bis(tetraethylammonium)-fac-tribromotricarbonylrhenate was prepared following a procedure reported by Alberto et al [28]. After refluxing, reaction mixture was allowed to cool down and then filtered.…”

“…Nitroimidazoles which show selective accumulation in hypoxic cells are the most widely explored molecules for delineating hypoxic tumor cells from normoxic cells [10]. Several nitroimidazole radiopharmaceuticals based on PET as well as SPECT isotopes are reported [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]. Presently, [ 18 F]fluoromisonidazole ([ 18 F]FMISO), a 2-nitroimidazole-radiotracer, is the radiopharmaceutical of choice for clinical imaging of tumor hypoxia [29].…”

Synthesis and Biological Evaluation of a New Nitroimidazole-99mTc-Complex for Imaging of Hypoxia in Mice Model

“…Nevertheless, these hypoxia markers contained several limitations such as selectivity deficiency and excessive background signal of blood [ 5 ]. As a result of this, alternative compounds that are able to identify tumor hypoxia and overcome these limitations may provide additional assistance [ 7 ]. The 5-nitroimidazole metronidazole with high affinity for hypoxic tumors in vitro and in vivo is one of the potential hypoxia makers, and it is considered to be the original material for preparing 99m Tc radiopharmaceuticals [ 8 ].…”