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

Abstract

BackgroundThis study was specifically designed to develop a new 99mTc compound with 3-amino-4-[2-(2-methyl-5-nitro-1H-imidazol)-ethylamino]-4-oxo-butyrate (5-ntm-asp) and to verify whether this compound is feasible to be a radiopharmaceutical for hypoxic tumors.Material/MethodsMetronidazole derivative 5-ntm-asp was synthesized and then radio-labeled by Na [99mTcO4], forming 99mTc-5-ntm-asp. Another two complexes of 99mTc-2- and 99mTc-5-nitroimidazole-iminodiacetic acid (99mTc-2-ntm-IDA and 99mTc-5-ntm-IDA) were also synthesized based on previous studies. Physicochemical properties (stability, lipophilicity, protein binding) of the compounds were compared, and we also assessed the accumulation status of the compounds within A549 cells under both hypoxic and aerobic conditions. Distribution of the complex was also studied in vivo using BALB/c nude mice that were injected with A549 cells.ResultsCompared with 99mTc-2-ntm-IDA and 99mTc-5-ntm-IDA, 99mTc-5-ntm-asp was more stable in both phosphate-buffered saline (PBS) buffer and human plasma (P<0.05). Besides that, 99mTc-5-ntm-asp offered lower lipophilicity and protein-binding rate than the two complexes (P<0.05). During assessment of hypoxic uptake status and high hypoxic/aerobic ratio in mice injected with A549 cells, 99mTc-5-ntm-asp exhibited a more favorable profile than 9mTc-2-ntm-IDA and 99mTc-5-ntm-IDA, including uptake ratio of tumor/blood and uptake ratio of tumor/muscle.ConclusionsWith overall consideration of physicochemical properties and biological uptake behavior, it is feasible to use 99mTc-5-ntm-asp as an imaging agent for tumor hypoxia.

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

“…Zhang et al [35] also used 5-nitroimidazol as a redox centre but conjugated the pharmacophore with asparagine through the nitrogen of the amide group. The resulting ligand has two nitrogen and one oxygen atoms as potential electron donors for coordination to 99m Tc.…”

“…Structure of various nitroimidazole derivatives proposed for the preparation of potential [ 99m Tc(V)O] 3+ hypoxia targeting agents[24,[27][28][29][30][31][33][34][35].…”

Metronidazole-functionalized iron oxide nanoparticles for molecular detection of hypoxic tissues

“…[22][23][24] The enzyme xanthine oxidases play a catalytic role in these reactions and may further reduce cellular components. 25 Based on their role as hypoxiaselective cytotoxins for cancer treatment, nitroheterocyclic compounds have started to be loaded onto colloidal carrier systems like solid lipid nanoparticles to enhance tumor drug uptake, 20 and are always more frequently involved in the preparation of various hypoxia-activated and redox-responsive drug delivery nanocarriers. [54][55][56] In this study, we postulated that in a reducing environment the exposure of metronidazole on the surface could facilitate the interaction and aggregation of NPs with intracellular components, leading to longer retention times.…”

“…[22][23][24] This property can be exploited to either selectively image hypoxic cells or to kill target cells (for instance for antimicrobial purposes). 25,26 Metronidazole has become a common starting material for the preparation of radiopharmaceuticals that efficiently recognize hypoxic tumors in vitro and in vivo, thanks to the ease of conjugation that preserves the specific sites of recognition and the biological activity of the ligand. 20 However, the use of non-radioactive IONPs as contrast agents would be preferable to avoid the limitations associated with radioactive tracers and to provide a nanosized platform for further treatment-oriented development (e.g., as drug carriers, or hyperthermic agents).…”

Recent Developments in PET and SPECT Radiotracers as Radiopharmaceuticals for Hypoxia Tumors

“…In 2016, Li and co-workers reported 99m Tc-labeled 5-ntm-asp (3-amino-4-[2- (2-methyl-5-nitro-1H-imidazol)-ethylamino]-4-oxo-butyrate) ([ 99m Tc] 41 ) ( Figure 20 ) [ 147 ]. Two previously reported 99m Tc-labeled complexes containing 2-ntm-IDA and 5-ntm-IDA ligands (2- and 5-nitroimidazole-iminodiacetic acid) ([ 99m Tc] 42 , [ 99m Tc] 43 ) were also synthesized.…”