Synthesis, in vitro and in vivo characterization of two novel 68Ga-labelled 5-nitroimidazole derivatives as potential agents for imaging hypoxia

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

doi:10.1016/j.nucmedbio.2012.11.003

Cited by 21 publications

(23 citation statements)

References 24 publications

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“…HBED-CC has been successfully applied in the theranostics of prostate cancer when conjugated to the prostate-specific membrane antigen (PSMA) (Virgolini et al, 2017 ) but the combination with oxygen sensitive groups is yet to been investigated. Gallium-68 labeled nitroimidazole complexes were studied in mice models with induced (xenografted) tumors for CT26 (colon cancer) (Seelam et al, 2015 ), A549 (Wu et al, 2015 ) or 3LL (Fernández et al, 2013 ) (lung cancer cell lines). The comparison with [ 18 F]F-FMISO revealed successful hypoxia imaging and improved clearance properties.…”

Section: Preclinical and Clinical Imaging Of Hypoxiamentioning

confidence: 99%

Oxygen Sensing, Hypoxia Tracing and in Vivo Imaging with Functional Metalloprobes for the Early Detection of Non-communicable Diseases

2018

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Hypoxia has been identified as one of the hallmarks of tumor environments and a prognosis factor in many cancers. The development of ideal chemical probes for imaging and sensing of hypoxia remains elusive. Crucial characteristics would include a measurable response to subtle variations of pO2 in living systems and an ability to accumulate only in the areas of interest (e.g., targeting hypoxia tissues) whilst exhibiting kinetic stabilities in vitro and in vivo. A sensitive probe would comprise platforms for applications in imaging and therapy for non-communicable diseases (NCDs) relying on sensitive detection of pO2. Just a handful of probes for the in vivo imaging of hypoxia [mainly using positron emission tomography (PET)] have reached the clinical research stage. Many chemical compounds, whilst presenting promising in vitro results as oxygen-sensing probes, are facing considerable disadvantages regarding their general application in vivo. The mechanisms of action of many hypoxia tracers have not been entirely rationalized, especially in the case of metallo-probes. An insight into the hypoxia selectivity mechanisms can allow an optimization of current imaging probes candidates and this will be explored hereby. The mechanistic understanding of the modes of action of coordination compounds under oxygen concentration gradients in living cells allows an expansion of the scope of compounds toward in vivo applications which, in turn, would help translate these into clinical applications. We summarize hereby some of the recent research efforts made toward the discovery of new oxygen sensing molecules having a metal-ligand core. We discuss their applications in vitro and/or in vivo, with an appreciation of a plethora of molecular imaging techniques (mainly reliant on nuclear medicine techniques) currently applied in the detection and tracing of hypoxia in the preclinical and clinical setups. The design of imaging/sensing probe for early-stage diagnosis would longer term avoid invasive procedures providing platforms for therapy monitoring in a variety of NCDs and, particularly, in cancers.

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Section: Preclinical and Clinical Imaging Of Hypoxiamentioning

confidence: 99%

Oxygen Sensing, Hypoxia Tracing and in Vivo Imaging with Functional Metalloprobes for the Early Detection of Non-communicable Diseases

2018

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“…49 The results obtained were comparable with reference images obtained with [ 18 F]FMISO and [ 18 F]FAZA, but the usage of methylated 5-nitroimidazole improved performance of 68 Ga-DOTA-nitroimidazoles in hypoxia imaging. 50…”

Section: General Oncology Imagingmentioning

confidence: 99%

68Ga-DOTA and analogs: Current status and future perspectives

Kilian

2014

Reports of Practical Oncology & Radiotherapy

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The construction of the Ge/Ga generator has increased application of radiopharmaceuticals labeled with this isotope in medicine. Ga-PET is widely employed in the management of neuroendocrine tumors but favorable chemistry with tri- and tetraaza-ring molecules has opened wide range ofGa application in other fields of PET imaging. This review covers the radiopharmaceuticals labeled with gallium in molecular imaging and shows perspectives on the use of gallium-68 as a substitute for technetium-99, fluorine-18 and carbon-11 in some applications.

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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%

“…This study has been previously validated by our group and used successfully in the evaluation of other [ 99m Tc]-complexes. [17][18][19] Results for [ 99m Tc(CO) 3 (L)] showed that the ratio between hypoxic and normoxic uptake was 1.6 ± 0.4. This result is statistically significant (p ˂ 0.05) and confirms selectivity towards hypoxia conditions.…”

Section: Biological Evaluationmentioning

confidence: 99%

“…[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%

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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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Synthesis, in vitro and in vivo characterization of two novel 68Ga-labelled 5-nitroimidazole derivatives as potential agents for imaging hypoxia

Abstract: Selective uptake and retention in tumour together with favourable tumour/muscle ratio make these compounds promising candidates for further evaluation as potential hypoxia imaging agents.

Cited by 21 publications

References 24 publications

Oxygen Sensing, Hypoxia Tracing and in Vivo Imaging with Functional Metalloprobes for the Early Detection of Non-communicable Diseases

Oxygen Sensing, Hypoxia Tracing and in Vivo Imaging with Functional Metalloprobes for the Early Detection of Non-communicable Diseases

68Ga-DOTA and analogs: Current status and future perspectives

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, in vitro and in vivo characterization of two novel 68Ga-labelled 5-nitroimidazole derivatives as potential agents for imaging hypoxia

Abstract: Selective uptake and retention in tumour together with favourable tumour/muscle ratio make these compounds promising candidates for further evaluation as potential hypoxia imaging agents.

Cited by 21 publications

References 24 publications

Oxygen Sensing, Hypoxia Tracing and in Vivo Imaging with Functional Metalloprobes for the Early Detection of Non-communicable Diseases

Oxygen Sensing, Hypoxia Tracing and in Vivo Imaging with Functional Metalloprobes for the Early Detection of Non-communicable Diseases

68Ga-DOTA and analogs: Current status and future perspectives

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