Design of Ga–DOTA-based bifunctional radiopharmaceuticals: Two functional moieties can be conjugated to radiogallium–DOTA without reducing the complex stability

Mukai, Takahiro; Suwada, Jun; Sano, Kohei; Okada, Mayumi; Yamamoto, Fujio; Maëda, Minoru

doi:10.1016/j.bmc.2009.05.041

Cited by 33 publications

(20 citation statements)

References 25 publications

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“…DOTA-MN2 was prepared as reported previously. 8) in brief, to a solution of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, 1,7-bis(tert-butyl) ester was added triethylamine, 1-(2-aminoethyl)-2-methyl-5-nitroimidazole dihydrochloride, HOBt, and 1-ethyl-3-[3-(dimethylamino) propyl] carbodiimide hydrochloride in an ice bath. After stirring for 48 h at room temperature, chloroform was added.…”

Section: Synthesis Of Dota-mn1 and Dota-mn2mentioning

confidence: 99%

“…1a), for hypoxia imaging, based on the concept of bifunctional radiopharmaceuticals. 8) Bifunctional radiopharmaceuticals have the recognition site of the molecular target and the chelation site for the radiometal independently in one molecule. [9][10][11][12] Ga-DOTA-MN2 containing two metronidazole moieties was designed in support of the previous crystallographic findings that the four nitrogens of the cyclen ring and two oxygens of the opposite carboxyl groups are coordinated to the gallium metal.…”

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confidence: 99%

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In Vivo Evaluation of a Radiogallium-Labeled Bifunctional Radiopharmaceutical, Ga-DOTA-MN2, for Hypoxic Tumor Imaging

Sano

Okada

Hisada

et al. 2013

Biological & Pharmaceutical Bulletin

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On the basis of the findings obtained by X-ray crystallography of Ga-DOTA chelates and the drug design concept of bifunctional radiopharmaceuticals, we previously designed and synthesized a radiogalliumlabeled DOTA chelate containing two metronidazole moieties, 67Ga-DOTA-MN2, for hypoxic tumor imaging. As expected, 67Ga-DOTA-MN2 exhibited high in vivo stability, although two carboxyl groups in the DOTA skeleton were conjugated with metronidazole moieties. In this study, we evaluated 67/68 Ga-DOTA-MN2 as a nuclear imaging agent for hypoxic tumors. Key words radiogallium; bifunctional radiopharmaceutical; hypoxic tumor imaging; positron emission tomography Tumor hypoxia results from an imbalance between oxygen supply and consumption, which is caused by abnormal structure and function of microvessels supplying the tumor, increased diffusion distances between the nutritive blood vessels and the tumor cells, and reduced O 2 transport capacity of the blood.1,2) Tumor hypoxia has been associated with an aggressive tumor phenotype, poor response to radiotherapy and chemotherapy, and increased risk of invasion and metastasis of tumors.3,4) Thus, non-invasive measurement of tumor hypoxia with positron emission tomography (PET) would have a distinct effect on characterizing tumor malignancy and determining a course of therapy.Metronidazole, nitroimidazole antibiotic medication used for anaerobic bacteria and protozoa in particular, has a tendency to accumulate in the hypoxic regions and enhance the lethal effect of ionizing radiation for hypoxic tissues.5) The reduction of the nitroimidazole (RNO 2 ) within cells proceeds in successive steps involving enzyme-mediated electron transfer via the free radical anion (RNO

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Section: Synthesis Of Dota-mn1 and Dota-mn2mentioning

confidence: 99%

mentioning

confidence: 99%

In Vivo Evaluation of a Radiogallium-Labeled Bifunctional Radiopharmaceutical, Ga-DOTA-MN2, for Hypoxic Tumor Imaging

Sano

Okada

Hisada

et al. 2013

Biological & Pharmaceutical Bulletin

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“…In NFSa tumour-bearing C3H/He mice, 83 displayed significant tumour uptake, fast blood clearance and high target to non-target ratios; its T/B and T/M ratios peaked at 6 h post-injection with values of 4.5 and 4.4, respectively. Overall, the results suggested that two metronidazole moieties conjugated with the radiogallium-DOTA centre did not reduce in vitro and in vivo stabilities and offered significant improvements in recognition of hypoxic sites by the biomarker [95].…”

Section: The Ligand Of Choice For 67mentioning

confidence: 85%

“…Based on promising preliminary animal studies with 83 [95], improved radiochemical yield (85%) and radiochemical purity (99%) were achieved using microwave-assisted reaction [96]. The effectiveness of the two metronidazole moieties in 83 was compared to the complex bearing only one metronidazole (84).…”

Section: The Ligand Of Choice For 67mentioning

confidence: 99%

“…On the basis that Ga 3+ -DOTA complexes form hexacoordinated structures, two metronidazole moieties were conjugated to the DOTA bifunctional chelator (Figure 32) [95]. 68 Ga-DOTA-MN2 (82) was prepared by heating a solution of the ligand with a non-radioactive gallium precursor, Ga(NO)3.xH2O in ammonium acetate buffer (pH=4.6).…”

Section: The Ligand Of Choice For 67mentioning

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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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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Design of Ga–DOTA-based bifunctional radiopharmaceuticals: Two functional moieties can be conjugated to radiogallium–DOTA without reducing the complex stability

Cited by 33 publications

References 25 publications

In Vivo Evaluation of a Radiogallium-Labeled Bifunctional Radiopharmaceutical, Ga-DOTA-MN2, for Hypoxic Tumor Imaging

In Vivo Evaluation of a Radiogallium-Labeled Bifunctional Radiopharmaceutical, Ga-DOTA-MN2, for Hypoxic Tumor Imaging

Bifunctional Metal – Nitroimidazole Complexes for Hypoxia Theranosis in Cancer

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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Design of Ga–DOTA-based bifunctional radiopharmaceuticals: Two functional moieties can be conjugated to radiogallium–DOTA without reducing the complex stability

Cited by 33 publications

References 25 publications

In Vivo Evaluation of a Radiogallium-Labeled Bifunctional Radiopharmaceutical, Ga-DOTA-MN2, for Hypoxic Tumor Imaging

In Vivo Evaluation of a Radiogallium-Labeled Bifunctional Radiopharmaceutical, Ga-DOTA-MN2, for Hypoxic Tumor Imaging

Bifunctional Metal – Nitroimidazole Complexes for Hypoxia Theranosis in Cancer

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