Abstract
Purpose. The assessment of tumor hypoxia by imaging modality prior to radiation therapy would provide a rational means of selecting patients for treatment with radiosensitizers or bioreductive drugs. This study aimed to develop a 99mTc-labeled metronidazole (MN) using ethylene-dicysteine (EC) as a chelator and evaluate its potential use to image tumor hypoxia.
Methods. EC was conjugated to amino analogue of MN using Sulfo-N-hydroxysuccinimide and l-ethyl-3-(3-dimethylaminopropyl) carbodiimide-HCl as coupling agents, the yield was 55%. Tissue distribution of 99mTc-EC-MN was determined in breast tumor-bearing rats at 0.5, 2, and 4 hrs. Planar imaging and whole-body autoradiograms were performed. The data was compared to that using 99mTc-EC (control), [l8F]fluoromisonidazole (FMISO) and [131I] iodomisonidazole (IMISO).
Results. In vivo biodistribution of 99mTc-EC-MN in breast tumor-bearing rats showed increased tumor-to-blood and tumor-to-muscle ratios as a function of time. Conversely, tumor-to-blood values showed time-dependent decrease with 99mTc-EC in the same time period. Planar images and autoradiograms confirmed that the tumors could be visualized clearly with 99mTc-EC-MN from 0.5 to 4 hrs. There was no significant difference of tumor-to-blood count ratios between 99mTc-EC-MN and [131I]IMISO at 2 and 4 hrs postinjection. From 0.5 to 4 hrs, both 99mTc-EC-MN and [131I]IMISO have higher tumor-to-muscle ratios compared to [18]FMISO.
Conclusions. It is feasible to use 99mTc-EC-MN to image tumor hypoxia.
Similar content being viewed by others
REFERENCES
E. J. Hall. The oxygen effect and reoxygenation. In E. J. Hall (ed.) Radiobiology for the radiobiologist, 3rd edition. J. B. Lippincott Co., Philadelphia, PA, 1988, pp. 137-160.
R. S. Bush, R. D. T. Jenkins, W. E. C. Allt, F. A. Beale, H. Bena, A. J. Dembo, and J. F. Pringle. Definitive evidence for hypoxic cells influencing cure in cancer therapy. Br. J. Cancer 37(Suppl. III):302-306 (1978).
L. H. Gray, A. D. Conger, M. Elbert, S. Morsney, and O.C.A. Scold. The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br. J. Radiol. 26:638-648 (1953).
S. Dische. A review of hypoxic-cell radiosensitization. Int. J. Radiat. Oncol. Biol. Phys. 20:147-152 (1991).
R. A. Gatenby, H. B. Kessler, J. S. Rosenblum, L. R. Coia, P. J. Moldofsky, W. H. Hartz, and G. J. Broder. Oxygen distribution in squamous cell carcinoma metastases and its relationship to outcome of radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 14:831-838 (1988).
M. Nordsmark, M. Overgaard, and J. Overgaard. Pretreatment oxygenation predicts radiation response in advanced squamous cell carcinoma of the head and neck. Radiother. Oncol. 41:31-39 (1996).
W-J Koh, J. S. Rasey, M. L. Evans, J. R. Grierson, T. K. Lewellen, M. M. Graham, K. A. Krohn, and T. W. Griffin. Imaging of hypoxia in human tumors with 18F fluoromisonidazole. Int. J. Radiat. Oncol. Biol. Phys. 22:199-212 (1992).
P. E. T. Valk, C. A. Mathis, M. D. Prados, J. C. Gilbert, and T. F. Budinger. Hypoxia in human gliomas: Demonstration by PET with [18F]fluoromisonidazole. J. Nucl. Med. 33:2133-2137 (1992).
G. V. Martin, J. H. Caldwell, J. S. Rasey, Z. Grunbaum, M. Cerqueia, and K. A. Krohn. Enhanced binding of the hypoxic cell marker [18F]fluoromisonidazole in ischemic myocardium. J. Nucl. Med. 30:194-201 (1989).
J. S. Rasey, W. J. Koh, J. R. Grieson, Z. Grunbaum, and K. A. Krohn. Radiolabeled fluoromisonidazole as an imaging agent for tumor hypoxia. Int J. Radiat. Oncol. Biol. Phys. 17:985-991 (1989).
J. S. Rasey, N. J. Nelson, L. Chin, M. L. Evans, and Z. Grunbaum. Characterization of the binding of labeled fluoromisonidazole in cells in vitro. Radiat. Res. 122:301-308 (1990).
D. J. Yang, S. Wallace, A. Cherif, C. Li, M. B. Gretzer, E. E. Kim, and D. A. Podoloff. Development of F-18-labeled fluoroerythronitroimidazole as a PET agent for imaging tumor hypoxia. Radiology 194:795-800 (1995).
A. Cherif, S. Wallace, D. J. Yang, R. Newman, V. Wilson, A. Nornoo, T. Inoue, C. Kim, L-R Kuang, E. E. Kim, and D. A. Podoloff. Development of new markers for hypoxic cells: [131I]io-domisonidazole and [131I]iodoerythronitroimidazole. J. Drug Targeting 4:31-39 (1996).
B. A. Teicher and E. A. Sotomayor. Chemical radiation sensitizers and protectors. In W. O. Foye (ed.), Cancer Chemotherapeutic Agents, American Chemical Society, Washington, D. C., 1995, pp. 501-527.
G. Johnson, K. N. Nguyen, Z. Lui, P. Gao, B. Edwards, C. M. Archer, A. C. King, T. L. North, R. D. Okada, and W. K. Warren. HL91 Technetium-99m: Kinetics of a new hypoxia avid imaging agent in normal and ischemic myocardium as assessed by gamma camera images. J. Am. Coll. Cardiol. 407A (1996).
K. Fukuchi, H. Kusuoka, K. Yutani, S. Hasegawa, and T. Nishimura. Assessment of reperfused myocardium using new hypoxia avid imaging agent Tc-99m HL91. J. Nucl. Med. 37:94 (Abstract) (1996).
T. Melo, J. Duncan, J. R. Ballinger, and A. M. Rauth. BMS 194796, a second generation Tc-99m labelled 2-nitroimidazole for imaging hypoxia in tumors. J. Nucl. Med. 39:219 (Abstract) (1998).
X. Zhang, T. Melo, J. R. Ballinger, and A. M. Rauth. Evaluation of Tc-99m butyleneamino oxime (BnAO), a non-nitroaromatic agent for imaging hypoxia in tumors. J. Nucl. Med. 39:216 (Abstract) (1998).
A. Davison, A. G. Jones, C. Orvig, and M. Sohn. A new class of oxotechnetium(+5) chelate complexes containing a TcON2S2 Core. Inorg. Chem. 20:1629-1632 (1981).
A. M. Verbruggen, D. L. Nosco, C. G. Van Nerom, G. M. Bormans, P. J. Adriaens, and M. J. De Roo. Tc-99m-L,L-ethylenedicysteine: A renal imaging agent. I. Labelling and evaluation in animals. J. Nucl. Med. 33:551-557 (1992).
C. G. Van Nerom, G. M. Bormans, M. J. De Roo, and A. M. Verbruggen. First experience in healthy volunteers with Tc-99m-L,L-ethylenedicysteine, a new renal imaging agent. Eur. J. Nucl. Med. 20:738-746 (1993).
M. J. Surma, J. Wiewiora, and J. Liniecki. Usefulness of Tc-99m-N,N′-ethylene-1-dicysteine complex for dynamic kidney investigations. Nucl. Med. Comm. 15:628-635 (1994).
S. Ratner and H. T. Clarke. The action of formaldehyde upon cysteine. J. Am. Chem. Soc. 59:200-206 (1937).
P. Blondeau, C. Berse, and D. Gravel. Dimerization of an intermediate during the sodium in liquid ammonia reduction of L-thiazolidine-4-carboxylic acid. Can. J. Chem. 45:49-52 (1967).
M. P. Hay, W. R. Wilson, J. W. Moselen, B. D. Palmer, and W. A. Denny. Hypoxia-selective antitumor agents. Bis(nitroimidazolyl)alkanecarboxamides: a new class of hypoxia-selective cytotoxins and hypoxic cell radiosensitizers. J. Med. Chem. 37:381-391 (1994).
A. Cherif, D. J. Yang, W. Tansey, E. E. Kim, and S. Wallace. Synthesis of [18F]fluoromisonidazole. Pharm. Res. 11:466-469 (1994).
G. V. Martin, J. H. Cardwell, M. M. Graham, J. R. Grierson, K. Kroll, M. J. Xowna, T. K. Lewellen, J. S. Rasey, J. J. Casciari, and K. A. Krohn. Noninvasive detection of hypoxic myocardium using [18F]fluoromisonidazole and PET. J. Nucl. Med. 33:2202-2208 (1992).
S. H. Yeh, R. S. Liu, H. H. Hu, C. P. Chang, L. S. Chu, K. L. Chou, and L. C. Wu. Ischemic penumbra in acute stroke: demonstration by PET with fluorine-18 fluoromisonidazole. J. Nucl. Med. 35:(5)205 (Abstract) (1994).
S. H. Yeh, R. S. Liu, L. C. Wu, D. J. Yang, S. H. Yen, C. W. Chang, T. W. Yu, K. L. Chou, and K. Y. Chen. Fluorine-18 fluoromisonidazole tumor to muscle retention ratio for the detection of hypoxia in nasopharyngeal carcinoma. Eur. J. Nucl. Med. 23:1378-1383 (1996).
R. S. Liu, S. H. Yeh, C. P. Chang, L. S. Chu, M. T. Lui, K. L. Chou, and L. C. Wu. Detection of odontogenic infections by [18F]fluoromisonidazole. J. Nucl. Med. 35:113 (Abstract) (1994).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Yang, D.J., Ilgan, S., Higuchi, T. et al. Noninvasive Assessment of Tumor Hypoxia with 99mTc Labeled Metronidazole. Pharm Res 16, 743–750 (1999). https://doi.org/10.1023/A:1018836911013
Issue Date:
DOI: https://doi.org/10.1023/A:1018836911013