Skip to main content
ADVANCED SEARCH
Log in
Top
Nuclear Medicine and Molecular Imaging
Published in:

25-04-2024 | Nitroimidazoles | Review

Recent Progress in Synthesis of 99mTc-labeled Complexes with Nitroimidazoles as SPECT Probes for Targeting Tumor Hypoxia

Authors: Anh Thu Nguyen, Hee-Kwon Kim

Published in: Nuclear Medicine and Molecular Imaging | Issue 5/2024

Login to get access

Abstract

The majority of solid tumors have hypoxia, or low oxygen levels, which is one of the hallmarks of cancer. Hypoxia was found to relate to cancer metastases and resistance to therapies, therefore, detection of hypoxia plays an important role in the process of cancer prognosis and treatment. Single-photon emission computed tomography (SPECT) is a non-invasive imaging technique using gamma-emitting radiopharmaceuticals to visualize biological activities within the body. SPECT is also applied for the detection of tumor hypoxia with the development of hypoxia-targeting radiopharmaceuticals. Radiopharmaceuticals containing nitroimidazole moieties have received increasing attention due to their bio-reducible characteristics which make the radiopharmaceuticals accumulate in the hypoxia regions. This review summarizes the recent development of 99mTc-labeled radiopharmaceuticals bearing nitroimidazoles for SPECT imaging of tumor hypoxia including the synthetic methods and results of animal studies.
Literature
1.
Massoud TF, Gambhir SS. Integrating noninvasive molecular imaging into molecular medicine: An evolving paradigm. Trends Mol Med. 2007;13:183–91.PubMedCrossRef
2.
3.
Murakami E, Nakamori M, Nakatani K, Shibata T, Tainaka K. Intracerebral distribution of CAG repeat-binding small molecule visualized by whole-brain imaging. Bioconjug Chem. 2023;34:2187–93.PubMedCrossRef
4.
Kim NH, Huh Y, Kim D. Benzo[g]coumarin-benzothiazole hybrid: A fluorescent probe for the detection of amyloid-beta aggregates. Bull Korean Chem Soc. 2022;43:764–8.CrossRef
5.
Sarker A, Suh M, Choi Y, Park JY, Kwon S, Kim H, et al. [64Cu] Cu-Albumin clearance imaging to evaluate lymphatic efflux of cerebrospinal space fluid in mouse model. Nucl Med Mol Imaging. 2022;56:137–46.PubMedPubMedCentralCrossRef
6.
Liu C, Zheng X, Dai T, Wang H, Chen X, Chen B, et al. Reversibly photoswitching upconversion nanoparticles for super‐sensitive photoacoustic molecular imaging. Angew Chem Int Ed. 2022; e202116802.
7.
Tan TH, Ismail R. Utility of lung perfusion SPECT/CT in detection of pulmonary thromboembolic disease: outcome analysis. Nucl Med Mol Imaging. 2023;57:1–8.PubMedCrossRef
8.
Luu TG, Kim HK. 18F-Radiolabeled translocator protein (TSPO) PET tracers: Recent development of TSPO radioligands and their application to PET study. Pharmaceutics. 2022;14:2545.PubMedPubMedCentralCrossRef
9.
Kim MH, Jung WJ, Jeong HJ, Lee K, Kil HS, Chung WS, et al. Off-target screening of amyloid-beta plaque targeting [18F]florapronol ([18F]FC119S) in postmortem Alzheimer’s disease tissues. Bull Korean Chem Soc. 2022;43:859–67.CrossRef
10.
Tran VH, Park H, Park J, Kwon YD, Kang S, Jung JH, et al. Synthesis and evaluation of novel potent TSPO PET ligands with 2-phenylpyrazolo [1, 5-a] pyrimidin-3-yl acetamide. Bioorg Med Chem. 2019;27:4069–80.CrossRef
11.
Hemrom A, Arora G, Damle NA, Bal C. Comparative role of 18F-DOPA PET/CT and 131I-MIBG scintigraphy in neuroblastoma and application of curie and SIOPEN scoring systems in 18F-DOPA PET/CT. Nucl Med Mol Imaging. 2022;56:236–44.PubMedPubMedCentralCrossRef
12.
Nguyen AT, Kim HK. Recent advances of 68Ga-Labeled PET radiotracers with nitroimidazole in the diagnosis of hypoxia tumors. Int J Mol Sci. 2023;24:10552.PubMedPubMedCentralCrossRef
13.
Kwon YD, Kang S, Park H, Cheong IK, Chang KA, Lee SY. Novel potential pyrazolopyrimidine based translocator protein ligands for the evaluation of neuroinflammation with PET. Eur J Med Chem. 2018;159:292–306.PubMedCrossRef
14.
15.
Kasten BB, Jiang K, Cole D, Jani A, Udayakumar N, Gillespie GY, et al. Targeting MMP-14 for dual PET and fluorescence imaging of glioma in preclinical models. Eur J Nucl Med Mol Imaging. 2020;47:1412–26.PubMedCrossRef
16.
17.
Kwon YD, Lee JY, La MT, Lee SJ, Lee SH, Park JH, et al. Novel multifunctional 18F-labelled PET tracer with prostate-specific membrane antigen-targeting and hypoxia-sensitive moieties. Eur J Med Chem. 2020;189:112099.PubMedCrossRef
18.
Kwon YD, Oh JM, La MT, Chung HJ, Lee SJ, Chun SK, et al. Synthesis and evaluation of multifunctional fluorescent inhibitors with synergistic interaction of prostate-specific membrane antigen and hypoxia for prostate cancer. Bioconjug Chem. 2019;30:90–100.PubMedCrossRef
19.
Zang J, Wen X, Lin R, Zeng X, Wang C, Shi M, et al. Synthesis, preclinical evaluation and radiation dosimetry of a dual targeting PET tracer [68Ga]Ga-FAPI-RGD. Theranostics. 2022;12:7180–90.PubMedPubMedCentralCrossRef
20.
Son H, Jang K, Lee H, Kim SE, Kang KW, Lee H. Use of molecular imaging in clinical drug development: a systematic review. Nucl Med Mol Imaging. 2019;53:208–15.PubMedPubMedCentralCrossRef
21.
22.
Willmann JK, van Bruggen N, Dinkelborg LM, Gambhir SS. Molecular imaging in drug development. Nat Rev Drug Discov. 2008;7:591–607.PubMedCrossRef
23.
Saraste A, Nekolla SG, Schwaiger M. Cardiovascular molecular imaging: An overview. Cardiovasc Res. 2009;83:643–52.PubMedCrossRef
24.
Strafella AP, Bohnen NI, Perlmutter JS, et al. Molecular imaging to track Parkinson’s disease and atypical parkinsonisms: New imaging frontiers. Mov Disord. 2017;32:181–92.PubMedCrossRef
25.
Wu W, Yu F, Zhang P, et al. 68Ga-DOTA-NT-20.3 Neurotensin receptor 1 PET imaging as a surrogate for neuroendocrine differentiation of prostate cancer. J Nucl Med. 2022;63:1394–400.
26.
Wang G, Li L, Zhu M, et al. A prospective head-to-head comparison of [68Ga]Ga-P16-093 and [68Ga]Ga-PSMA-11 PET/CT in patients with primary prostate cancer. Eur J Nucl Med Mol Imaging. 2023;50:3126–36.PubMedCrossRef
27.
Pauwels E, Celen S, Baete K, et al. [18F] MFBG PET imaging: biodistribution, pharmacokinetics, and comparison with [123I] MIBG in neural crest tumour patients. Eur J Nucl Med Mol Imaging. 2023;50:1134–45.PubMedCrossRef
28.
Al Badarin FJ, Malhotra S. Diagnosis and prognosis of coronary artery disease with SPECT and PET. Curr Cardiol Rep. 2019;21:57.PubMedCrossRef
29.
Zhong X, Yan J, Ding X, Su C, Xu Y, Yang M. Recent advances in bioorthogonal click chemistry for enhanced PET and SPECT radiochemistry. Bioconjug Chem. 2023;34:457–76.PubMedCrossRef
30.
Bui TT, Kim HK. Recent advances in photo-mediated radiofluorination. Chem Asian J. 2021;16:2155–67.PubMedCrossRef
31.
Luu TG, Kim HK. Recent progress on radiofluorination using metals: Strategies for generation of C-18F bonds. Org Chem Front. 2023;13:5746–81.CrossRef
32.
Kwon YD, Byun Y, Kim HK. 18F-labelled BODIPY dye as a dual imaging agent: Radiofluorination and applications in PET and optical imaging. Nucl Med Biol. 2021;93:22–36.PubMedCrossRef
33.
Israel O, Pellet O, Biassoni L, et al. Two decades of SPECT/CT - the coming of age of a technology: An updated review of literature evidence. Eur J Nucl Med Mol Imaging. 2019;46:1990–2012.PubMedPubMedCentralCrossRef
34.
35.
Schillaci O, Filippi L, Manni C, Santoni R. Single-photon emission computed tomography/computed tomography in brain tumors. Semin Nucl Med. 2007;37:34–47.PubMedCrossRef
36.
Israel O, Pellet O, Biassoni L, De Palma D, Estrada-Lobato E, Gnanasegaran G, Kuwert T, et al. Two decades of SPECT/CT - the coming of age of a technology: An updated review of literature evidence. Eur J Nucl Med Mol Imaging. 2019;46:1990–2012.PubMedPubMedCentralCrossRef
37.
Papagiannopoulou D. Technetium-99m radiochemistry for pharmaceutical applications. J Labelled Comp Radiopharm. 2017;60:502–20.PubMedCrossRef
38.
EmamiNejad A, Najafgholian S, Rostami A, et al. The role of hypoxia in the tumor microenvironment and development of cancer stem cell: a novel approach to developing treatment. Cancer Cell Int. 2021;21:62.CrossRef
39.
Hayashi Y, Yokota A, Harada H, Huang G. Hypoxia/pseudohypoxia-mediated activation of hypoxia-inducible factor-1α in cancer. Cancer Sci. 2019;110:1510–7.PubMedPubMedCentralCrossRef
40.
Farina AR, Cappabianca L, Sebastiano M. et al. Hypoxia-induced alternative splicing: the 11th Hallmark of Cancer. J Exp Clin Cancer Res. 2020;39:110.
41.
42.
Walsh JC, Lebedev A, Aten E, Madsen K, Marciano L, Kolb HC. The clinical importance of assessing tumor hypoxia: relationship of tumor hypoxia to prognosis and therapeutic opportunities. Antioxid Redox Signal. 2014;21:1516–54.PubMedPubMedCentralCrossRef
43.
Mittal S, Mallia MB. Molecular imaging of tumor hypoxia: Evolution of nitroimidazole radiopharmaceuticals and insights for future development. Bioorg Chem. 2023;139:106687.PubMedCrossRef
44.
Kwon YD, Oh JM, Chun S, Kim HK. Synthesis and evaluation of multivalent nitroimidazole-based near-infrared fluorescent agents for neuroblastoma and colon cancer imaging. Bioorg Chem. 2021;113:104990.PubMedCrossRef
45.
Yang X, Wang F, Zhu H, Yang Z, Chu T. Synthesis and bioevaluation of novel [18F]FDG-conjugated 2-nitroimidazole derivatives for tumor hypoxia imaging. Mol Pharm. 2019;16:2118–28.PubMedCrossRef
46.
Lu J, Zhang C, Yang X, Yao XJ, Zhang Q, Sun XC. Synthesis and preliminary evaluation of a novel 18F-labeled 2-nitroimidazole derivative for hypoxia imaging. Front Oncol. 2021;10:1–9.CrossRef
47.
Giglio J, Dematteis S, Fernández S, Cerecetto H, Rey A. Synthesis and evaluation of a new 99mTc(I)-tricarbonyl complex bearing the 5-nitroimidazol-1-yl moiety as potential hypoxia imaging agent. J Labelled Comp Radiopharm. 2014;57:403–9.PubMedCrossRef
48.
Wang J, Zheng X, Wu W, Yang W, Liu Y. Synthesis and preliminary biological evaluation of 99mTc(CO)3-labeled pegylated 2-nitroimidazoles. J Radioanal Nucl Chem. 2014;300:1013–20.CrossRef
49.
Alberto R, Schibli R, Egli A, Schubiger AP. A novel organometallic aqua complex of technetium for the labeling of biomolecules: Synthesis of [99mTc(OH2)3(CO)3]+ from [99mTcO4]- in aqueous solution and its reaction with a bifunctional ligand. J Am Chem Soc. 1998;120:7987–8.CrossRef
50.
Alberto R, Schibli R, Waibel R, Abram U, Schubiger AP. Basic aqueous chemistry of [M(OH2)3(CO)3]+ (M=Re, Tc) directed towards radiopharmaceutical application. Coord Chem Rev. 1999;190–192:901–19.CrossRef
51.
Mallia MB, Subramanian S, Mathur A, Sarma HD, Banerjee S. A study on nitroimidazole-99mTc(CO)3 complexes as hypoxia marker: some observations towards possible improvement in in vivo efficacy. Nucl Med Biol. 2014;41:600–10.PubMedCrossRef
52.
Mallia MB, Subramanian S, Mathur A, Sarma HD, Venkatesh M, Banerjee S. Synthesis and evaluation of 2-, 4- and 5-substituted nitroimidazole-iminodiacetic acid-99mTc(CO)3 complexes to target hypoxic tumors. J Label Compd Radiopharm. 2010;53:535–42.CrossRef
53.
Sun W, Chu T. In vivo click reaction between Tc-99m-labeled azadibenzocyclooctyne-MAMA and 2-nitroimidazole-azide for tumor hypoxia targeting. Bioorg Med Chem Lett. 2015;25:4453–6.PubMedCrossRef
54.
Mallia MB, Mittal S, Sarma HD, Banerjee S. Modulation of in vivo distribution through chelator: Synthesis and evaluation of a 2-nitroimidazole-dipicolylamine-99mTc(CO)3 complex for detecting tumor hypoxia. Bioorg Med Chem Lett. 2016;26:46–50.PubMedCrossRef
55.
Bhadwal M, Mallia MB, Sarma HD, Banerjee S. Neutral 99mTc(CO)3 complexes of “clicked” nitroimidazoles for the detection of tumor hypoxia. J Radioanal Nucl Chem. 2016;307:69–77.CrossRef
56.
Zhang Q, Zhang Q, Guan Y, Liu S, Chen Q, Li X. Synthesis and biological evaluation of a new nitroimidazole-99mTc-complex for imaging of hypoxia in mice model. Med Sci Monit. 2016;22:3778–91.PubMedPubMedCentralCrossRef
57.
Vats K, Mallia MB, Mathur A, Sarma HD, Banerjee S. ‘4+ 1’Mixed ligand strategy for the preparation of 99mTc-radiopharmaceuticals for hypoxia detecting applications. ChemistrySelect. 2017;2:2910–6.CrossRef
58.
Rizvi SFA, Zhang H, Mehmood S, Sanad M. Synthesis of 99mTc-labeled 2-Mercaptobenzimidazole as a novel radiotracer to diagnose tumor hypoxia. Transl Oncol. 2020;13:100854.PubMedPubMedCentralCrossRef
59.
Ruan Q, Gan Q, Zhang X, Fang S, Zhang J. Preparation and bioevaluation of novel 99mTc-labeled complexes with a 2-nitroimidazole HYNIC derivative for imaging tumor hypoxia. Pharmaceuticals. 2021;14:158.PubMedPubMedCentralCrossRef
60.
Su H, Chu T. Synthesis and bioevaluation of the cyclopentadienyl tricarbonyl technetium-99m 2-nitroimidazole derivatives for tumor hypoxia imaging. Bioorg Med Chem Lett. 2022;60:128583.PubMedCrossRef
61.
Wang F, Fan D, Qian J, Zhang Z, Zhu J, Chen J. Preparation and biodistribution of technetium-99m-labeled bis-Misonidazole (MISO) as an imaging agent for tumour hypoxia. Med Chem. 2015;11:649–55.PubMedCrossRef
62.
Li S, Chu T. Improving tumor/muscle and tumor/blood ratios of 99mTc-labeled nitroimidazole propylene amine oxime (PnAO) complexes with ethylene glycol linkers. Bioorg Med Chem Lett. 2023;82:129154.PubMedCrossRef
63.
Huang H, Zhou H, Li Z, Wang X, Chu T. Effect of a second nitroimidazole redox centre on the accumulation of a hypoxia marker: synthesis and in vitro evaluation of 99mTc-labeled bisnitroimidazole propylene amine oxime complexes. Bioorg Med Chem Lett. 2012;22:172–7.PubMedCrossRef
64.
Lin X, Fang S, Teng Y, Zhang J. Preparation and biological evaluation of a technetium-99m labeled 4-nitroimidazole derivative for imaging tumor hypoxia. J Radioanal Nucl Chem. 2017;313:39–45.CrossRef
65.
Hay MP, Wilson WR, Moselen JW, Palmer BD, Denny WA. Hypoxia-selective antitumor agents. 8. Bis(nitroimidazolyl)alkanecarboxamides: a new class of hypoxia-selective cytotoxins and hypoxic cell radiosensitisers. J Med Chem. 1994;37:381–91.PubMedCrossRef
66.
Russell CD, Crittenden RC, Cash AG. Determination of net ionic charge on Tc-99m DTPA and Tc-99m EDTA by a column ion-exchange method. J Nucl Med. 1980;21:354–60.PubMed
67.
Lin X, Ruan Q, Lin L, Zhang X, Duan X, Teng Y, Zhang J. Biological evaluation and SPECT imaging of tumor hypoxia using a novel technetium-99m labeled tracer with 2-nitroimidazole moiety. J Radioanal Nucl Chem. 2018;317:1463–8.CrossRef
68.
Huellner MW, Strobel K. Clinical applications of SPECT/CT in imaging the extremities. Eur J Nucl Med Mol Imaging. 2014;41(Suppl 1):S50–8.PubMedCrossRef
69.
Sergieva S, Mangaldgiev R, Dimcheva M, Nedev K, Zahariev Z, Robev B. SPECT-CT Imaging with [99mTc]PSMA-T4 in patients with recurrent prostate cancer. Nucl Med Rev Cent East Eur. 2021;24:70–81.PubMedCrossRef
70.
Mariani G, Bruselli L, Kuwert T, et al. A review on the clinical uses of SPECT/CT. Eur J Nucl Med Mol Imaging. 2010;37:1959–85.PubMedCrossRef
71.
Ćwikła JB, Roslan M, Skoneczna I, et al. Initial experience of clinical use of [99mTc]Tc-PSMA-T4 in patients with prostate cancer. A Pilot Study Pharmaceuticals. 2021;14:1107.PubMedCrossRef
72.
Urbán S, Meyer C, Dahlbom M, et al. Radiation dosimetry of 99mTc-PSMA I&S: A single-center prospective study. J Nucl Med. 2021;62:1075–81.PubMedCrossRef
73.
Werner P, Neumann C, Eiber M, Wester HJ, Schottelius M. [99mTc]Tc-PSMA-I&S-SPECT/CT: experience in prostate cancer imaging in an outpatient center. EJNMMI Res. 2020;10(1):45.PubMedPubMedCentralCrossRef
Metadata
Title
Recent Progress in Synthesis of 99mTc-labeled Complexes with Nitroimidazoles as SPECT Probes for Targeting Tumor Hypoxia
Authors
Anh Thu Nguyen
Hee-Kwon Kim
Publication date
25-04-2024
Publisher
Springer Nature Singapore
Keyword
Nitroimidazoles
Published in
Nuclear Medicine and Molecular Imaging / Issue 5/2024
Print ISSN: 1869-3474
Electronic ISSN: 1869-3482
DOI
https://doi.org/10.1007/s13139-024-00860-7

Other articles of this Issue 5/2024

Semi-Quantitative Analysis of Lung Perfusion SPECT/CT for Evaluation of Response to Balloon Pulmonary Angioplasty in Chronic Thromboembolic Pulmonary Hypertension

Unilateral Increased Brown Fat Activities on 18F-FDG PET/CT in a Patient with Contralateral Anhidrosis After Surgical Treatment of Metastatic Osteosarcoma in the Upper Thoracic Spine

Optimized Production of 188Re-HYNIC-Bombesin: New Therapeutic Agent for GRPR Targeting

  • Original Article

Can Radionuclide Therapy be the Solution for Hepatitis B Virus Infection?

Stent-Induced [68Ga]Ga-FAPI Diffuse Expression in a Patient with Pancreatic Cancer: Navigating Non-oncologic Challenges

68Ga-DOATATOC Brain PET/CT Imaging in a case of Dural Metastasis from Synovial Sarcoma