1. Comparison of three 18 F-labeled 2-nitroimidazoles for imaging hypoxia in breast cancer xenografts: [ 18 F]FBNA, [ 18 F]FAZA and [ 18 F]FMISO.
- Author
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Dos Santos SN, Wuest M, Jans HS, Woodfield J, Nario AP, Krys D, Dufour J, Glubrecht D, Bergman C, Bernardes ES, and Wuest F
- Subjects
- Humans, Mice, Animals, Female, Heterografts, Tissue Distribution, Hypoxia, Positron-Emission Tomography methods, Cell Hypoxia, Radiopharmaceuticals, Breast Neoplasms diagnostic imaging, Nitroimidazoles chemistry
- Abstract
Background: Tumour hypoxia is associated with increased metastasis, invasion, poor therapy response and prognosis. Most PET radiotracers developed and used for clinical hypoxia imaging belong to the 2-nitroimidazole family. Recently we have developed novel 2-nitroimidazole-derived PET radiotracer [
18 F]FBNA (N-(4-[18 F]fluoro-benzyl)-2-(2-nitro-1H-imidazol-1-yl)-acet-amide), an18 F-labeled analogue of antiparasitic drug benznidazole. The present study aimed to analyze its radio-pharmacological properties and systematically compare its PET imaging profiles with [18 F]FMISO and [18 F]FAZA in preclinical triple-negative (MDA-MB231) and estrogen receptor-positive (MCF-7) breast cancer models., Methods: In vitro cellular uptake experiments were carried out in MDA-MB321 and MCF-7 cells under normoxic and hypoxic conditions. Metabolic stability in vivo was determined in BALB/c mice using radio-TLC analysis. Dynamic PET experiments over 3 h post-injection were performed in MDA-MB231 and MCF-7 tumour-bearing mice. Those PET data were used for kinetic modelling analysis utilizing the reversible two-tissue-compartment model. Autoradiography was carried out in tumour tissue slices and compared to HIF-1α immunohistochemistry. Detailed ex vivo biodistribution was accomplished in BALB/c mice, and this biodistribution data were used for dosimetry calculation., Results: Under hypoxic conditions in vitro cellular uptake was elevated in both cell lines, MCF-7 and MDA-MB231, for all three radiotracers. After intravenous injection, [18 F]FBNA formed two radiometabolites, resulting in a final fraction of 65 ± 9 % intact [18 F]FBNA after 60 min p.i. After 3 h p.i., [18 F]FBNA tumour uptake reached SUV values of 0.78 ± 0.01 in MCF-7 and 0.61 ± 0.04 in MDA-MB231 tumours (both n = 3), representing tumour-to-muscle ratios of 2.19 ± 0.04 and 1.98 ± 0.15, respectively. [18 F]FMISO resulted in higher tumour uptakes (SUV 1.36 ± 0.04 in MCF-7 and 1.23 ± 0.08 in MDA-MB231 (both n = 4; p < 0.05) than [18 F]FAZA (0.66 ± 0.11 in MCF-7 and 0.63 ± 0.14 in MDA-MB231 (both n = 4; n.s.)), representing tumour-to-muscle ratios of 3.24 ± 0.30 and 3.32 ± 0.50 for [18 F]FMISO, and 2.92 ± 0.74 and 3.00 ± 0.42 for [18 F]FAZA, respectively. While the fraction per time of radiotracer entering the second compartment (k3) was similar within uncertainties for all three radiotracers in MDA-MB231 tumours, it was different in MCF-7 tumours. The ratios k3/(k3 + k2) and K1*k3/(k3 + k2) in MCF-7 tumours were also significantly different, indicating dissimilar fractions of radiotracer bound and trapped intracellularly: K1*k3/(k2 + k3) [18 F]FMISO (0.0088 ± 0.001)/min, n = 4; p < 0.001) > [18 F]FAZA (0.0052 ± 0.002)/min, n = 4; p < 0.01) > [18 F]FBNA (0.003 ± 0.001)/min, n = 3). In contrast, in MDA-MB231 tumours, only K1 was significantly elevated for [18 F]FMISO. However, this did not result in significant differences for K1*k3/(k2 + k3) for all three 2-nitroimidazoles in MDA-MB231 tumours., Conclusion: Novel 2-nitroimidazole PET radiotracer [18 F]FBNA showed uptake into hypoxic breast cancer cells and tumour tissue presumably associated with elevated HIF1-α expression. Systematic comparison of PET imaging performance with [18 F]FMISO and [18 F]FAZA in different types of preclinical breast cancer models revealed a similar tumour uptake profile for [18 F]FBNA with [18 F]FAZA and, despite its higher lipophilicity, still a slightly higher muscle tissue clearance compared to [18 F]FMISO., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)- Published
- 2023
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