Comparison of three 18F-labeled 2-nitroimidazoles for imaging hypoxia in breast cancer xenografts
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ARIAN PEREZ NARIO
EMERSON SOARES BERNARDES
SOFIA NASCIMENTO DOS SANTOS
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Nuclear Medicine and Biology
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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 [18F]FBNA (N-(4-[18F]fluoro-
benzyl)-2-(2-nitro-1H-imidazol-1-yl)-acet-amide), an 18F-labeled analogue of antiparasitic drug benznidazole.
The present study aimed to analyze its radio-pharmacological properties and systematically compare its
PET imaging profiles with [18F]FMISO and [18F]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, [18F]FBNA formed two radiometabolites, resulting in a
final fraction of 65 ± 9 % intact [18F]FBNA after 60 min p.i. After 3 h p.i., [18F]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 tumourto-
muscle ratios of 2.19 ± 0.04 and 1.98 ± 0.15, respectively. [18F]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 [18F]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 [18F]FMISO, and 2.92 ± 0.74 and 3.00 ± 0.42 for [18F]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) [18F]FMISO (0.0088 ± 0.001)/min, n = 4; p < 0.001) >
[18F]FAZA (0.0052 ± 0.002)/min, n = 4; p < 0.01) > [18F]FBNA (0.003 ± 0.001)/min, n = 3). In contrast, in
MDA-MB231 tumours, only K1 was significantly elevated for [18F]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 [18F]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 [18F]FMISO and [18F]FAZA in different types of preclinical breast cancer models revealed a similar tumour uptake profile for [18F]FBNA with [18F]FAZA and, despite its higher lipophilicity, still
a slightly higher muscle tissue clearance compared to [18F]FMISO.
Como referenciar
SANTOS, SOFIA N. dos; WUEST, MELINDA; JANS, HANS-SONKE; WOODFIELD, JENILEE; NARIO, ARIAN P.; KRYS, DANIEL; DUFOUR, JENNIFER; GLUBRECHT, DARRYL; BERGMAN, CODY; BERNARDES, EMERSON S.; WUEST, FRANK. Comparison of three 18F-labeled 2-nitroimidazoles for imaging hypoxia in breast cancer xenografts: [18F]FBNA, [18F]FAZA and [18F]FMISO. Nuclear Engineering and Design, v. 124-125, p. 1-14, 2023. DOI: 10.1016/j.nucmedbio.2023.108383. Disponível em: http://repositorio.ipen.br/handle/123456789/34376. Acesso em: 20 Mar 2026.
Esta referência é gerada automaticamente de acordo com as normas do estilo IPEN/SP (ABNT NBR 6023) e recomenda-se uma verificação final e ajustes caso necessário.