Nuclear Medicine and Biology ( IF 3.6 ) Pub Date : 2023-08-26 , DOI: 10.1016/j.nucmedbio.2023.108383 Sofia Nascimento Dos Santos 1 , Melinda Wuest 2 , Hans-Sonke Jans 2 , Jenilee Woodfield 2 , Arian Pérez Nario 1 , Daniel Krys 2 , Jennifer Dufour 2 , Darryl Glubrecht 2 , Cody Bergman 2 , Emerson Soares Bernardes 1 , Frank Wuest 2
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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 tumour-to-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.
中文翻译：
三种 18F 标记的 2-硝基咪唑对乳腺癌异种移植物缺氧成像的比较：[18F]FBNA、[18F]FAZA 和 [18F]FMISO
背景
肿瘤缺氧与转移、侵袭增加、治疗反应不良和预后相关。大多数开发并用于临床缺氧成像的 PET 放射性示踪剂属于 2-硝基咪唑家族。最近我们开发了新型2-硝基咪唑衍生的PET放射性示踪剂[ 18 F]FBNA ( N -(4-[ 18 F]氟-苄基)-2-(2-硝基-1 H-咪唑-1-基)-乙酰-酰胺），抗寄生虫药物苯并硝唑的18 F 标记类似物。本研究旨在分析其放射药理学特性，并在临床前三阴性（MDA-MB231）和雌激素受体阳性（MCF-7）中系统地将其 PET 成像特征与 [ 18 F]FMISO 和 [ 18 F]FAZA 进行比较乳腺癌模型。
方法
在常氧和低氧条件下在 MDA-MB321 和 MCF-7 细胞中进行体外细胞摄取实验。使用放射 TLC 分析确定 BALB/c 小鼠的体内代谢稳定性。在 MDA-MB231 和 MCF-7 荷瘤小鼠中进行注射后 3 小时的动态 PET 实验。这些 PET 数据用于利用可逆两组织室模型进行动力学建模分析。对肿瘤组织切片进行放射自显影，并与 HIF-1α 免疫组织化学进行比较。在 BALB/c 小鼠中完成了详细的离体生物分布，并且该生物分布数据用于剂量测定计算。
结果
在缺氧条件下，两种细胞系（MCF-7 和 MDA-MB231）对所有三种放射性示踪剂的体外细胞摄取均升高。静脉注射后，[ 18 F]FBNA 形成两种放射性代谢物，导致注射后 60 分钟后最终分数为 65 ± 9 % 完整 [ 18 F]FBNA 注射后 3 小时后，[ 18 F]FBNA 肿瘤摄取达到 SUV 值 0.78 MCF-7 中为 ± 0.01，MDA-MB231 肿瘤中为 0.61 ± 0.04（均为n = 3），分别代表肿瘤与肌肉的比率为 2.19 ± 0.04 和 1.98 ± 0.15。与[ 18 F]FAZA（MCF-7 中的 SUV 0.66 ± 0.11）相比，[ 18 F]FMISO 导致更高的肿瘤摄取（MCF-7 中的 SUV 为 1.36 ± 0.04，MDA-MB231 中的 SUV 为 1.23 ± 0.08 （均为n = 4； p < 0.05））。 MDA-MB231 中为 7 和 0.63 ± 0.14（n = 4；ns）），代表 [ 18 F]FMISO 的肿瘤与肌肉比率为 3.24 ± 0.30 和 3.32 ± 0.50，对于 [ 18 F]FMISO 则为 2.92 ± 0.74 和 3.00 ± 0.42 [ 18 F]FAZA 分别，虽然 MDA-MB231 肿瘤中所有三种放射性示踪剂的每次放射性示踪剂进入第二室的分数 (k3) 在不确定性内相似，但在 MCF-7 肿瘤中却不同。 MCF-7 肿瘤中的 k3 + k2) 和 K1*k3/(k3 + k2) 也显着不同，表明细胞内结合和捕获的放射性示踪剂的比例不同：K1*k3/(k2 + k3) [ 18 F]FMISO (0.0088 ± 0.001)/分钟， n = 4； p < 0.001) > [ 18 F]FAZA (0.0052 ± 0.002)/分钟，n = 4； p < 0.01) > [ 18 F]FBNA (0.003 ± 0.001)/分钟， n = 3)。相比之下，在 MDA-MB231 肿瘤中，[ 18 F]FMISO 仅 K1 显着升高。 然而，这并没有导致 MDA-MB231 肿瘤中所有三种 2-硝基咪唑的 K1*k3/(k2 + k3) 存在显着差异。
结论
新型 2-硝基咪唑 PET 放射性示踪剂 [ 18 F]FBNA 显示缺氧乳腺癌细胞和肿瘤组织的吸收，推测与 HIF1-α 表达升高相关。在不同类型的临床前乳腺癌模型中对 [ 18 F]FMISO 和 [ 18 F]FAZA 的 PET 成像性能进行系统比较，结果显示 [ 18 F]FBNA 与 [ 18 F]FAZA 具有相似的肿瘤摄取特性，尽管其亲脂性更高，与 [ 18 F]FMISO 相比，肌肉组织清除率仍略高。
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