Synthesis and Preclinical Evaluation of [18F]SiFA-PSMA Inhibitors in a Prostate Cancer Model,Journal of Medicinal Chemistry

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Synthesis and Preclinical Evaluation of [18F]SiFA-PSMA Inhibitors in a Prostate Cancer Model
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-10-21 , DOI: 10.1021/acs.jmedchem.1c00812
Justin J Bailey ₁ , Melinda Wuest ₁ , Michael Wagner ₁ , Atul Bhardwaj ₁ , Carmen Wängler ₂ , Bjoern Wängler ₂ , John F Valliant ₃ , Ralf Schirrmacher ₁ , Frank Wuest ₁

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Positron emission tomography (PET) imaging of prostate-specific membrane antigen (PSMA) with gallium-68 (⁶⁸Ga) and fluorine-18 (¹⁸F) radiotracers has aroused tremendous interest over the past few years. The use of organosilicon-[¹⁸F]fluoride acceptors (SiFA) conjugated to urea-based peptidomimetic PSMA inhibitors provides a “kit-like” multidose synthesis technology. Nine novel ¹⁸F-labeled SiFA-bearing PSMA inhibitors with different linker moieties were synthesized and analyzed for their in vitro binding against [¹²⁵I]I-TAAG-PSMA in LNCaP cells. IC₅₀ values ranged from 58–570 nM. Among all compounds, [¹⁸F]SiFA-Asp₂-PEG₃-PSMA (IC₅₀ = 125 nM) showed the highest tumor uptake in LNCaP tumors (SUV_60min 0.73). A substantial increase in molar activity (A_m) (from 7.5 ± 0.5 to 86 ± 3 GBq/μmol) led to a significant increase in LNCaP tumor uptake (SUV_60min 1.18; Δ 0.45 corresponding to +62%). In vivo blocking with DCFPyL resulted in −32% uptake after 60 min. The SiFA-isotopic exchange chemistry offers a method that is readily adaptable for a “kit-type” labeling procedure and clinical translation.

中文翻译：

[18F]SiFA-PSMA 抑制剂在前列腺癌模型中的合成和临床前评估

在过去几年中，使用 gal-68 ( ⁶⁸ Ga) 和 18 ( ¹⁸ F) 放射性示踪剂对前列腺特异性膜抗原 (PSMA) 进行正电子发射断层扫描 (PET) 成像引起了极大的兴趣。使用有机硅-[ ¹⁸ F] 氟化物受体 (SiFA) 与基于尿素的拟肽 PSMA 抑制剂偶联，提供了一种“类似试剂盒”的多剂量合成技术。合成了九种具有不同接头部分的新型¹⁸ F 标记的带有 SiFA 的 PSMA 抑制剂，并分析了它们在 LNCaP 细胞中对 [ ¹²⁵ I] I-TAAG-PSMA 的体外结合。IC ₅₀值范围为 58–570 nM。在所有化合物中，[ ¹⁸ F]SiFA-Asp₂ -PEG ₃ -PSMA (IC₅₀ = 125 nM) 在 LNCaP 肿瘤中显示出最高的肿瘤摄取 (SUV_{60 分钟}0.73)。摩尔活性（A大幅增加阿_米）（从7.5±0.5至86±3吉贝/微摩尔）导致在LNCaP肿瘤摄取一个显著增加（SUV_60分1.18;Δ0.45对应于+ 62％）。用 DCFPyL 进行体内阻断导致 60 分钟后 -32% 的吸收。SiFA 同位素交换化学提供了一种易于适用于“试剂盒类型”标记程序和临床翻译的方法。

更新日期：2021-11-11

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