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Fluorine-18 Labeling of the MDM2 Inhibitor RG7388 for PET Imaging: Chemistry and Preliminary Evaluation
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2021-09-15 , DOI: 10.1021/acs.molpharmaceut.1c00531
Zhengyuan Zhou 1 , Michael R Zalutsky 1 , Satish K Chitneni 1
Affiliation  

RG7388 (Idasanutlin) is a potent inhibitor of oncoprotein murine double minute 2 (MDM2). Herein we investigated the feasibility of developing 18F-labeled RG7388 as a radiotracer for imaging MDM2 expression in tumors with positron emission tomography (PET). Two fluorinated analogues of RG7388, 6 and 7, were synthesized by attaching a fluoronicotinyl moiety to RG7388 via a polyethylene glycol (PEG3) or a propyl linker. The inhibitory potency (IC50) of 6 and 7 against MDM2 was determined by a fluorescence polarization (FP)-based assay. Next, compound 6 was labeled with 18F using a trimethylammonium triflate precursor to obtain [18F]FN-PEG3-RG7388 ([18F]6), and its properties were evaluated in MDM2 expressing wild-type p53 tumor cell lines (SJSA-1 and HepG2) in vitro and in tumor xenografts in vivo. The FP assays revealed an IC50 against MDM2 of 119 nM and 160 nM for 6 and 7, respectively. 18F-labeling of 6 was achieved in 50.3 ± 7.5% radiochemical yield. [18F]6 exhibited a high uptake (∼70% of input dose) and specificity in SJSA-1 and HepG2 cell lines. Saturation binding assays revealed a binding affinity (Kd) of 128 nM for [18F]6 on SJSA-1 cells. In mice, [18F]6 showed fast clearance from blood with a maximum tumor uptake of 3.80 ± 0.85% injected dose per gram (ID/g) in HepG2 xenografts at 30 min postinjection (p.i.) and 1.32 ± 0.32% ID/g in SJSA-1 xenografts at 1 h p.i. Specificity of [18F]6 uptake in tumors was demonstrated by pretreatment of mice with SJSA-xenografts with a blocking dose of RG7388 (35 mg/kg body weight, i.p.). In vivo stability studies in mice using HPLC showed ∼60% and ∼30% intact [18F]6 remaining in plasma at 30 min and 1 h p.i., respectively, with the remaining activity attributed to polar peaks. Our results suggest that RG7388 is a promising molecular scaffold for 18F-labeled probe development for MDM2. Additional labeling strategies and functionalizing locations on RG7388 are under development to improve binding affinity and in vivo stability of the 18F-labeled compound to make it more amenable for PET imaging of MDM2 in vivo.

中文翻译:

用于 PET 成像的 MDM2 抑制剂 RG7388 的氟 18 标记:化学和初步评估

RG7388 (Idasanutlin) 是鼠癌蛋白双分钟 2 (MDM2) 的有效抑制剂。在这里,我们研究了开发18 F-标记的 RG7388 作为放射性示踪剂,用正电子发射断层扫描 (PET) 对肿瘤中的 MDM2 表达进行成像的可行性。RG7388 的两种氟化类似物67是通过聚乙二醇 (PEG 3 ) 或丙基接头将氟烟碱基部分连接到 RG7388 来合成的。67对MDM2的抑制效力(IC 50 )通过基于荧光偏振(FP)的测定法确定。接下来,化合物618标记F使用三甲基三氟甲磺酸铵前体获得[ 18 F]FN-PEG 3 -RG7388 ([ 18 F] 6 ),并在体外在表达MDM2的野生型p53肿瘤细胞系(SJSA-1和HepG2)中评价其性质在体内的肿瘤异种移植物中。FP 测定揭示了针对 MDM2 的 IC 50对于67分别为 119 nM 和 160 nM 。6的18 F-标记以 50.3 ± 7.5% 的放射化学收率实现。[ 18 F] 6在 SJSA-1 和 HepG2 细胞系中表现出高摄取(~70% 的输入剂量)和特异性。饱和结合测定揭示了结合亲和力(Kd ) SJSA-1 细胞上的 [ 18 F] 6为 128 nM 。在小鼠中,[ 18 F] 6显示出从血液中快速清除,在注射后 30 分钟 (pi) 和 1.32 ± 0.32% ID/g 的 HepG2 异种移植物中,最大肿瘤摄取量为每克注射剂量 3.80 ± 0.85% (ID/g)注射后 1 小时的 SJSA-1 异种移植物中 [ 18 F] 6在肿瘤中摄取的特异性通过用阻断剂量的 RG7388 (35mg/kg 体重,ip) 用 SJSA-异种移植物预处理小鼠来证明。使用 HPLC 对小鼠进行的体内稳定性研究显示 ∼60% 和 ∼30% 完整的 [ 18 F] 6分别在 30 分钟和 1 小时后保留在血浆中,剩余的活性归因于极性峰。我们的研究结果表明,RG7388 是一种很有前途的分子支架,可用于开发 MDM2 的18 F 标记探针。RG7388 上的其他标记策略和功能化位置正在开发中,以提高18 F 标记化合物的结合亲和力和体内稳定性,使其更适合于体内 MDM2 的 PET 成像。
更新日期:2021-10-04
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