Development and evaluation of a 99mTc-labeled olaparib analog for PARP imaging.

IF 4.4 Q1 CHEMISTRY, INORGANIC & NUCLEAR
Wei Xu, Junjie Yan, Xinlin Zhong, Donghui Pan, Xinyu Wang, Yuping Xu, Lizhen Wang, Chongyang Chen, Min Yang
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引用次数: 0

Abstract

Background: Poly(ADP-ribose) polymerase (PARP) is an important therapeutic target in cancer treatment, and dynamic assessment of its expression level is essential for achieving precision therapy. Although 18F-labeled PARP-targeted radiotracers have demonstrated remarkable tumor-imaging capabilities in preclinical studies, their high lipophilicity leads to increased non-specific uptake in abdominal organs, which has severely hindered their clinical translation. Furthermore, while PET imaging provides superior resolution and sensitivity, its infrastructure and operational demands may limit widespread accessibility in certain regions. Therefore, the development of SPECT-based PARP radiotracers could offer a complementary approach, potentially expanding access to PARP imaging in a broader range of clinical settings. To provide a more affordable and accessible alternative to PET probes, hydrazinonicotinamide (HYNIC)-olaparib was radiolabeled with technetium-99m (99mTc) and evaluated both in vitro and in vivo using the MDA-MB-453 breast cancer model.

Results: [99mTc][Tc-HYNIC/EDDA]-olaparib exhibits a high radiochemical yield (> 90%), excellent radiochemical purity (> 90%), and good in vitro stability. The introduction of ethylenediamine-N, N'-diacetic acid (EDDA) and tricine facilitated the synthesis of 99mTc complex, and improved the hydrophilicity (logP = 0.63 ± 0.25) of the probe as well, resulting in reduced the accumulation of radiation in the abdomen. In vitro results indicated that [99mTc][Tc-HYNIC/EDDA]-olaparib could target PRAP-1 in MDA-MB-453 cells. In vivo experiments, micro SPECT/CT imaging provided clear visualization of MDA-MB-453 tumors with significant tumor-to-background distinction, and accumulation of [99mTc][Tc-HYNIC/EDDA]-olaparib was quantified at 3.45 ± 0.17%ID/g at 1 h post intravenous injection.

Conclusion: These findings suggest that [99mTc][Tc-HYNIC/EDDA]-olaparib holds great promise as a novel radiotracer for PARP imaging.

用于PARP成像的99mtc标记奥拉帕尼类似物的开发和评估。
背景:聚(adp -核糖)聚合酶(PARP)是肿瘤治疗的重要靶点,动态评估其表达水平是实现精准治疗的必要条件。尽管18f标记的parp靶向放射性示踪剂在临床前研究中显示出卓越的肿瘤成像能力,但其高亲脂性导致腹部器官的非特异性吸收增加,这严重阻碍了其临床转化。此外,虽然PET成像提供了卓越的分辨率和灵敏度,但其基础设施和操作要求可能会限制某些地区的广泛可及性。因此,基于spect的PARP放射性示踪剂的开发可以提供一种补充方法,潜在地扩大PARP成像在更广泛的临床环境中的应用。为了提供一种比PET探针更实惠和更容易获得的替代品,HYNIC -olaparib用锝-99m (99mTc)进行放射性标记,并使用MDA-MB-453乳腺癌模型在体外和体内进行评估。结果:[99mTc][Tc-HYNIC/EDDA]-olaparib放射化学产率高(> 90%),放射化学纯度高(> 90%),体外稳定性好。乙二胺-N, N'-二乙酸(EDDA)和三辛的引入促进了99mTc配合物的合成,也提高了探针的亲水性(logP = 0.63±0.25),从而减少了辐射在腹部的积累。体外实验结果表明[99mTc][Tc-HYNIC/EDDA]-olaparib可靶向MDA-MB-453细胞中的PRAP-1。在体内实验中,微SPECT/CT成像显示MDA-MB-453肿瘤清晰可见,具有明显的肿瘤-背景差异,静脉注射后1 h,定量测定[99mTc][Tc-HYNIC/EDDA]-奥拉帕尼的累积量为3.45±0.17%ID/g。结论:这些发现表明[99mTc][Tc-HYNIC/EDDA]-olaparib作为PARP成像的新型放射性示踪剂具有很大的前景。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
7.20
自引率
8.70%
发文量
30
审稿时长
5 weeks
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