State Key Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
School of Pharmacy, University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
Eur J Nucl Med Mol Imaging. 2024 Nov;51(13):3840-3853. doi: 10.1007/s00259-024-06843-2. Epub 2024 Jul 16.
Overexpression of Poly (ADP-ribose) polymerase (PARP) is associated with many diseases such as oncological diseases. Several PARP-targeting radiotracers have been developed to detect tumor in recent years. Two F labelled probes based on Olaparib and Rucaparib molecular scaffolds have been evaluated in clinical trials, but their slow hepatic clearance hinders their tumor imaging performance. Although a number of positron emission tomography (PET) probes with lower liver uptake have been designed, the tumor to background ratios remains to be low. Therefore, we designed a probe with low lipid-water partition coefficient to solve this problem.
A pyridine-containing quinazoline-2,4(1 H,3 H)-dione PARP-targeting group was rationally designed and used to conjugate with the chelator 2,2',2'',2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA) to prepare the lead compound named as SMIC-2001 for radiolabeling. In vitro experiments, the lipid-water partition coefficient, stability, binding affinity, and cellular uptake of [Ga]Ga-SMIC-2001 were determined. In vivo experiments, the U87MG xenograft models were used to evaluate its tumor imaging properties.
[Ga]Ga-SMIC-2001 showed a low Log D (-3.82 ± 0.06) and high affinity for PARP-1 (48.13 nM). In vivo study revealed that it exhibited a high tumor-to-background contrast in the U87MG xenograft models and mainly renal clearance. And the ratios of tumor to main organs were high except for the kidney (e.g. tumor to liver ratio reached 2.20 ± 0.51) at 60 min p.i.
In summary, pyridine-containing quinazoline-2,4(1 H,3 H)-dione is a novel PARP-targeting molecular scaffold for imaging probe development, and [Ga]Ga-SMIC-2001 is a highly promising PET probe capable of imaging tumors with PARP overexpression.
多聚（ADP-核糖）聚合酶（PARP）的过度表达与许多疾病有关，如肿瘤疾病。近年来，已经开发了几种 PARP 靶向放射性示踪剂来检测肿瘤。两种基于奥拉帕利和鲁卡帕利分子支架的 F 标记探针已经在临床试验中进行了评估，但它们缓慢的肝清除率阻碍了它们的肿瘤成像性能。尽管已经设计了许多具有较低肝摄取的正电子发射断层扫描（PET）探针，但肿瘤与背景的比值仍然较低。因此，我们设计了一种具有较低脂水分配系数的探针来解决这个问题。
合理设计了含有吡啶的喹唑啉-2,4(1H,3H)-二酮 PARP 靶向基团，并将其与螯合剂 2,2',2'',2'''-(1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸（DOTA）偶联，制备了一种名为 SMIC-2001 的先导化合物，用于放射性标记。在体外实验中，测定了[Ga]Ga-SMIC-2001 的脂水分配系数、稳定性、结合亲和力和细胞摄取率。在体内实验中，使用 U87MG 异种移植模型评估其肿瘤成像特性。
[Ga]Ga-SMIC-2001 表现出低 Log D（-3.82±0.06）和对 PARP-1 的高亲和力（48.13 nM）。体内研究表明，它在 U87MG 异种移植模型中表现出高肿瘤与背景的对比度，主要通过肾脏清除。并且，除了肾脏（例如，肿瘤与肝脏的比值达到 2.20±0.51）外，在 60 分钟时，肿瘤与主要器官的比值都很高。
总之，含有吡啶的喹唑啉-2,4(1H,3H)-二酮是一种用于成像探针开发的新型 PARP 靶向分子支架，[Ga]Ga-SMIC-2001 是一种很有前途的 PET 探针，能够对 PARP 过度表达的肿瘤进行成像。
