目的:聚(ADP-核糖)聚合酶(PARP)的过表达与许多疾病如肿瘤疾病有关。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Olaparib和Rucaparib分子支架的18F标记探针已在临床试验中进行了评估,但是他们缓慢的肝清除阻碍了他们的肿瘤影像学表现。尽管已经设计了许多具有较低肝脏摄取的正电子发射断层扫描(PET)探针,肿瘤与背景的比率仍然很低。因此,我们设计了一种低脂-水分配系数的探针来解决这个问题。
方法:含吡啶的喹唑啉-2,4(1H,3H)-二酮PARP靶向基团被合理设计并用于与螯合剂2,2'偶联,2\'\',2\'\'\'-(1,4,7,10-四氮杂环十二烷-1,4,7,10-四烷基)四乙酸(DOTA)制备名为SMIC-2001的铅化合物,用于放射性标记。体外实验,脂水分配系数,稳定性,结合亲和力,并测定[68Ga]Ga-SMIC-2001的细胞摄取。体内实验,U87MG异种移植模型用于评估其肿瘤影像学特性.
结果:[68Ga]Ga-SMIC-2001显示低LogD7.4(-3.82±0.06)和对PARP-1的高亲和力(48.13nM)。体内研究表明,它在U87MG异种移植模型中表现出很高的肿瘤背景对比,主要是肾清除。60分钟p.i.
结论:总之,除肾脏外,肿瘤与主要器官的比率较高(例如肿瘤与肝脏的比率达到2.20±0.51)。含吡啶的喹唑啉-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,和[68Ga]Ga-SMIC-2001是能够对具有PARP过表达的肿瘤进行成像的非常有前途的PET探针。
OBJECTIVE: 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 18F 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.
METHODS: 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 [68Ga]Ga-SMIC-2001 were determined. In vivo experiments, the U87MG xenograft models were used to evaluate its tumor imaging properties.
RESULTS: [68Ga]Ga-SMIC-2001 showed a low Log D7.4 (-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.
CONCLUSIONS: In summary, pyridine-containing quinazoline-2,4(1 H,3 H)-dione is a novel PARP-targeting molecular scaffold for imaging probe development, and [68Ga]Ga-SMIC-2001 is a highly promising PET probe capable of imaging tumors with
PARP overexpression.