Al<sup>18</sup>F标记白蛋白结合剂修饰的PARP靶向显像探针的制备及初步生物学评价

徐伟; 严骏杰; 潘栋辉; 李梦; 吴威; 杨敏

doi:10.3724/j.0253-3219.2025.hjs.48.250184

您当前的位置：

首页 >

文章列表页 >

Al¹⁸F标记白蛋白结合剂修饰的PARP靶向显像探针的制备及初步生物学评价

核化学、放射化学、放射性药物和核医学 | 更新时间：2025-11-27

- Al¹⁸F标记白蛋白结合剂修饰的PARP靶向显像探针的制备及初步生物学评价
- Preparation and preliminary biological evaluation of [¹⁸F]AlF-labeled Albumin-binding agent modified PARP-targeted imaging probe
- 核技术 2025年48卷第11期文章编号：110302
- 作者机构：
  
  1.江南大学生命科学与健康工程学院无锡 214122
  2.江南大学化学与材料工程学院无锡 214122
  3.国家卫生健康委员会核医学重点实验室，江苏省分子核医学重点实验室，江苏省原子医学研究所无锡 214063
- 作者简介：
  
  徐伟，男，1984年出生，2010年毕业于南京工业大学，现为博士研究生，研究领域为分子影像
  杨敏，E-mail：yangmin@jsinm.org
- 基金信息：
  
  国家自然科学基金(32371434)
- DOI：10.3724/j.0253-3219.2025.hjs.48.250184
  中图分类号： TL99
- 收稿：2025-04-26，
  
  修回：2025-06-30，
  
  纸质出版：2025-11-15
- 稿件说明：
移动端阅览
徐伟,严骏杰,潘栋辉等.Al¹⁸F标记白蛋白结合剂修饰的PARP靶向显像探针的制备及初步生物学评价[J].核技术,2025,48(11):110302.

XU Wei,YAN Junjie,PAN Donghui,et al.Preparation and preliminary biological evaluation of [¹⁸F]AlF-labeled Albumin-binding agent modified PARP-targeted imaging probe[J].NUCLEAR TECHNIQUES,2025,48(11):110302.
徐伟,严骏杰,潘栋辉等.Al¹⁸F标记白蛋白结合剂修饰的PARP靶向显像探针的制备及初步生物学评价[J].核技术,2025,48(11):110302. DOI： 10.3724/j.0253-3219.2025.hjs.48.250184. CSTR： 32193.14.hjs.CN31-1342/TL.2025.48.250184.

XU Wei,YAN Junjie,PAN Donghui,et al.Preparation and preliminary biological evaluation of [¹⁸F]AlF-labeled Albumin-binding agent modified PARP-targeted imaging probe[J].NUCLEAR TECHNIQUES,2025,48(11):110302. DOI： 10.3724/j.0253-3219.2025.hjs.48.250184. CSTR： 32193.14.hjs.CN31-1342/TL.2025.48.250184.

摘要

多聚腺苷二磷酸核糖聚合酶（Poly(ADP-ribose) Polymerase，PARP）是癌症治疗中的重要靶点，动态评估其表达水平是实现精准治疗的必要前提。本研究拟基于PARP抑制剂奥拉帕利（Olaparib）的母核，设计并合成一种偶联白蛋白结合剂的新型

F标记PARP靶向正电子发射型计算机断层（Positron Emission Computed Tomography，PET）显像探针［

F］AlF-NOTA-LA，并结合体外实验与荷瘤小鼠活体microPET显像对探针的显像性能进行评估。研究表明，［

F］AlF-NOTA-LA标记时间约15 min，标记产率为（49.2±2.5）%，比活度为3.14 GBq∙μmol

-1

，放射化学纯度大于99%，脂水分配系数log

为-1.1±0.013，体外稳定性好。60 min时，［

F］AlF-NOTA-LA在MDA-MB-453细胞的摄取为（3.83±0.26）%AD，显著高于在A549细胞中的摄取（1.89±0.12）%AD。microPET显像结果显示，MDA-MB-453荷瘤鼠肿瘤对探针的摄取在10 min时达到最大值为（5.31±0.20）%ID∙g

-1

，而A549荷瘤鼠及阻断组的最大摄取分别为（3.04±0.03）%ID∙g

-1

和（2.23±0.11）%ID∙g

-1

。临床前研究结果初步表明，该探针体内药代动力学特性较差，经过结构改造后期望具有作为PARP靶向PET显像探针的潜力。

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.

Purpose

This study aims to assess the feasibility of using a novel albumin-binding PARP-targeted PET imaging probe for detecting PARP expression levels.

Methods

Firstly

based on the core structure of the PARP inhibitor Olaparib

the precursor NOTA-LA was synthesized using 4-(4-fluoro-3-(piperazine-1-carbonyl)benzyl) phthalazin-1(2H)-one and 4-(4-iodophenyl) butanoic acid as starting materials. Then

the target imaging probe

[

]

AlF-NOTA-LA

was radiolabeled

via

the non-covalent [

]

AlF method

and the probe was then characterized by determining its radiolabeling yield

radiochemical purity

molar activity

partition coefficient

and

in vitro

stability. Finally

the imaging performance of [

]

AlF-NOTA-LA was evaluated through

in vitro

cell-based assays and

in vivo

microPET imaging studies in A549 and MDA-MB-453 tumor-bearing mice.

Results

The radiolabeling of [

]

AlF-NOTA-LA is completed in approximately 15 min

yielding a radiolabeling efficiency of (49.2±2.5)%

with radiochemical purity exceeding 99%

a molar activity of 3.14 GBq∙μmol

-1

a log

value of -1.1±0.013

and excellent in vitro stability. After 60 min

the cellular uptake of [

]

AlF-NOTA-LA in MDA-MB-453 cells is (3.83±0.26)%AD

significantly higher than that in A549 cells (1.89±0.12)%AD. MicroPET imaging reveals that in MDA-MB-453 tumor-bearing mice

the probe's tumor uptake peaks at 10 min

reaching a maximum value of (5.31±0.20)%ID∙g

-1

(percentage injected dose per gram of tissue). In contrast

A549 tumor-bearing mice and blocking group showed significantly lower peak uptakes of (3.04±0.03)%ID∙g

-1

and (2.23±0.11)%ID∙g

-1

respectively.

Conclusions

Preliminary preclinical findings in this study indicate that the probe exhibited suboptimal pharmacokin

etic properties

in vivo

. Following structural modifications

it is anticipated to have potential as a PARP-targeted PET imaging probe.

关键词

Keywords

references

Kraus W L . PARPs and ADP-ribosylation: 50 years ... and counting [J ] . Molecular Cell , 2015 , 58 ( 6 ): 902 – 910 . DOI : 10.1016/j.molcel.2015.06.006 http://dx.doi.org/10.1016/j.molcel.2015.06.006 .

Ray Chaudhuri A , Nussenzweig A . The multifaceted roles of PARP1 in DNA repair and chromatin remodelling [J ] . Nature Reviews Molecular Cell Biology , 2017 , 18 ( 10 ): 610 – 621 . DOI: 10.1038/nrm.2017.53 http://dx.doi.org/10.1038/nrm.2017.53 .

Pilié P G , Tang C , Mills G B , et al . State-of-the-art strategies for targeting the DNA damage response in cancer [J ] . Nature Reviews Clinical Oncology , 2019 , 16 : 81 – 104 . DOI: 10.1038/s41571-018-0114-z http://dx.doi.org/10.1038/s41571-018-0114-z .

Negi P , Lakshmanan K , Patel P K , et al . An update on poly(ADP-ribose) polymerase I-a brief review [J ] . Mini Reviews in Medicinal Chemistry , 2023 , 23 ( 18 ): 1762 – 1771 . DOI: 10.2174/1389557523666230221145844 http://dx.doi.org/10.2174/1389557523666230221145844 .

Mateo J , Lord C J , Serra V , et al . A decade of clinical development of PARP inhibitors in perspective [J ] . Annals of Oncology , 2019 , 30 ( 9 ): 1437 – 1447 . DOI: 10.1093/annonc/mdz192 http://dx.doi.org/10.1093/annonc/mdz192 .

Dea S . PARP and PARG inhibitors in cancer treatment [J ] . Genes & Development , 2020 , 34 ( 5–6 ): 360 – 394 . DOI: 10.1101/gad.334516.119 http://dx.doi.org/10.1101/gad.334516.119 .

李祎萍 , 张予菲 , 孙光志 , 等 . PARPi通过抑制XRCC1的表达增加食管鳞癌放射治疗敏感性 [J ] . 辐射研究与辐射工艺学报 , 2023 , 41 ( 3 ): 030303 . DOI: 10.11889/j.1000-3436.2022-0122 http://dx.doi.org/10.11889/j.1000-3436.2022-0122 .

LI Yiping , ZHANG Yufei , SUN Guangzhi , et al . PARPi increases radiotherapy sensitivity of esophageal squamous cell carcinoma by inhibiting XRCC1 expression [J ] . Journal of Radiation Research and Radiation Processing , 2023 , 41 ( 3 ): 030303 . DOI: 10.11889/j.1000-3436.2022-0122 http://dx.doi.org/10.11889/j.1000-3436.2022-0122 .

丰俊东 , 刘亮 , 刘雯倩 , 等 . 瓜氨酸对辐射致小鼠肠道损伤的防护作用及机制研究 [J ] . 核技术 , 2024 , 47 ( 2 ): 020301 . DOI: 10.11889/j.0253-3219.2024.hjs.47.020301 http://dx.doi.org/10.11889/j.0253-3219.2024.hjs.47.020301 .

FENG Jundong , LIU Liang , LIU Wenqian , et al . Protective effect and mechanism of citrulline on intestinal injury induced by radiation in mice [J ] . Nuclear Techniques , 2024 , 47 ( 2 ): 020301 . DOI: 10.11889/j.0253-3219.2024.hjs.47.020301 http://dx.doi.org/10.11889/j.0253-3219.2024.hjs.47.020301 .

Curtin N J , Szabo C . Poly(ADP-ribose) polymerase inhibition: past, present and future [J ] . Nature Reviews Drug Discovery , 2020 , 19 ( 10 ): 711 – 736 . DOI: 10.1038/s41573-020-0076-6 http://dx.doi.org/10.1038/s41573-020-0076-6 .

Zhu H , Wei M Y , Xu J , et al . PARP inhibitors in pancreatic cancer: molecular mechanisms and clinical applications [J ] . Molecular Cancer , 2020 , 19 ( 1 ): 49 . DOI: 10.1186/s12943-020-01167-9 http://dx.doi.org/10.1186/s12943-020-01167-9 .

Wang S S Y , Jie Y E , Cheng S W , et al . PARP inhibitors in breast and ovarian cancer [J ] . Cancers , 2023 , 15 ( 8 ): 2357 . DOI: 10.3390/cancers15082357 http://dx.doi.org/10.3390/cancers15082357 .

Teyssonneau D , Margot H , Cabart M , et al . Prostate cancer and PARP inhibitors: progress and challenges [J ] . Journal of Hematology & Oncology , 2021 , 14 ( 1 ): 51 . DOI: 10.1186/s13045-021-01061-x http://dx.doi.org/10.1186/s13045-021-01061-x .

Tew W P , Lacchetti C , Kohn E C , et al . Poly(ADP-ribose) polymerase inhibitors in the management of ovarian cancer: ASCO guideline rapid recommendation update [J ] . Journal of Clinical Oncology , 2022 , 40 ( 33 ): 3878 – 3881 . DOI: 10.1200/JCO.22.01934 http://dx.doi.org/10.1200/JCO.22.01934 .

王策 , 潘栋辉 , 谭思怡 , 等 . 新型α突触核蛋白PET探针的合成及初步生物学评价 [J ] . 核技术 , 2024 , 47 ( 10 ): 100301 . DOI: 10.11889/j.0253-3219.2024.hjs.47.100301 http://dx.doi.org/10.11889/j.0253-3219.2024.hjs.47.100301 .

WANG Ce , PAN Donghui , TAN Siyi , et al . Synthesis and preliminary biological evaluation of a novel PET tracer for α-synuclein PET imaging [J ] . Nuclear Techniques , 2024 , 47 ( 10 ): 100301 . DOI: 10.11889/j.0253-3219.2024.hjs.47.100301 http://dx.doi.org/10.11889/j.0253-3219.2024.hjs.47.100301 .

Carney B , Carlucci G , Salinas B , et al . Non-invasive PET imaging of PARP1 expression in glioblastoma models [J ] . Molecular Imaging and Biology , 2016 , 18 ( 3 ): 386 – 392 . DOI: 10.1007/s11307-015-0904-y http://dx.doi.org/10.1007/s11307-015-0904-y .

Bowden G D , Stotz S , Kinzler J , et al . DoE optimization empowers the automated preparation of enantiomerically pure [ 18 F ] talazoparib and its in vivo evaluation as a PARP radiotracer [J ] . Journal of Medicinal Chemistry , 2021 , 64 ( 21 ): 1 5690– 15701 . DOI: 10.1021/acs.jmedchem.1c00903 http://dx.doi.org/10.1021/acs.jmedchem.1c00903 .

Wang X W , Liu W , Li K , et al . PET imaging of PARP expression using 68 Ga-labelled inhibitors [J ] . European Journal of Nuclear Medicine and Molecular Imaging , 2023 , 50 ( 9 ): 2606 – 2620 . DOI: 10.1007/s00259-023-06249-6 http://dx.doi.org/10.1007/s00259-023-06249-6 .

Chan C Y , Chen Z J , Destro G , et al . Imaging PARP with [ 18 F ] rucaparib in pancreatic cancer models [J ] . European Journal of Nuclear Medicine and Molecular Imaging , 2022 , 49 ( 11 ): 3668 – 3678 . DOI: 10.1007/s00259-022-05835-4 http://dx.doi.org/10.1007/s00259-022-05835-4 .

Huang T , Hu P C , Banizs A B , et al . Initial evaluation of Cu-64 labeled PARPi-DOTA PET imaging in mice with mesothelioma [J ] . Bioorganic & Medicinal Chemistry Letters , 2017 , 27 ( 15 ): 3472 – 3476 . DOI: 10.1016/j.bmcl.2017.05.077 http://dx.doi.org/10.1016/j.bmcl.2017.05.077 .

Ullah A , Shin G , Lim S I . Human serum albumin binders: a piggyback ride for long-acting therapeutics [J ] . Drug Discovery Today , 2023 , 28 ( 10 ): 103738 . DOI: 10.1016/j.drudis.2023.103738 http://dx.doi.org/10.1016/j.drudis.2023.103738 .

Lau J , Jacobson O , Niu G , et al . Bench to bedside: albumin binders for improved cancer radioligand therapies [J ] . Bioconjugate Chemistry , 2019 , 30 ( 3 ): 487 – 502 . DOI: 10.1021/acs.bioconjchem.8b00919 http://dx.doi.org/10.1021/acs.bioconjchem.8b00919 .

Zhou D , Chu W H , Xu J B , et al . Synthesis, [ 18 F ] radiolabeling, and evaluation of poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors for in vivo imaging of PARP-1 using positron emission tomography [J ] . Bioorganic & Medicinal Chemistry , 2014 , 22 ( 5 ): 1700 – 1707 . DOI: 10.1016/j.bmc.2014.01.019 http://dx.doi.org/10.1016/j.bmc.2014.01.019 .

Wilson T C , Xavier M A , Knight J , et al . PET imaging of PARP expression using 18 F-olaparib [J ] . Journal of Nuclear Medicine , 2019 , 60 ( 4 ): 504 – 510 . DOI: 10.2967/jnumed. 118.213223 http://dx.doi.org/10.2967/jnumed.118.213223 .

Chen Z J , Destro G , Guibbal F , et al . Copper-mediated radiosynthesis of [ 18 F ] rucaparib [J ] . Organic Letters , 2021 , 23 ( 18 ): 7290 – 7294 . DOI: 10.1021/acs.orglett.1c02770 http://dx.doi.org/10.1021/acs.orglett.1c02770 .

Makvandi M , Pantel A , Schwartz L , et al . A PET imaging agent for evaluating PARP-1 expression in ovarian cancer [J ] . The Journal of Clinical Investigation , 2018 , 128 ( 5 ): 2116 – 2126 . DOI: 10.1172/JCI97992 http://dx.doi.org/10.1172/JCI97992 .

浏览量

下载量

CSCD

文章被引用时，请邮件提醒。

提交

工具集

关联资源

¹³¹Ⅰ-B2-S22-AFA对HER-2高表达乳腺癌细胞的杀伤作用

基于GATE的双平板正电子发射乳腺断层成像系统的仿真研究

(S-¹⁸F-氟代甲基)-L-半胱氨酸的半自动化合成及其初步炎症PET显像

乳腺癌雌激素受体分子影像探针16α-[¹⁸F]氟-17β-雌二醇的自动化合成

雌激素受体β分子探针前体的合成及^99mTc标记

Al18F标记白蛋白结合剂修饰的PARP靶向显像探针的制备及初步生物学评价

Preparation and preliminary biological evaluation of [18F]AlF-labeled Albumin-binding agent modified PARP-targeted imaging probe

DOI：10.3724/j.0253-3219.2025.hjs.48.250184

摘要

Abstract

关键词

Keywords

references

Al¹⁸F标记白蛋白结合剂修饰的PARP靶向显像探针的制备及初步生物学评价

Preparation and preliminary biological evaluation of [¹⁸F]AlF-labeled Albumin-binding agent modified PARP-targeted imaging probe