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Brain Penetrant PARP Targeted PET Imaging Probes

脑部渗透 PARP 靶向 PET 成像探针

基本信息

批准号：
10287654
负责人：
Zhengxin Cai
金额：
$ 8.28万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2022-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10287654
关键词：
APP-PS1 Administrative Supplement Affinity Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease patient Anatomy Animal Disease Models Animals Binding Blood - brain barrier anatomy Brain Brain Neoplasms Cancer Patient Cerebellum Chemotherapy and/or radiation Clinic Clinical Trials DNA Repair Data Development Drug Kinetics Funding Future Genetic Glioblastoma Glioma Grant Hippocampus (Brain)Human Hydrogen Bonding Image In Vitro Kinetics Lead Malignant Neoplasms Mediating Metabolism Modeling Molecular Weight Mus Penetration Plasma Poly(ADP-ribose) Polymerases Positron-Emission Tomography Precision therapeutics Prediction of Response to Therapy Prognosis Property Radiation therapy Rattus Rodent Model Series Specificity Spleen Synapses Testing Tracer Transgenic Organisms Translating United States National Institutes of Health base blood-brain barrier penetration blood-brain barrier permeabilization brain tissue cancer survival clinical imaging familial Alzheimer disease frontal lobe imaging agent imaging modality imaging probe imaging study improved in vivo inhibitor/antagonist kinetic model mouse model neoplastic cell neuroimaging nonhuman primate novel parent grant patient stratification pharmacokinetic model prognostic public health relevance radiotracer response translational study tumor uptake white matter

项目摘要

ABSTRACT of the funded parent grant Because tumor cells can survive chemo/radiation therapies through DNA repairment mediated by poly(ADP- ribose) polymerase-1 (PARP-1). PARP-1 inhibitors (PARPis) alone, or in combination with chemotherapy or radiation therapy, have led to substantial gains in the overall survival of cancer patients, by obstructing PARP- catalyzed single DNA repair. With multiple ongoing clinical trials using PARPis to treat glioma, to quantify baseline PARP expression levels through quantitative PARP PET imaging will provide prognostic information to guide future precision treatment. However, none of the current PARP imaging agents under development is brain penetrant, making reliable in vivo quantification of PARP-1 in the brain challenging. Herein, we propose to evaluate several BBB penetrant PARP-1 inhibitors as potential PET imaging agents.

受资助的家长资助摘要因为肿瘤细胞可以通过聚(ADP-)介导的DNA修复在化疗/放射治疗中存活。核糖)聚合酶-1(PARP-1)。PARP-1抑制剂(PARPis)单独使用，或与化疗或放射治疗，通过阻止PARP-1，导致癌症患者的总体存活率大幅提高。催化的单DNA修复。使用PARPis治疗胶质瘤的多项正在进行的临床试验，以量化通过定量PARP PET成像的基线PARP表达水平将提供预后信息指导今后的精准治疗。然而，目前正在开发的PARP显像剂中没有一种是大脑渗透剂，使大脑中PARP-1的体内定量变得可靠，具有挑战性。在此，我们建议评价几种血脑屏障穿透性PARP-1抑制剂作为潜在的PET显像剂。