Probe Optimization for Prostate Cancer Detection

前列腺癌检测的探针优化

基本信息

批准号：
8212357
负责人：
Clifford Berkman
金额：
$ 45.9万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-05 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8212357
关键词：
Address Affinity Aftercare Androgens Animal Model Animals Antibodies Antigen Targeting Attention Binding Binding Sites Biodistribution Biological Biological Markers Blood Circulation Cancer Biology Cancer Detection Cancer Prognosis Capromab Pendetide Carbonic Anhydrase Inhibitors Cell Surface Receptors Cell surface Characteristics Charge Chemicals Chemistry Clinical Clinical Sciences Coupled Cyclotrons Data Detection Development Diagnosis Diagnostic Diagnostic Imaging Discipline of Nuclear Medicine Disease Doctor of Medicine Doctor of Philosophy Drug Kinetics Effectiveness Endothelium Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Evaluation Excretory function Exhibits Fluorine Foundations Generations Glutamate Carboxypeptidase II Goals Half-Life Hospitals Human Image Label Malignant Neoplasms Malignant neoplasm of prostate Metastatic Prostate Cancer Modeling Modification Molecular Weight Monitor Mus Nature Neoplasm Metastasis New Agents Nuclear Organic Chemistry Outcome Pharmacodynamics Positron-Emission Tomography Procedures Property Prostate Prostatic Neoplasms Radiation therapy Radioisotopes Radiolabeled Radionuclide Imaging Radiopharmaceuticals Renal clearance function Reporter Research Solid Staging Structure Structure of base of prostate Technology Testing Therapeutic Therapeutic Agents Translating Translations Urea Validation Work Xenograft procedure Zinc analog anticancer research base cancer cell cancer imaging carina clinically relevant commercialization cost effective design experience functional group imaging modality imaging probe improved in vitro Assay in vivo inhibitor/antagonist innovation insight lipophilicity molecular imaging multidisciplinary neovasculature novel novel diagnostics novel therapeutics peptidomimetics phosphoramidate pre-clinical public health relevance radiotracer scaffold single photon emission computed tomography small molecule success sulfamate targeted delivery tool tumor uptake

项目摘要

DESCRIPTION (provided by applicant): PSMA is an important biomarker for prostate cancer prognosis and an appropriate target for therapy due to its restricted expression mainly on late-stage, androgen-independent and metastatic prostate cancer cells. While currently there is only one clinical PSMA targeted agent for SPECT imaging (the antibody-based Prostascint), high-affinity small-molecule inhibitors to PSMA have not been fully exploited for targeting and imaging prostate cancer. The overall objective of this application is to optimize a novel imaging probe for the in vivo detection of PSMA positive prostate tumors. Our central hypothesis for the proposed work is that structural modifications made to the core and linker components of peptidomimetic PSMA inhibitors will improve tumor uptake and clearance properties of imaging probes constructed from these small-molecules. The rationale for undertaking the proposed research is that optimized PSMA imaging constructs will serve as the foundation for translating this research into a clinically relevant imaging modality for the diagnosis and post-treatment assessment of prostate cancer. Additionally, demonstrating the effectiveness of our prostate tumor imaging probes in vivo will serve as initial validation steps for the subsequent development of radiotherapeutic agents based on the general design. The PIs will test the central hypothesis and accomplish the overall objective of this application by pursuing the following specific aims: 1) refine the structure of peptidomimetic inhibitors of PSMA for enhanced affinity and lipophilicity; 2) optimize the current design of the prostate cancer positron emission tomography (PET) imaging agent; and 3) develop single photon emission computed tomography (SPECT) imaging agents for prostate cancer based on PSMA targeting agents. The proposed work is expected to yield the following outcomes. First, novel 2nd-generation PSMA-targeting agents designed to exploit auxiliary binding sites remote from the catalytic center of PSMA are expected to exhibit both improved affinity towards PSMA and increased lipophilicity to ameliorate the rapid renal clearance observed with these types of agents. Secondly, PET imaging agents for prostate cancer detection with improved pharmacokinetics will be developed. Thirdly, versatile SPECT imaging agents for prostate cancer will be developed with the potential for substituting the imaging radionuclide with a therapeutic radionuclide. The high-affinity small-molecule targeting platform upon which these agents are based is unique compared to other targeting molecules because they have demonstrated irreversible or slowly-reversible binding to the prostate tumor biomarker PSMA. These unique characteristics make these compounds a more attractive targeting platform for prostate tumor binding with enhanced translational potential. It is expected that the proposed work will result in optimized prostate cancer imaging agents, which is important because better detection agents are essential for assisting clinicians in staging prostate cancer, developing personalized therapy, and monitoring treatment. PUBLIC HEALTH RELEVANCE: The overall objective of this application is to optimize a novel imaging probe for prostate cancer for the in vivo detection of prostate tumors. The proposed work is important, in that it will demonstrate the feasibility of developing a clinically-relevant detection agent for prostate cancer for assisting clinicians in staging prostate cancer, developing personalized therapy, and monitoring treatment. It is expected that the simplicity of the designs for these agents will not be prone to the same technological and regulatory issues associated with the development of biological targeting agents such as antibodies.

描述（由申请人提供）：PSMA 是前列腺癌预后的重要生物标志物，也是适当的治疗靶点，因为它主要在晚期、雄激素非依赖性和转移性前列腺癌细胞中受限表达。虽然目前临床上只有一种用于 SPECT 成像的 PSMA 靶向药物（基于抗体的前列腺素），但 PSMA 的高亲和力小分子抑制剂尚未充分用于前列腺癌的靶向和成像。该应用的总体目标是优化一种新型成像探针，用于 PSMA 阳性前列腺肿瘤的体内检测。我们对拟议工作的中心假设是，对拟肽 PSMA 抑制剂的核心和连接体成分进行结构修饰将改善由这些小分子构建的成像探针的肿瘤摄取和清除特性。进行拟议研究的理由是，优化的 PSMA 成像结构将作为将该研究转化为临床相关成像模式的基础，用于前列腺癌的诊断和治疗后评估。此外，证明我们的前列腺肿瘤成像探针在体内的有效性将作为后续基于总体设计开发放射治疗剂的初步验证步骤。 PI将测试中心假设并通过追求以下具体目标来实现本申请的总体目标：1）完善PSMA的拟肽抑制剂的结构以增强亲和力和亲脂性； 2）优化目前前列腺癌正电子发射断层扫描（PET）显像剂的设计； 3）基于PSMA靶向剂开发用于前列腺癌的单光子发射计算机断层扫描（SPECT）成像剂。拟议的工作预计将产生以下成果。首先，设计用于利用远离 PSMA 催化中心的辅助结合位点的新型第二代 PSMA 靶向剂预计将表现出对 PSMA 的亲和力提高和亲脂性增加，以改善使用这些类型的药物观察到的快速肾脏清除率。其次，将开发具有改进的药代动力学的用于前列腺癌检测的PET成像剂。第三，将开发用于前列腺癌的多功能 SPECT 成像剂，具有用治疗性放射性核素替代成像放射性核素的潜力。与其他靶向分子相比，这些药物所基于的高亲和力小分子靶向平台是独特的，因为它们已被证明与前列腺肿瘤生物标志物 PSMA 具有不可逆或缓慢可逆的结合。这些独特的特性使这些化合物成为前列腺肿瘤结合更具吸引力的靶向平台，并具有增强的转化潜力。预计所提出的工作将产生优化的前列腺癌成像剂，这很重要，因为更好的检测剂对于协助临床医生对前列腺癌进行分期、开发个性化治疗和监测治疗至关重要。公共健康相关性：本申请的总体目标是优化一种新型前列腺癌成像探针，用于前列腺肿瘤的体内检测。拟议的工作很重要，因为它将证明开发临床相关的前列腺癌检测剂的可行性，以协助临床医生对前列腺癌进行分期、开发个性化治疗和监测治疗。预计这些药剂的设计简单，不会容易出现与抗体等生物靶向剂的开发相关的相同技术和监管问题。