Development of a novel PET imaging agent for prostate cancer

开发一种新型前列腺癌 PET 显像剂

• 批准号: 8334190
• 负责人: Beatrice Langton-Webster
• 金额: $ 114.51万
• 依托单位: CANCER TARGETED TECHNOLOGY, LLC
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-28 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8334190
• 关键词: Affinity; Aftercare; Androgens; Animal Model; Animals; Antibodies; Binding; Biochemical; Biological; Biological Markers; Biological Models; Cancer Prognosis; Capromab Pendetide; Characteristics; Chemicals; Chemistry; Clinical; Clinical Pathology; Clinical Trials; Coupled; Coupling; Cyclotrons; Data; Detection; Development; Diagnosis; Diagnostic; Diagnostic Imaging; Diagnostic Neoplasm Staging; Drug Kinetics; Effectiveness; Endothelium; Ensure; Evaluation; Fluorides; Fluorine; Foundations; Generations; Glutamate Carboxypeptidase II; Goals; Half-Life; Histopathology; Hospitals; Hour; Image; Investigation; Investigational New Drug Application; Kinetics; Label; Lead; Lymph; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Methods; Monitor; Mus; Outcome; Pathway interactions; Pharmaceutical Preparations; Phase; Positron-Emission Tomography; Property; Prostatic Neoplasms; Radiation therapy; Radioactive; Radioisotopes; Reporter; Research; Safety; Solid; Staging; Structure; System; Testing; Therapeutic; Toxicokinetics; Toxicology; Tracer; Translating; United States; Work; Xenograft Model; Xenograft procedure; analog; base; cancer cell; cancer imaging; clinically relevant; design; imaging modality; imaging probe; in vivo; inhibitor/antagonist; innovation; neovasculature; novel; overexpression; peptidomimetics; public health relevance; safety testing; single photon emission computed tomography; small molecule; tumor; uptake

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 an F-18 labeled irreversible inhibitor to PSMA coupled with PET scan could be used for prostate cancer staging as well as localization of lymph and bone metastasis. The rationale for undertaking the proposed research is that optimized F-18 labeled PSMA imaging constructs will serve as the foundation for a clinically relevant imaging modality for the diagnosis and post-treatment assessment of prostate cancer. This labeling needs to be in a chemistry that is readily available to the growing number of hospitals with cyclotrons and PET scanners. Additionally, demonstrating the effectiveness of our prostate tumor imaging probes in vivo and safety in animal models will serve as initial steps for the subsequent development of a radiotherapeutic agent for clinical use. The PIs will test the central hypothesis and accomplish the overall objective of this application by pursuing the following specific aims: Phase I 1) optimize the nucleophilic 18F labeling of CTT-54; 2) chemical/biochemical evaluation of lead compounds from AIM 1. Phase II Aims: 1) In vivo evaluation of selected PET tracers produced by Phase I and In vivo testing of lead compound for safety and pharmacokinetics Milestones include: labeling of CTT-54 with 1) an overall yield of 40%, high specific activity (>500 Ci/mmole), stability of >90% for up to 6 hours, 2) targeting of prostate cancer in mouse xenograft model and 3) a safety profile that will support filing an IND. The proposed work is expected to yield the following outcomes. First, a labeling chemistry that can be used in any one of the 277 PET centers in the United States. Secondly, a safety profile of the labeled lead compound that would support an investigation new drug application with the FDA. The high- affinity small-molecule targeting platform upon which our lead compound is based is unique compared to other targeting molecules because it has demonstrated irreversible binding to the prostate tumor biomarker PSMA. These unique characteristics make this compound is 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 goal of this application is to develop a novel clinically relevant diagnostic for prostate cancer that capitalizes on the potency and specific affinity of small-molecule inhibitors to PSMA. The overall objectives of this application are to further the development our primary PSMA inhibitor, CTT-54 by optimizing the 18F-labeling chemistry, demonstrating PET imaging of prostate cancer in animal models systems, and initiate toxicology studies in support of clinical trials. The preliminary data presented demonstrates that a small molecule inhibitor of PSMA can target and image prostate cancer when coupled to a radionuclide tracer.

描述(申请人提供)：PSMA是前列腺癌预后的重要生物标志物，由于其在晚期、雄激素非依赖性和转移性前列腺癌细胞中的表达受到限制，因此是合适的治疗靶点。虽然目前临床上只有一种PSMA靶向SPECT显像剂(基于抗体的ProstaScint)，但PSMA的高亲和力小分子抑制剂还没有被完全开发出来用于前列腺癌的靶向和成像。这项应用的总体目标是优化一种新的成像探针，用于体内检测PSMA阳性的前列腺肿瘤。我们提出的工作的中心假设是，F-18标记的PSMA不可逆抑制物结合PET扫描可以用于前列腺癌分期以及淋巴和骨转移的定位。开展这项拟议研究的理由是，优化的F-18标记PSMA成像结构将作为前列腺癌诊断和治疗后评估的临床相关成像模式的基础。这种标签需要使用一种化学物质，以便越来越多的拥有回旋加速器和PET扫描仪的医院随时可以获得。此外，在体内证明我们的前列腺癌成像探针的有效性和在动物模型中的安全性，将作为后续开发用于临床的放射治疗剂的第一步。PIs将检验中心假设并通过追求以下具体目标来实现这一应用的总体目标：第一阶段1)优化CTT-54的亲核18F标记；2)来自AIM 1的先导化合物的化学/生物化学评价。第二阶段目标：1)对第一阶段产生的选定的PET示踪剂进行体内评估，并对先导化合物进行体内安全性和药代动力学里程碑测试包括：1)CTT-54的总收率为40%，高比活度(&GT；500Ci/Mmole)，&GT的稳定性；90%，长达6小时，2)靶向前列腺癌在小鼠异种移植模型中，以及3)将支持提交IND的安全性简介。拟议的工作预计将产生以下结果。首先，一种可以在美国277个PET中心中的任何一个使用的标记化学。其次，标记的先导化合物的安全性概况，这将支持FDA对新药申请的调查。我们的先导化合物所基于的高亲和力小分子靶向平台与其他靶向分子相比是独一无二的，因为它已经显示出与前列腺癌生物标记物PSMA的不可逆结合。这些独特的特性使该化合物成为更具吸引力的前列腺癌结合靶向平台，具有增强的翻译潜力。预计这项拟议的工作将产生优化的前列腺癌显像剂，这一点很重要，因为更好的检测试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。 公共卫生相关性：这项应用的总体目标是开发一种新的前列腺癌临床相关诊断方法，利用小分子抑制剂对PSMA的效力和特异性亲和力。这项应用的总体目标是通过优化18F标记化学，进一步开发我们的主要PSMA抑制剂CTT-54，在动物模型系统中展示前列腺癌的PET成像，并启动毒理学研究，以支持临床试验。提供的初步数据表明，当PSMA的小分子抑制剂与放射性核素示踪剂结合时，可以靶向前列腺癌并进行成像。