Development of a novel PET imaging agent for prostate cancer

描述（由申请人提供）：PSMA主要在晚期、雄激素非依赖性和转移性前列腺癌细胞中表达受限，是前列腺癌预后的重要生物标志物，也是合适的治疗靶点。虽然目前只有一种用于SPECT成像的PSMA靶向药物（基于抗体的Prostascint），但PSMA的高亲和力小分子抑制剂尚未完全用于前列腺癌的靶向和成像。本应用的总体目标是优化一种新的成像探针，用于PSMA阳性前列腺肿瘤的体内检测。我们提出的工作的中心假设是，F-18标记的不可逆PSMA抑制剂与PET扫描结合可用于前列腺癌分期以及淋巴和骨转移的定位。开展本研究的基本原理是，优化的F-18标记PSMA成像构建体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。这种标签必须是一种化学物质，便于越来越多的医院使用回旋加速器和PET扫描仪。此外，证明我们的前列腺肿瘤成像探针在体内的有效性和动物模型的安全性将作为后续开发用于临床的放射治疗药物的第一步。pi将通过追求以下具体目标来检验中心假设并实现本申请的总体目标：第一阶段1)优化CTT-54的亲核18F标记；2) AIM中先导化合物的化学/生化评价第二阶段目标:1)体内评价选择宠物追踪器产生的阶段我和体内的铅化合物测试安全性和药物动力学的里程碑包括:标签的CTT-54 1)整体收益率为40%,比活度高(> 500 Ci / mmole), > 90%的稳定时间长达6小时,2)针对前列腺癌异种移植物模型和3)的安全性支持申请一个印第安纳州。该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签化学。其次，标记的先导化合物的安全性概况，以支持FDA对新药申请的调查。与其他靶向分子相比，我们的先导化合物所基于的高亲和力小分子靶向平台是独一无二的，因为它已被证明与前列腺肿瘤生物标志物PSMA具有不可逆的结合。这些独特的特性使该化合物成为前列腺肿瘤结合的更有吸引力的靶向平台，具有增强的翻译潜力。我们期望这项工作能够优化前列腺癌显像剂，这是非常重要的，因为更好的检测剂对于帮助临床医生分期前列腺癌、开发个性化治疗和监测治疗至关重要。

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 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.