Development of a novel PET imaging agent for prostate cancer

描述（由申请人提供）：PSMA是前列腺癌预后的重要生物标志物，并且由于其主要在晚期、雄激素非依赖性和转移性前列腺癌细胞上的限制性表达，是治疗的适当靶标。虽然目前只有一种用于SPECT成像的临床PSMA靶向剂（基于抗体的Prostascint），但PSMA的高亲和力小分子抑制剂尚未被充分开发用于靶向和成像前列腺癌。本申请的总体目标是优化用于体内检测PSMA阳性前列腺肿瘤的新型成像探针。我们对所提出的工作的中心假设是，F-18标记的PSMA不可逆抑制剂与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。进行拟议研究的基本原理是，优化的F-18标记的PSMA成像结构将作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。这种标签需要在一个化学，是容易获得越来越多的医院与回旋加速器和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在动物模型中的安全性将作为随后开发用于临床的放射性药物的初始步骤。PI将检验中心假设，并通过追求以下特定目标实现本申请的总体目标：I期1）优化CTT-54的亲核18 F标记; 2）AIM 1中先导化合物的化学/生物化学评价。第二阶段目标：1）I期生产的所选PET示踪剂的体内评价和先导化合物的安全性和药代动力学的体内测试CTT-54的标记：1）总产率为40%，高比活性（>500 Ci/mmole），稳定性>90%，长达6小时，2）在小鼠异种移植模型中靶向前列腺癌和3）支持提交IND的安全性特征。预计拟议的工作将产生以下结果。首先，一种标记化学品，可用于美国277个PET中心中的任何一个。第二，标记的先导化合物的安全性特征，这将支持FDA的新药申请调查。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特的，因为它已证明与前列腺肿瘤生物标志物PSMA的不可逆结合。这些独特的特性使得该化合物是一个更有吸引力的前列腺肿瘤结合的靶向平台，具有增强的翻译潜力。预计拟议的工作将导致优化的前列腺癌成像剂，这是重要的，因为更好的检测剂是必不可少的，以协助临床医生分期前列腺癌，开发个性化治疗，并监测治疗。 公共卫生相关性：本申请的总体目标是开发一种新的前列腺癌临床相关诊断方法，该方法利用小分子抑制剂对PSMA的效力和特异性亲和力。本申请的总体目标是通过优化18F标记化学，在动物模型系统中展示前列腺癌的PET成像，并启动支持临床试验的毒理学研究，进一步开发我们的主要PSMA抑制剂CTT-54。所呈现的初步数据表明，当与放射性核素示踪剂偶联时，PSMA的小分子抑制剂可以靶向前列腺癌并对其成像。

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.