Probe Optimization for Prostate Cancer Detection

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而成为合适的治疗靶标。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完全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，对拟肽PSMA抑制剂的核心和接头组分进行的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成像结构将作为将这项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初步验证步骤，为后续开发的放射性药物的基础上的一般设计。PI将检验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）改进PSMA的拟肽抑制剂的结构以增强亲和力和亲脂性; 2）优化前列腺癌正电子发射断层扫描（PET）成像剂的当前设计;以及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靶向剂预期表现出对PSMA的改善的亲和力和增加的亲脂性，以改善用这些类型的药剂观察到的快速肾清除。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显像剂，其具有用治疗性放射性核素替代显像性放射性核素的潜力。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，因为它们已证明与前列腺肿瘤生物标志物PSMA的不可逆或缓慢可逆结合。这些独特的特性使这些化合物成为具有增强的翻译潜力的前列腺肿瘤结合的更有吸引力的靶向平台。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优化用于前列腺癌的新型成像探针，用于前列腺肿瘤的体内检测。拟议的工作是重要的，因为它将证明开发临床相关的前列腺癌检测剂的可行性，以帮助临床医生分期前列腺癌，开发个性化治疗和监测治疗。预期这些试剂的设计的简单性将不会倾向于与开发生物靶向试剂如抗体相关的相同技术和监管问题。

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.