Probe Optimization for Prostate Cancer Detection

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，对拟肽PSMA抑制剂的核心和连接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。开展本研究的基本原理是，优化的PSMA成像结构将作为将本研究转化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。此外，在体内证明前列腺肿瘤成像探针的有效性将作为基于一般设计的放射治疗药物后续开发的初始验证步骤。PIs将通过追求以下具体目标来测试中心假设并实现本应用的总体目标：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靶向剂开发前列腺癌单光子发射计算机断层扫描（SPECT）显像剂。拟议的工作预计将产生以下结果。首先，新的第二代PSMA靶向药物旨在利用远离PSMA催化中心的辅助结合位点，预计将表现出对PSMA的亲和力提高和亲脂性提高，以改善这些类型的药物所观察到的快速肾脏清除。其次，将开发改善药代动力学的前列腺癌PET显像剂。第三，前列腺癌的多功能SPECT显像剂将被开发出来，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一无二的，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 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.