Probe Optimization for Prostate Cancer Detection

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。我们对拟议工作的中心假设是，对多肽类PSMA抑制剂的核心和连接物成分进行结构修改将改善由这些小分子构建的成像探针的肿瘤摄取和清除性能。开展这项拟议研究的理由是，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，在体内证明我们的前列腺癌成像探针的有效性，将作为基于总体设计的后续放射治疗药物开发的初步验证步骤。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：1)优化PSMA的肽类抑制剂的结构，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)显像剂的当前设计；以及3)开发基于PSMA靶向试剂的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，设计用于开发远离PSMA催化中心的辅助结合部位的新型第二代PSMA靶向剂有望既表现出对PSMA的更高亲和力，又表现出更强的亲脂性，以改善用这些类型的试剂观察到的快速肾脏清除。其次，将开发用于前列腺癌检测的PET显像剂，并改善其药代动力学。第三，将开发用于前列腺癌的多功能SPECT显像剂，有可能用治疗性放射性核素取代成像放射性核素。这些药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，因为它们已经证明了与前列腺癌生物标记物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优化一种新的前列腺癌成像探针，用于体内前列腺癌的检测。这项拟议的工作很重要，因为它将证明开发一种与临床相关的前列腺癌检测试剂的可行性，以帮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。预计这些制剂设计的简单性将不会出现与开发抗体等生物靶向制剂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.