Inhibitor-Directed Imaging of Prostate Cancer

描述（由申请人提供）：紧密结合的小分子抑制剂对前列腺特异性膜抗原（PSMA）的抑制尚未完全用于化疗或成像策略。我们的长期目标是利用细胞表面水解酶紧密结合抑制剂的效力和特异性亲和力，为细胞毒性或显像剂开发新的递送机制。本R21应用的总体目标是证明PMSA的有效抑制剂的概念，PMSA具有放射性核素螯合基序，当与锝-99m （Tc-99m）结合时，将选择性地标记前列腺癌细胞进行SPECT（单光子发射计算机断层扫描）。我们提出的工作的中心假设是，配备金属螯合基序的PSMA小分子抑制剂可以将放射性核素特异性地传递给表达PSMA的前列腺癌细胞。开展这项拟议研究的基本原理是，一旦我们证明携带放射性核素的PSMA强效小分子抑制剂可以选择性地递送到表达PSMA的细胞中，它将在随后的R01提案中作为开发前列腺癌新治疗和成像技术的概念证明。首先使用模块化合成方法生成具有金属螯合基序的选择性PSMA抑制剂库。当装载Tb（lll）或Eu（lll）时，这些拴系金属螯合抑制剂的荧光特性将允许通过荧光显微镜和流式细胞术对这些探针进行体外评估。最后，螯合剂拴系抑制剂将装载99Tc，选择性地将这种成像放射性核素特异性地递送到表达psma的癌细胞。这些结果预期的积极影响是为前列腺癌的新诊断策略奠定基础。这些成就很重要，因为这些新的PSMA抑制剂可以在以后进行修饰，以传递其他适合前列腺癌治疗应用的放射性核素。

DESCRIPTION (provided by applicant): The inhibition of prostate-specific membrane antigen (PSMA) by tight-binding small-molecule inhibitors has not been fully exploited for chemotherapeutic or imaging strategies. Our long-term goal is to develop novel delivery mechanisms for either cytotoxic or imaging agents that capitalize on the potency and specific affinity of tight-binding inhibitors for cell-surface hydrolytic enzymes. The overall objective of this R21 application is to prove the concept that potent inhibitors of PMSA which bear a radionuclide-chelating motif that, when bound to technetium-99m (Tc-99m), will selectively tag prostate cancer cells for SPECT (single photon emission computed tomography). Our central hypothesis for the proposed work is that small-molecule inhibitors of PSMA outfitted with a metal-chelating motif can deliver radionuclides specifically to prostate cancer cells that express PSMA. The rationale for undertaking the proposed research is that, once we demonstrate that potent small-molecule inhibitors of PSMA bearing a radionuclide can be selectively delivered to PSMA-expressing cells, it will serve as a proof-of-concept for the development of novel therapeutic and imaging technology for prostate cancer in a subsequent R01 proposal. A library of selective PSMA inhibitors possessing a metal-chelating motif will first be generated using a modular synthetic approach. When loaded with Tb(lll) or Eu(lll), the fluorescent properties of these tethered metal-chelate inhibitors will allow for in vitro evaluation of these probes by fluorescence microscopy and flow cytometry. Lastly, the chelator-tethered inhibitors will be loaded with 99Tc to selectively deliver this imaging radionuclide specifically to PSMA-expressing cancer cells. The expected positive impact of these results is that a foundation for new diagnostic strategies for prostate cancer will be established. These accomplishments are important, because these novel inhibitors of PSMA can later modified to deliver other radionuclides suitable for therapeutic applications for prostate cancer.