PSMA-based PET Ligands for Prostate Cancer Imaging

用于前列腺癌成像的基于 PSMA 的 PET 配体

• 批准号: 7099180
• 负责人: MARTIN G POMPER
• 金额: $ 18.62万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-07 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7099180
• 关键词: SCID mouse; bioimaging /biomedical imaging; chemical synthesis; disease /disorder model; fluorine; hydropathy; inhibitor /antagonist; nanotechnology; neoplasm /cancer classification /staging; neoplasm /cancer diagnosis; neoplasm /cancer imaging; neoplasm /cancer radiodiagnosis; pharmacokinetics; positron emission tomography; prostate neoplasms; prostate specific antigen; protein localization; radiopharmacology; radiotracer; single photon emission computed tomography; small molecule; surface antigens; technology /technique development; urea; xenotransplantation

DESCRIPTION (provided by applicant): One (1) in every 6 American men will be diagnosed with prostate cancer (PCa) over the course of their lifetimes, with 31,000 dying each year from the disease. Therapy for locally advanced disease remains contentious and an increasing number of options are available. More accurate staging would facilitate treatment decisions and lead to a better outcome for patients. In particularly dire need is a way to detect small lesions, i.e., recurrent tumors in the surgical bed, local lymph node invasion and other subtle manifestations of the disease in men with an elevated serum prostate specific antigen (PSA) but no other obvious symptoms. The current standard of PCa staging is shifting. Metabolic imaging techniques such as magnetic resonance spectroscopy (MRS), positron emission tomography (PET) and single photon emission computed tomography (SPECT) are gaining favor over the anatomic techniques of computed tomography (CT) and MR, which merely detect enlarged tissue, revealing nothing of its underlying physiology. In particular, SPECT using the radiolabeled monoclonal antibody (mAb) 1111n-capromab pendetide (Cyt-356, ProstaScint) is being used in the clinic for identifying candidates for salvage radiotherapy. ProstaScint takes advantage of binding to the prostate specific membrane antigen (PSMA), a cell surface protein that has enzymatic activity and is becoming increasingly recognized as an important prognostic factor and marker of androgen-independent disease. Because of the well-known complexity of obtaining and interpreting ProstaScint images as well as the inherently difficult pharmacokinetics of antibody-mediated imaging and therapy, we have embarked upon a program that focuses on the development of small molecule probes for PSMA-based PCa imaging. Those probes are based on our initial success in synthesizing inhibitors of glutamate carboxypeptidase II (GCPII, a.k.a. N-acetylated-a-linked acidic dipeptidase or NAALADase) because PSMA possesses glutamate carboxypeptidase activity and has a nearly identical pharmacological and molecular profile to GCPII. Although we have achieved the fundamentals of success with regard to a new PET-based imaging agent for PCa in this fashion, we intend to expand upon that by synthesizing 9 new PET radiopharmaceuticals and testing them using the GE explore Vista small animal PET imaging system.

描述（由申请人提供）：每 6 名美国男性中就有一 (1) 人在其一生中会被诊断出患有前列腺癌 (PCa)，每年有 31,000 人死于该疾病。局部晚期疾病的治疗仍然存在争议，并且有越来越多的选择。更准确的分期将有助于治疗决策并为患者带来更好的结果。特别迫切需要一种检测小病变的方法，即在血清前列腺特异性抗原（PSA）升高但没有其他明显症状的男性中，手术床上的复发性肿瘤、局部淋巴结侵犯和疾病的其他微妙表现。当前 PCa 分期的标准正在发生变化。磁共振波谱 (MRS)、正电子发射断层扫描 (PET) 和单光子发射计算机断层扫描 (SPECT) 等代谢成像技术比计算机断层扫描 (CT) 和 MR 等解剖技术更受青睐，后者仅检测扩大的组织，揭示了与它的基本生理学无关。特别是，使用放射性标记单克隆抗体 (mAb) 1111n-capromab pendetide（Cyt-356，ProstaScint）的 SPECT 在临床中用于识别挽救性放射治疗的候选者。 ProstaScint 利用与前列腺特异性膜抗原 (PSMA) 的结合，这是一种具有酶活性的细胞表面蛋白，并且越来越被认为是雄激素非依赖性疾病的重要预后因素和标志物。由于获取和解释 ProstaScint 图像的复杂性众所周知，以及抗体介导的成像和治疗的药代动力学本身就很困难，我们已经开始了一个项目，重点开发用于基于 PSMA 的 PCa 成像的小分子探针。这些探针基于我们最初成功合成谷氨酸羧肽酶 II（GCPII，又名 N-乙酰化-α-连接酸性二肽酶或 NAALADase）抑制剂，因为 PSMA 具有谷氨酸羧肽酶活性，并且具有与 GCPII 几乎相同的药理学和分子特征。尽管我们已经以这种方式在基于 PET 的新型 PCa 成像剂方面取得了成功，但我们打算通过合成 9 种新型 PET 放射性药物并使用 GE explore Vista 小动物 PET 成像系统对其进行测试来扩展这一点。