Novel glutamate conjugates for radiotargeting PSMA

用于放射性靶向 PSMA 的新型谷氨酸缀合物

• 批准号: 6833141
• 负责人: John W Babich
• 金额: $ 32.72万
• 依托单位: MOLECULAR INSIGHT PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6833141
• 关键词: X ray crystallography; aminoacid analog; athymic mouse; carboxypeptidase; cell line; chemical binding; chemical conjugate; chemical synthesis; dipeptides; drug design /synthesis /production; enzyme activity; glutamates; mass spectrometry; neoplasm /cancer radioimmunotherapy; neoplasm /cancer transplantation; neoplastic cell; prostate neoplasms; radiochemistry; radiotracer; surface antigens; xenotransplantation

DESCRIPTION (provided by applicant): The development of novel approaches for radioimmunoimaging and radioimmunotherapy is driven by the high incidence and mortality rate associated with prostate cancer in the United States. One strategy to diagnostic and prognostic markers exploits prostate-specific membrane antigen (PSMA), an integral transmembrane glycoprotein, associated with the prostate epithelium, prostatic tumor cells and the neovasculature of other tumor types, which is also highly homologous to NAALDase (N-acetylated a-Iinked acidic dipeptidase) which releases the neurotransmitter glutamate. A range of PSMA inhibitors have been reported, based on two fundamental structures, phosphonate and phosphinate containing transition state analogues and novel dipeptides connected through a simple urea linkage. One objective of the research is to prepare derivatives of the urea-based inhibitors modified at the terminus not involved with binding to the specificity pocket with an amino acid containing a head group suitable for coordination to the {M(CO)3} *1 core (M = Tc and Re). Our approach relies on our recently developed a novel approach to 99mTc-radiolabeling of peptides based on single amino acid analogues (SAAC) modified to provide three potential donor groups for facial chelation to the {M(CO)3} *1 core (M = Tc or Re). We have demonstrated the rapid and simple introduction of SAAC into bioactive peptides via standard solid phase peptide synthesis protocols and subsequent labeling with 99mTc and Re28 The innovation of this proposal is to incorporate single amino acid chelators into the existing medicinal chemistry knowledge base of inhibitors of PSMA, so as to allow subsequent labeling with 99mTc or 186/1888Re radioisotopes for imaging or therapeutic applications, respectively. The urea-based analogues will be comprised of a glutamate coupled to a single amino acid chelate by a urea linkage through the a-NH2 groups. Representative SAACs include e-derivatives of lysine. The SAACs will be derivatized at the amino terminus with donor groups based on pyridine, imidazole, carboxylate, thiolate and thiazole. Altering the donor group substituents will yield changes in overall charge, hydrophobicity and steric influence. A series of SAAC glutamate conjugates will be prepared as potential NAAG inhibitors allowing the assessment of the influence of factors such as donor group identity, tether length and geometry, steric influences and charge on enzyme inhibition and binding. The {Re(CO)3} *1 complexes of the conjugates will be prepared as models for the {Tc(CO)3} *1 complexes and will be used for biological assays. The 99mTc(CO)3(H20) 3}¿1core is readily prepared using the Isolink TM kit, which has been supplied by Tyco-Mallinckrodt, Inc. The SAAC-urea-glutamate series of complexes will be evaluated for binding and inhibitory activity. Cell uptake studies will be performed using PSMA-positive and PSMA-negative cell lines. Upon evaluation of these results, compounds that demonstrate specific binding in PSMA-positive cells in vitro will be studied further in mice containing both PSMA-positive and PSMA-negative human prostate tumor models.

描述（由申请人提供）： 在美国，与前列腺癌相关的高发病率和死亡率推动了放射免疫成像和放射免疫治疗新方法的发展，一种诊断和预后标记物的策略利用了前列腺特异性膜抗原（PSMA），一种与之相关的完整跨膜糖蛋白。与上皮细胞、前列腺肿瘤细胞和其他肿瘤类型的新血管系统具有高度同源性，NAALDase（N-乙酰化α-连接酸性已报道了一系列可释放神经递质谷氨酸的 PSMA 抑制剂，其基于两种基本结构：含有过渡态类似物的膦酸盐和次膦酸盐以及通过简单的脲键连接的新型二肽。在末端修饰的基于尿素的抑制剂不涉及与含有适合与{M(CO)3}配位的头基的氨基酸的特异性口袋的结合*1 芯（M = Tc 和 Re）。 我们的方法依赖于我们最近开发的一种基于单氨基酸类似物 (SAAC) 的肽 99mTc 放射性标记新方法，该方法经过修改，可提供三个潜在的供体基团，用于与 {M(CO)3} *1 核心进行面部螯合 (M =我们已经证明了通过标准固相肽合成方案以及随后用 99mTc 和 Re28 标记可以快速、简单地将 SAAC 引入生物活性肽。该提案的创新之处在于将单一氨基酸螯合剂纳入现有的 PSMA 抑制剂药物化学知识库中，以便随后分别用 99mTc 或 186/1888Re 放射性同位素进行标记，用于成像或治疗应用。 基于尿素的类似物由通过α-NH 2 基团与单个氨基酸螯合物偶联的谷氨酸组成。代表性的SAAC包括赖氨酸的e-衍生物。SAAC将在氨基末端用供体基团衍生化。基于吡啶、咪唑、羧酸盐、硫醇盐和噻唑改变供体基团取代基会产生变化。将制备一系列 SAAC 谷氨酸盐作为潜在的 NAAG 抑制剂，从而评估供体基团身份、系链缀合物长度和几何形状、空间影响和电荷等因素对酶抑制和结合的影响。 。 缀合物的 {Re(CO)3} *1 复合物将被制备为 {Tc(CO)3} *1 复合物的模型，并将用于生物测定 99mTc(CO)3(H2O) 3}。 ¿ 1core 可以使用 Tyco-Mallinckrodt, Inc. 提供的 Isolink TM 试剂盒轻松制备。SAAC-尿素-谷氨酸系列复合物将使用 PSMA 阳性和细胞摄取研究进行结合和抑制活性评估。 PSMA 阴性细胞系评估这些结果后，将在含有 PSMA 阳性和 PSMA 阴性人类前列腺肿瘤模型的小鼠中进一步研究在体外证明与 PSMA 阳性细胞特异性结合的化合物。