Small Molecule GPCR Ligands for Oncologic Imaging

用于肿瘤成像的小分子 GPCR 配体

• 批准号: 9977505
• 负责人: Buck E. Rogers
• 金额: $ 19.68万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977505
• 关键词: Affinity; Animals; Binding; Biodistribution; Biological Models; Bombesin; Bombesin Receptor; Breast Cancer Cell; Cell Surface Receptors; Cells; Detection; Development; Dissociation; Emission-Computed Tomography; Family; Future; G-Protein-Coupled Receptors; Genes; Glutamine; Goals; Human; Image; Immunohistochemistry; In Situ Hybridization; In Vitro; Individual; Kinetics; Label; Ligands; Malignant Neoplasms; Malignant neoplasm of prostate; Mammalian Cell; Messenger RNA; Mus; Neurotensin Receptors; Normal tissue morphology; PC3 cell line; Penetration; Peptide Receptor; Peptides; Permeability; Physiological Processes; Play; Positron; Positron-Emission Tomography; Property; Publications; Quantitative Autoradiography; Radioactive; Radioisotopes; Radiolabeled; Radionuclide Imaging; Radiopharmaceuticals; Role; Serum; Somatostatin Receptor; Surveys; T47D; Tissues; Tracer; Tumor Tissue; Vasoactive Intestinal Peptide Receptors; Xenograft procedure; analog; base; cancer cell; cancer imaging; cancer type; design; human tissue; imaging agent; imaging study; in vivo; insight; lipophilicity; malignant breast neoplasm; metabolic abnormality assessment; mouse model; neurotransmission; novel; overexpression; peptide analog; peptide hormone; piperidine; pre-clinical; prostate cancer cell; radiochemical; radioligand; radiotracer; receptor; small molecule; subcutaneous; success; tumor; tumor xenograft; uptake

Abstract G protein-coupled receptors (GPCRs) are the largest family of cell surface receptor proteins in mammalian cells. In humans, they are encoded by over 800 individual genes and are widely expressed in human tissues, where they control a wide range of physiological processes. They play a prominent role in neurotransmission, but also have been shown to be overexpressed in a variety of cancers. While small organic molecule based positron-emission tomography (PET) imaging agents have been developed for imaging GPCRs involved in neurotransmission, GPCRs that are expressed on cancer cells have been targeted with radioactively labeled hormone peptides. In this regard, somatostatin receptors (SSTRs), gastrin-releasing peptide receptors (GPCRs), neurotensin receptors (NTSRs), and vasoactive intestinal peptide receptors (VPACs) have been targeted in a variety of cancer types with different radiolabeled peptides. These peptide based agents have had some success for both imaging and therapy of tumors (particularly the SSTR peptides), however, the development of small molecule analogs may have advantages over peptides since they can be suitably designed to modulate potency, selectivity, lipophilicity, and cell permeability to possibly avoid poor tissue penetration, poor serum stability, and quick elimination. This would be the first study to evaluate a small molecule PET agent for imaging GPCRs expressed on tumors. We propose to target GRPR as a model system. In recent years, our group and others have focused on the development of bombesin (BN) peptide analogs radiolabeled with positron-emitting radionuclides for positron-emission tomographic (PET) imaging of GRPR-positive tumors in preclinical mouse models. Some of these peptide analogs have been evaluated in human trials with the most prominent being 68Ga-RM2. A survey of the existing small molecule compounds which act against GRPR has identified the antagonist, PD176252, as a potential starting point for developing radiolabeled analogs that bind to GRPR in the context of prostate and breast cancer. The scientific premise is that these small molecule analogs will have different properties in terms of cell uptake and dissociation kinetics as compared to peptide tracers and thus may be superior as imaging agents.

抽象的 G 蛋白偶联受体 (GPCR) 是哺乳动物细胞表面受体蛋白的最大家族 细胞。在人类中，它们由 800 多个个体基因编码，并在人体组织中广泛表达， 它们控制着广泛的生理过程。它们在神经传递中发挥着重要作用， 但也已被证明在多种癌症中过度表达。而基于有机小分子 正电子发射断层扫描 (PET) 显像剂已被开发用于对参与的 GPCR 进行成像 神经传递，癌细胞上表达的 GPCR 已被放射性标记为目标 激素肽。在这方面，生长抑素受体（SSTR）、胃泌素释放肽受体 (GPCR)、神经降压素受体 (NTSR) 和血管活性肠肽受体 (VPAC) 使用不同的放射性标记肽针对多种癌症类型。这些基于肽的药物具有 在肿瘤成像和治疗（特别是 SSTR 肽）方面取得了一些成功，但是 小分子类似物的开发可能比肽具有优势，因为它们可以进行适当的设计 调节效力、选择性、亲脂性和细胞渗透性，以避免组织渗透性差、 血清稳定性好，消除快。这将是第一项评估小分子 PET 制剂的研究 对肿瘤上表达的 GPCR 进行成像。我们建议将 GRPR 作为模型系统。近年来，我们的 小组和其他人专注于开发用放射性标记的铃蟾肽（BN）肽类似物 正电子发射放射性核素用于 GRPR 阳性肿瘤的正电子发射断层扫描 (PET) 成像 临床前小鼠模型。其中一些肽类似物已在人体试验中进行了评估，效果最显着 突出的是68Ga-RM2。对现有对抗 GRPR 的小分子化合物进行了调查 确定了拮抗剂 PD176252，作为开发结合的放射性标记类似物的潜在起点 GRPR 在前列腺癌和乳腺癌的背景下。科学前提是这些小分子类似物 与肽示踪剂相比，在细胞摄取和解离动力学方面将具有不同的特性 因此作为显像剂可能是优越的。