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）是哺乳动物中最大的细胞表面受体蛋白家族 细胞。在人类中，它们由800多个单独的基因编码，并在人体组织中广泛表达， 他们控制着广泛的生理过程。他们在神经传递中扮演着重要角色， 但也证明在各种癌症中都过表达。而基于有机分子的小 已开发了正电子发射断层扫描（PET）成像剂，用于成像涉及的GPCR 神经传递，在癌细胞上表达的GPCR已针对放射性标记 激素肽。在这方面，生长抑素受体（SSTR），胃蛋白释放的肽受体 （GPCR），神经素受体（NTSR）和血管活性肠道肽受体（VPAC）已是 针对多种具有不同标记肽的癌症类型。这些基于肽的剂已经 然而 小分子类似物的开发可能比肽具有优势，因为它们可以适当设计 调节效力，选择性，亲脂性和细胞渗透性，以免避免组织渗透不良，不良 血清稳定性和快速消除。这将是评估小分子宠物剂的第一项研究 成像GPCR在肿瘤上表达。我们建议将GRPR作为模型系统。近年来，我们的 小组和其他人的重点是孟买（BN）肽类似物的发展。 正电子放射性核素用于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。这些肽类似物中的一些已经在人类试验中评估了最多 突出是68GA-RM2。对反对GRPR作用的现有小分子化合物的调查 鉴定拮抗剂PD176252是开发结合的放射标记类似物的潜在起点 在前列腺和乳腺癌的背景下向GRPR致GRPR。科学的前提是这些小分子类似物 与肽示踪剂相比 因此，作为成像剂可能是优越的。