Small Molecule GPCR Ligands for Oncologic Imaging

用于肿瘤成像的小分子 GPCR 配体

基本信息

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
项目类别：
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

项目摘要

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。