Small Molecule GPCR Ligands for Oncologic Imaging

摘要 G蛋白偶联受体（GPCRs）是哺乳动物细胞表面最大的受体蛋白家族 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， 它们控制着一系列的生理过程它们在神经传递中起着重要作用， 而且已经显示在多种癌症中过表达。虽然基于小有机分子 正电子发射断层扫描（PET）成像剂已经被开发用于成像涉及以下的GPCR： 在神经传递中，在癌细胞上表达的GPCR已经被放射性标记的靶向 激素肽在这方面，生长抑素受体（SSTR）、胃泌素释放肽受体（GAR）、 GPCR、神经降压素受体（NTSR）和血管活性肠肽受体（VPAC）已经被广泛应用于治疗糖尿病。 用不同的放射性标记肽靶向多种癌症类型。这些基于肽的药剂具有 在肿瘤的成像和治疗（特别是SSTR肽）方面取得了一些成功，然而， 小分子类似物的开发可能比肽具有优势，因为它们可以适当地设计， 为了调节效力、选择性、亲脂性和细胞渗透性，以可能避免不良的组织渗透，不良的 血清稳定，消除迅速。这将是第一项评估小分子PET试剂用于治疗糖尿病的研究。 对肿瘤上表达的GPCR进行成像。我们建议将GRPR作为一个模型系统。近年来承担的 小组和其他人已经专注于用放射性标记的蛙皮素（BN）肽类似物的开发。 用于GRPR阳性肿瘤的正电子发射断层扫描（PET）成像的正电子发射放射性核素 临床前小鼠模型。这些肽类似物中的一些已经在人体试验中进行了评估， 68 Ga-RM 2是一款非常出色的产品。对现有的抗GRPR的小分子化合物进行了综述， 鉴定了拮抗剂PD 176252，作为开发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。科学的前提是这些小分子类似物 在细胞摄取和解离动力学方面与肽示踪剂相比具有不同的性质， 因此作为显像剂可能是上级的。

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.