Small Molecule GPCR Ligands for Oncologic Imaging

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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.