Application Of Platform Imaging Biomarkers In Drug Discovery - Focus On Neuroscience, Oncology And Cardiovascular

Thomas Bocan
Senior Director, Head of Preclinical BioImaging Center, Worldwide Research and Development, Pfizer, Inc. Eastern Point Rd Groton, CT 06340, USA

Abstract:
Due to improvements in technology associated with high throughput screening, gen omics and proteomics, emphasis has shifted to in vivo testing of whether the drug candidate binds to the target and expresses a desirable pharmacological effect. Multi-modality, platform, imaging approaches afford one the opportunity to provide clinically translatable biomarkers of efficacy/safety, to enhance confidence in target and to allow for preclinical characterization of lead compounds using non-invasive or semi-invasive tools that are clinically translatable. Platform imaging approaches such as FDG/FLT PET, PET receptor occupancy, MR spectroscopy (MRS), structural CT and MRI and functional MRI (fMRI) allow for broader impact across multiple disease areas. For instance, FDG-PET is commonly used for assessment of tumor metabolism but with minor adaptations the methodology can also be used to measure changes in brain metabolism associated with drug intervention or changes in inflammation associated with atherosclerosis, COPD and/or rheumatoid arthritis. FDG-PET has been used to differentiate rabbit atherosclerotic lesions rich in macrophages from fibrotic lesions. FDG-PET was shown to detect dose-dependent changes in rat cortical and thalamic glucose utilization following exposure to the AMPA receptor potentiator, LY451646. FDG-PET has differentiated doses associated with cognitive enhancement from unwanted cerebellum-mediated changes in posture. MRS has been successfully used to detect reductions in rat hippocampus glutamate levels following administration of the Kv7 potassium channel opener, retigabine, and thereby provide a mechanistic biomarker of the glutaminergic pathway. In addition to assessment of functional changes, novel PET tracers can be used to measure receptor occupancy to demonstrate target organ uptake, drug candidate binding to the target and guide clinical dose selection. Through broadening the use of currently available imaging tools and methods, building novel small molecule or protein-based PET tracers and targeted MR and CT contrast agents, imaging biomarkers can potentially be used to study novel biologic agents such as proteins, antibodies and antibody fragments, siRNA and stem cells and provide greater opportunities for studying conventional pharmacologic agents.