Chapter 75 - Molecular and Functional Imaging in Central Nervous System Drug Development

Abstract

To date, there is an ever-increasing plethora of imaging methods available for studying biological systems in vivo, which are of interest for drug discovery and development. During discovery and early preclinical development phases, microscopy techniques including intravital microscopy are indispensable as they provide the exquisite resolution required for studying molecular events at cellular and subcellular resolution. For example, the structure and function of neural circuitry have been extensively investigated using imaging across spatial and temporal scales. Intravital two-photon microscopy has revealed unprecedented insights into neuronal processing at cellular resolution and a temporal resolution of the order of milliseconds. Yet, these methods are hampered by the interaction of the light photons with tissue, which limits light penetration and prevents the study of deep-lying structures/organs. Hence, for later stages in drug development and in particular for studies in humans, methods capable of coping with the dimensions of the human body are used, even at the expense of inferior spatial resolution. These are the clinically widely available radiological imaging methods for collecting structural/functional and nuclear medicine imaging methods for collecting molecular information. In view of this translational perspective, we will focus on these macroscopic imaging techniques, although the limited spatial (and temporal) resolution provided by these techniques constitutes a formidable challenge in understanding the nature of the signals both at a qualitative and quantitative level. We will illustrate the role of imaging in drug development in discussing examples in the context of neurodegenerative diseases, neuroinflammation, and psychiatric diseases, although the concepts outlined should be of general validity.