The Use of Positron Emission Tomography in Drug Discovery and Development

Abstract

Alzheimer's disease (AD) is defined histologically by the presence of extracellular -amyloid (A ) plaques and intraneuronal neurofibrillary tangles in the cerebral cortex. The diagnosis of dementia, along with the prediction of who will develop dementia, has been assisted by magnetic resonance imaging and positron emission tomography (PET) by using (18)Ffluorodeoxyglucose (FDG). These techniques, however, are not specific for AD. Based on the chemistry of histologic staining dyes, several A -specific positron-emitting radiotracers have been developed to image neuropathology of AD. Among these, (11)CPiB is the most studied A -binding PET radiopharmaceutical in the world. The histologic and biochemical specificity of PiB binding across different regions of the AD brain was demonstrated by showing a direct correlation between A -containing amyloid plaques and in vivo (11)CPiB retention measured by PET imaging. Because (11)C is not ideal for commercialization, several (18)F-labeled tracers have been developed. At this time, (18)F3'-F-PiB (Flutemetamol), (18)F-AV-45 (Florbetapir), and (18)F-AV-1 (Florbetaben) are undergoing extensive phase II and III clinical trials. This article provides a brief review of the amyloid biology and chemistry of A -specific (11)C and (18)F-PET radiopharmaceuticals. Clinical trials have clearly documented that PET radiopharmaceuticals capable of assessing A content in vivo in the brains of AD subjects and subjects with mild cognitive impairment will be important as diagnostic agents to detect in vivo amyloid brain pathology. In addition, PET amyloid imaging will also help test the amyloid cascade hypothesis of AD and as an aid to assess the efficacy of antiamyloid therapeutics currently under development in clinical trials.