The Class PET: Accelerating CNS Drug Development with Molecular Imaging

Organizers: Silke Miller, Lundbeck Research USA; Donna Maier, AstraZeneca Pharmaceuticals

Speakers: Dean F. Wong, Johns Hopkins Medical Institutions; Michael Klimas, Merck Research Laboratories; Stephen L. Dewey, Brookhaven National Laboratory; Svante Nyberg, AstraZeneca R&D

Molecular imaging techniques, especially positron emission tomography (PET), have been increasingly applied in contemporary CNS drug discovery and development. Such techniques allow in the living animal or human subjects the assessment of compound exposure in the CNS, binding to the designated target(s), and the relationship of occupancy and pharmacodynamic effects, as well as the development of biomarkers. Speakers will address advantages and pitfalls, and current methods of molecular imaging for CNS drug discovery and/or development, and provide a range of examples of successful PET tracer development for novel therapeutics.

The BPDG at the New York Academy of Sciences represents a diverse group of scientists and others with an interest in biochemistry, molecular biology, biomedical research, and related areas. Members are from pharmaceutical and biotechnology companies, and university and medical center research facilities across the Eastern United States. The group also serves as the Biochemical Topical Group for the American Chemical Society's New York Section. The purpose of the BPDG is to bring together diverse institutions and communities, industrial and academic, to share new and relevant information at the frontiers of research and development.

Speaker Abstracts

Functional Neuroimaging as a Roadmap for Drug Discovery and Drug Development: Current Status and Future Directions
Dean F. Wong
Johns Hopkins Medical Institutions

Neuroimaging, especially that of neuroreceptor radioisotope and functional magnetic resonance imaging (fMRI), has played a fundamental role in neuropharmacology and neurophysiology. Because of the unique and pioneering role, especially of the radiolabeling of central nervous system (CNS) drugs for receptor and neurotransmitter system imaging, there is an increasingly major role to aid in CNS drug development. One component is providing evidence for proof of concept of the target for which candidate drugs are being tested for receptor occupancy mechanism of action and ultimately rational drug dosing. There is also a role for other areas of neuroimaging, including fMRI and magnetic resonance spectroscopy in other magnetic resonance-based techniques that, together with radioisotope imaging, represent 'CNS molecular imaging.' The role of these approaches and a review of the recent advances in such neuroimaging is the subject of this presentation. Possible algorithms for early discovery/phase I development using neuroimaging will be presented for this increasingly vital approach of these emerging methodologies.

Imaging and the Treatment of Disease: Today and Future Opportunities
Michael Klimas
Merck Research Laboratories

Positron Emission Tomography (PET) has become a core tool for the evaluation of central nervous system target engagement in non-human primates and clinical settings. This valuable contribution to understanding the dose—blood pharmacokinetic—receptor occupancy relationship is only the beginning of PET's potential in therapy discovery and development. Next steps in PET's applications to drug discovery include development of more formal biomarker characteristics including the integration of PET imaging into larger imaging and non-imaging information, a qualification/validation path and PET imaging process advancement. Other therapeutic areas such as oncology leverage PET imaging information as pharmacodynamic information. Developments in new PET tracers require biochemical and histological qualification. Lastly, PET is providing important insight to the relationship between receptor occupancy and functional central nervous system responses. These topics will be discussed using Merck experience in PET imaging applied to therapy discovery and development.

Exploring Putatative CNS Drug Targets with PET. Examples and Recent Advances.
Svante Nyberg
AstraZeneca R&D

The Pharmaceutical industry is committed to continuous investment in technologies to improve the drug R&D process in spite of relatively flat product approvals over the past two decades. Human Positron Emission Tomography (PET) microdosing is technology that allows the safe and early evaluation of biodistribution of radiolabeled drugs in plasma and target organs. Using appropriate radiotracers, PET can in addition be used to study interactions with specific drug targets, assess pharmacodynamic response, visualise disease pathology and monitor effect of treatment.

In this presentation, examples are provided on how PET has been utilized in a translational approach to explore putative CNS drug targets, such as the mGluR5 and 5-HT1b receptors, and ab amyloid deposits. Moreover, recent PET findings on quetiapine illustrate how new insights are gained on mechanism of action of an already well established psychotropic drug.