William Z. Potter

Merck, USA

Abstract

[O26] Biomarkers to establish brain activity of neuropeptides in humans

Development of relevant PET ligands for any neuropeptide target of interest should be undertaken whenever receptor density and localization allow. Clinical studies of Substance P antagonism demonstrate the value such a ligand. For targets such as CRF-1 receptors, PET ligands may not be feasible. Complexity increases when one moves beyond antagonist ligands to those suitable for detecting agonists or allosteric modulators.

The field therefore continues to depend on indirect downstream functional read outs as evidence of brain activity.  The simplest example involves EEG effects of orexin antagonism especially on sleep architecture (PSG). In the more typical cases whereby antagonism or modulation of a specific neuropeptide target might not yield a clear acute subjective or easily measured physiological change we are dependent on an emerging tool kit of functional markers of brain activity. Of these, the most extensively studied remains EEG with all of its limitations. Magneto encephalography (MEG) should permit interrogation of activity within deeper brain structures but application to drug development is not established.

Functional PET (FDG and 0¹⁵ ), functional MRI (arterial spin labeling and BOLD), transcranial magnetic stimulation and various “omic” measures in cerebrospinal fluid can all potentially be applied to establish that a compound has modified CNS function.  None of these, however, is standardized as a general platform that can produce replicated quantitative dose response relationships across sites. 

Much of the needed biomarker method development, qualification and standardization may be best carried out in so called “pre-competitive” space in which academia, government and industry can work together.  An example of this is provided by recent efforts to see if BOLD fMRI can be utilized to detect regionally specific effects of compounds utilized in the treatment of pain, an approach which could be applied to some neuropeptides of interest.   It is critical that we continue to invest in platforms that enable us to establish, either directly or indirectly, that we have engaged a specific target.  Only with such tools in place can we know whether any particular compound actually tests a hypothesis that stimulation or antagonism of a specific neuropeptide system has an impact on a neuropsychiatric condition.

Biography

Bill Potter earned his B.A., M.S., M.D., and Ph.D. at Indiana University, after which he functioned in positions of increasing responsibility and seniority over the next twenty-five years at the National Institutes of Health focused on translational neuroscience.  While at the NIH, Bill was widely published and appointed to many societies, committees, and boards; a role which enabled him to develop a wide reputation as an expert in psychopharmacological sciences and championing the development of novel treatments for CNS disorders.

Bill left the NIH in 1996 to accept a position as Executive Director and Research Fellow at Lilly Research Labs, specializing in the Neuroscience Therapeutic Area and in 2004 joined Merck Research Labs as VP of Clinical Neuroscience, then the newly created position of Translational Neuroscience in 2006. His experience at Lilly and MRL in identifying, expanding and developing methods of evaluating CNS effects of compounds in human brain cover state of the art approaches across multiple modalities. These include brain imaging and cerebrospinal fluid proteomics (plus metabolomics) as well as development of more sensitive clinical, psychophysiological and performance measures allowing a range of novel targets to be tested in a manner which actually addresses the underlying hypotheses.  Bill has become a widely recognized champion for the position that more disciplined hypothesis testing of targets in humans is the best near term approach to moving CNS drug development forward.