BLRD Research Career Development Transition Award Application

Va Puget Sound Healthcare System, Seattle WA

Investigators

Abstract

This proposal seeks to support Garth Terry, MD, PhD, a VA psychiatrist, and clinician scientist, during his Merit Review award and the initial phase of his independent research career. Dr. Terry has over two decades experience developing radiotracers for use in positron emission tomography (PET), which allows non-invasive imaging of central nervous system (CNS) activity in living persons. PET imaging has been responsible for critical breakthroughs in the understanding of many neuropsychiatric disorders and has been employed in the development of novel drugs for their treatment. Dr. Terry’s training in radiochemistry, preclinical and clinical research, and his clinical experience as a psychiatrist make him particularly well suited for developing novel radiotracers for PET imaging of CNS systems implicated in neuropsychiatric disorders affecting Veterans. Specifically, the goal of this proposal is to provide support and protected time for Dr. Terry to continue development of a CNS α1 adrenoceptor (α1 AR) PET radiotracer (the Specific Aims of his Merit Review award), advance that radiotracer to first-in-human imaging studies, expand his successful radiotracer development pipeline, continue collaborative research projects, and prepare funding applications to maintain his career as a successful VA investigator. The overall focus of Dr. Terry’s radiotracer development efforts is on imaging CNS receptors implicated in the pathophysiology of neuropsychiatric disorders common among Veterans, such as posttraumatic stress disorder (PTSD), mild traumatic brain injury and persistent postconcussive symptoms, alcohol and cannabis use, and neurodegenerative disorders. CNS adrenergic, endocannabinoid, and neuroinflammatory systems all mediate stress response, are biologically interconnected in these disorders, and are clinically accessible by therapeutic medications. Therefore, they constitute targets for the development of PET radiotracers in his laboratory. Excessive noradrenergic (NA) activity has been identified as an important contributor to PTSD pathology, and prazosin, a non-selective α1 AR antagonist, has demonstrated effectiveness in reducing PTSD-related nightmares, sleep disturbances, and dysregulated alcohol use in Veterans and Servicemembers (SMs). Unfortunately, for reasons that remain unclear, not all Veterans and SMs tolerate or respond to prazosin therapy. A major factor impeding research into understanding NA system regulation in PTSD and the variable therapeutic response to prazosin has been the inability to image α1 ARs in living human brain. Dr. Terry’s laboratory has developed a carbon-11-labeled PET radiotracer that displays high affinity and selectivity for α1A ARs and shows promise for CNS PET imaging. However, its widespread use is limited by its short radioactive half-life (20.3 min). The Merit Review award seeks to mitigate this limitation by developing a fluorine-18 labeled radiotracer with a longer half-life (109 min) and prepare an exploratory investigational new drug application. Efforts in this proposal beyond the Merit Review seek to use the α1 AR radiotracer to map α1 AR distribution and binding affinity in Veterans with versus without PTSD, in an effort to obtain direct in vivo data supporting or refuting the role of CNS α1 ARs in the pathophysiology of PTSD. Human imaging of brain α1 ARs will also allow determination of the CNS concentrations of prazosin associated with amelioration of PTSD symptoms, information that could potentially assist VA clinicians in determining clinically effective doses of prazosin. As the first radiotracer for imaging CNS α1 ARs in human, the radiotracer can be expected stimulate collaborative efforts with VA and non-VA researchers, further extending its impact. It also provides proof-of- concept that Dr. Terry’s PET radiotracer development pipeline can support the development of additional CNS radiotracers targeting Veteran-relevant neuropsychiatric conditions. Protected time and support are required to achieve these goals and further their efforts through preparation of competitive funding applications. Doing so will provide the launch for a successful VA research career.