Development and translation of a novel radiotracer to image alpha-1 adrenoceptors using positron emission tomography for use in imaging posttraumatic stress disorder

Va Puget Sound Healthcare System, Seattle WA

Investigators

Abstract

Successful pharmacological treatment of posttraumatic stress disorder (PTSD) is challenging and remains a significant unmet need for Veterans, their families, and VA. Excessive noradrenergic (NA) activity has been identified as an important contributor to PTSD pathology, and prazosin, a non-selective alpha-1 adrenoceptor (α1 AR) antagonist, has demonstrated effectiveness in reducing PTSD-related nightmares, sleep disturbances, and dysregulated alcohol use in Veterans and Servicemembers (SMs). Unfortunately, not all Veterans and SMs tolerate or respond to prazosin therapy for reasons that remain unclear. Biomarkers for measuring brain NA activity and identifying who will respond to prazosin have been difficult to establish and are not consistently reliable or easy to implement. Currently, a major limitation to understanding NA system regulation in PTSD and strategies to improve upon prazosin is the lack of means to image α1 AR in living human brain. Positron emission tomography (PET) is a non-invasive, translational imaging modality capable of selectively imaging targets in the central nervous system (CNS) with high specificity and sensitivity. CNS PET radioligands have provided critical breakthroughs in the understanding of many neuropsychiatric disorders and have assisted and expedited novel drug development. To date, attempts at developing an α1 AR radiotracer have failed due to lack of target selectivity, inadequate brain penetrance, and/or high non-specific binding, yielding images of poor quality that cannot be meaningfully quantified. Members of the pharmaceutical industry often develop novel CNS PET radiotracers in tandem with therapeutic lead agents, but given the generic status of prazosin, the motivation for CNS α1 AR radiotracer development outside VA is likely limited. A series of radiolabeled analogues of a well-described highly selective α1A AR antagonist have shown promise as novel radiotracers for PET imaging. They exhibit favorable characteristics as CNS PET radiotracers with high α1A AR affinity, moderate lipophilicity, demonstrated engagement with human brain α1 AR, capability of imaging α1 AR and its occupancy by prazosin in brain of living rats, low non-specific binding, and lack of affinity to the permeability-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) drug efflux transporters at the blood-brain barrier (BBB). However, their use is limited by carbon-11 (radioactive half-life = 20 minutes) which requires production by an on-site cyclotron and limits available imaging time. A series of compounds based on the promising lead and amenable to labeling with fluorine-18 (radioactive half-life = 109 minutes) will greatly extend their availability and utility. These compounds will be synthesized with minor modifications consistent with prior PET radiotracers. Using an enhanced high- throughput radiotracer development pipeline they will be progressively screened to: 1) assess their in vitro properties by α1 AR binding in human membrane preparation and brain tissue; 2) assess brain entry in rats, α1 AR engagement assessed by prazosin blockade, and P-gp substrate identification by blockade using the P-gp inhibitor elacridar by means of ex vivo LC-MS/MS; and 3) assess their performance as CNS PET radiotracers for α1 AR in rats. These assessments will provide a further screening basis for selection of the best performing candidate, which will be advanced for radiation dosimetry analysis, full CNS target binding, and toxicology studies prior to an exploratory Investigational New Drug (eIND) submission to the FDA. The ultimate goal beyond this project is to develop a successful PET radiotracer to quantify α1 AR receptor availability in human brain, identify PTSD patients responsive to prazosin treatment, and expedite the development of novel PTSD therapeutics targeting CNS α1 ARs. A radiotracer for imaging α1 AR in human brain is the only tool capable of non-invasively interrogating prazosin at its site of action and α1 AR regulation of the CNS noradrenergic system in vivo, providing a direct means for developing novel therapeutic drugs for treatment of Veterans and Servicemembers with PTSD.