We propose to validate a new PET radioligand [18F]ASEM for the a7 subtype of the nicotinic acetylcholine receptor system (a7-nAChR) for imaging schizophrenia (SCZ). [18F]ASEM is the first successful human radioligand for PET imaging of a7-nAChR. [18F]ASEM was developed at our center to address a major unmet pathophysiological and treatment need involving the a7- nAChR, a target relevant to cognition in various neuropsychiatric disorders including SCZ. The critical role of a7 in SCZ has been supported by multiple lines of evidence including clinical studies with a7 agonists - emerging drugs for treatment cognitive dysfunction. Despite a decade of effort to develop a sensitive and specific PET radiotracer for imaging a7-nAChR in human subjects by us and others worldwide, only recently have we synthesized the first such agent [18F]ASEM, and have pilot data used to PET image brain a7 in normal humans. Based on the extensive post-mortem literature, the primary hypothesis is that there are decreased a7-nAChR's in patients with SCZ relative to healthy controls. We will validate the post-mortem data in vivo by measuring the a7-nAChR's with PET-[18F]ASEM in healthy controls (Aims 1) and patients with SCZ (Aims 2). The a7-nAChR receptor occupancy (RO) will be measured by PET-[18F]ASEM in healthy controls and patients with SCZ treated with a7-nAChR partial agonist drug DMXB-A and is hypothesized to demonstrate dose dependent RO which has never been possible before [18F]ASEM (Aims 3&4). Currently, DMXB-A is a fully academically supported drug in clinical trials for treatment of cognitive dysfunction in SCZ and other disorders. The PET occupancy study will provide an evidence that the binding of [18F]ASEM in human brain is mediated by a7- nAChR. This RO study will also help validate in humans the a7-nAChR mechanism of action of DMXB-A.
In Aim 5 (exploratory), we will examine the effect of the polymorphism in the a7-nAChR gene CHRNA7 that is associated with SCZ on the [18F]ASEM binding and a7-nAChR occupancy with DMXB-A in human subjects. Our long term goal is to use [18F]ASEM as an important tool for studying a7-nAChR in the pathophysiology of SCZ and other neuropsychiatric disorders and conditions including Alzheimer's disease, bipolar disorder and traumatic brain injury and a significant tool for a7- nAChR drug development.
The main objective of this project is to validate [18F]ASEM, the first successful PET radioligand for the a7 subtype of the nicotinic acetylcholine receptors (a7-nAChR), for imaging schizophrenia (SCZ). We will confirm for first time in vivo that a7-nAChR's are reduced in patients with SCZ versus healthy controls. The second objective is to validate in humans the a7- nAChR mechanism of action of DMXB-A, a clinical drug for treatment of cognitive dysfunction in SCZ.
| Coughlin, Jennifer M; Du, Yong; Rosenthal, Hailey B et al. (2018) The distribution of the alpha7 nicotinic acetylcholine receptor in healthy aging: An in vivo positron emission tomography study with [18F]ASEM. Neuroimage 165:118-124 |
| Phan, Jenny-Ann; Landau, Anne M; Jakobsen, Steen et al. (2017) Radioligand binding analysis of ? 2 adrenoceptors with [11C]yohimbine in brain in vivo: Extended Inhibition Plot correction for plasma protein binding. Sci Rep 7:15979 |
