Traumatic brain injury (TBI) is a major public health problem that raises the need to accurately measure its effects non-invasively. A biological target mechanistically linked to TBI and suitable for molecular imaging with diagnostic and prognostic implications could provide a quantitative non-invasive biomarker for TBI. Presently, such a biomarker does not exist. Multiple lines of evidence have demonstrated that TBI triggers a biochemical cascade that reduces the density of cerebral alpha7-nAChRs, one of the major subtypes of nicotinic acetylcholine receptors. Preliminary data from our laboratory has demonstrated that our novel positron-emission tomography (PET) radiotracer [18F]ASEM can accurately report the distribution of alpha7-nAChRs in control animals and that it exhibits strikin bilateral reduction of binding (32-73%) in rats with controlled cortical impact (CCI) TBI model. Currently, [18F]ASEM is the only alpha7-nAChR radioligand that has demonstrated excellent imaging properties with high specific binding in rodent and non-human primate PET studies. The main objective of this proposal is to validate the PET imaging properties of [18F]ASEM in two models of TBI in rats, focal - CCI and diffuse - impact acceleration (IA). 1) Cerebral alpha7-nAChR binding and distribution will be measured with [18F]ASEM - PET in CCI and IA models of TBI in rats. In agreement with previous in vitro alpha7-nAChR autoradiography data in animals with TBI reported by others and our preliminary PET results, our hypothesis is that the cerebral specific binding of [18F]ASEM in TBI will be significantly reduced. The reduction of the [18F]ASEM specific binding will correlate with the TBI severity and progression. 2) The PET results will be confirmed by immunofluorescent staining that will demonstrate significant alteration of the alpha7-nAChR protein in TBI rat brain tissue (in neurons and glia). The experimental focus of this proposal is to carry out proof-of-concept studies and obtain evidence of the suitability of [18F]ASEM for quantification of alpha7-nAChRs by PET in TBI models in rats. Our future goal is to evaluate alpha7-nAChRs as a potential biomarker of TBI in humans by studying the course of receptor changes in TBI and their sensitivity to the effects of various treatments.
The cerebral alpha7-subtype of the nicotinic acetylcholine receptor (alpha7-nAChR) has been implicated in a wide variety of diseases and conditions including traumatic brain injury (TBI). The goal of this proposal is to validate [18F]ASEM, the first highly specific PET radioligand for imaging alpha7-nAChRs, as a biomarker of TBI in two rat models. The availability of this PET radioligand has the potential to transform how we study and treat patients with TBI.