Development and preclinical evaluation of 11C- and 18F-labelled radioligands for PET imaging of alpha7 nAChRs in the brain

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This project aims at identifying preclinical candidate radioligands for quantitative non-invasive imaging of a7 nicotinic acetylcholine receptor (a7 nAChR) by positron emission tomography (PET) and to investigate the suitability of a7 nAChR PET imaging as biomarker for inflammatory processes in the brain. The physiological processes modulated by a7 nAChR as one predominant regulator of the central and peripheral effects of the neurotransmitter acetylcholine suggest high therapeutic potential in treating neuropsychiatric disorders as well as certain forms of cancer. Accordingly, imaging of a7 nAChR availability under physiological and pathological conditions by PET is of high interest for the evaluation and validation of current diagnostic and drug development concepts. A main hurdle for a larger implementation of this imaging modality in clinical research on a7 nAChR is the scientifically challenging development of clinically applicable a7 nAChR radiotracers with respect to brain uptake, target specificity, and metabolism. By analysis of the knowledge obtained so far in the molecular design of PET radiotracers for imaging a7 nAChRs it gets evident that radiotracers related to the core structure of diazabicyclononanes are the most promising class of compounds. Our strategy is to design, evaluate, and identify by a data-driven experimental approach novel oxadiazolyl-diazabicyclononane a7 nAChR ligands for 11C- and 18F-radiolabelling. Subsequently, preclinical biological evaluation will be performed to validate the potential of the new compounds for future translation into more effective imaging of a7 nAChR in brain by PET. The clinical applicability of a7 nAChR PET as diagnostic tool will furthermore be assessed by imaging studies focussing on inflammation-related changes in the availability of this particular receptor. As a7 nAChRs are of considerable importance for the regulation of the inflammatory microglia activity in brain, we aim to validate the potential of our previously developed and currently most suitable PET radiotracer [18F]NS10743 to visualise and quantify neuroinflammatory processes in Alzheimers disease and stroke. This objective will we achieve by a combination of two [18F]NS10743-based imaging approaches applied in two species, i.e. autoradiography studies using post-mortem brain tissue and PET studies applied in the Leipzig large animal model of ischemic stroke, which finally will improve the reliability of an estimation of the imaging potential of the novel a7 nAChR radiotracer [18F]NS10743 to be expected in clinical PET studies in general. Taken together, this project has the potential to for the first time gaining non-invasive and quantitative access to a7 nAChRs in the living brain by employing the PET technology, with important implications to improve diagnosis and drug research in a number of brain disorders.