The Lundbeck Foundation supports NRU research
- Published: Friday, 28 October 2016 13:23
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The alpha7 nicotinic acetylcholine receptor (nAChR) is considered one of the most promising potential drug targets for treatment of cognitive deficits. In accordance, recent proof-of-concept clinical trials have confirmed pro-cognitive efficacy of alpha7 nAChR partial agonists in patients with schizophrenia. With the alpha7 nAChR being an important and approachable target for therapeutic intervention, development of alpha7 nAChR selective ligands for neuroimaging methods would greatly help the understanding of this very important human brain receptor in relation to drug development and disease pathology. Progress in accurate mapping and quantification of alpha7 nAChRs in the living human brain has so far been impeded by the lack of applicable radiotracers with sufficiently high receptor binding affinity and selectivity. A novel selective high-affinity alpha7 nAChRs lead compound, ASEM, has recently been reported to show promise as a potential ligand for neuroimaging of alpha7 nAChRs, making this molecule highly relevant for further validation. Therefore, this project aims to characterize 125I-ASEM and 18F-ASEM for neuroimaging of the alpha7 nAChRs in the mammalian brain. Comparative studies will be performed using in situ receptor binding (in vitro autoradiography) vs. positron emission tomography (PET) which allows for in vivo neuroimaging. To determine cross-species applicability, we will assess brain in vitro binding properties of 125I-ASEM in several mammalian species, including the rat, mouse, pig and human. To compare with in vivo settings, 18F-ASEM will be investigated for brain uptake and target selectivity in PET studies conducted in the pig. In combination, these methods will enable us to validate radiolabelled ASEM as a suitable ligand for the detection and quantification of the amount and distribution of alpha7 nAChRs in the human brain.