Synthesis of novel alpha7-nAchR ligands : from an idea to in rodent results for Alzheimer [¹⁸F] TEP imaging

            The neurotransmitter acetylcholine (ACh) exerts its effects on the central nervous system (CNS) through two distinct muscarinic mAChRs and nicotinic nAChRs receptors types: nAChRs belong to the superfamily of ligand-gated ion channels possessing a pentameric structure.¹ Because of their distribution and abundance in the CNS (in particular in the hippocampus and cortex), the a7 subtypes are potential diagnosis and therapeutic targets for brain disorders that involve these cerebral regions. In this field, α7 nAChR agonists were identified and allowed the design of novel therapeutic agents for Alzheimer Disease (AD). Having in hand a human compatible [¹⁸F]-labeled positron emission tomography (PET) tracer to realize the early diagnostic or to validate the efficiency of therapies in clinical trials for AD is indubitably crucial.

            In this aim, based on our expertise in heterocyclic bio-mimetic development,² we also envisioned to design novel α7 nAChR ligands and their transformation into a [¹⁸F] PET tracer. We synthesized a library of potent α7 nAChR ligands containing a quinuclidine, a tropane or a 8H-quinolizine moiety. We present herein chemistry,³ SAR studies, molecular modelling docking studies which confirmed the binding mode of the developed ligands, in vitro efficiency (SAR), radiolabeling and in vivo results in rats.

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2. C. Neagoie, E. Vedrenne, F. Buron, J. Y Merour, S. Rosca, S. Bourg, O. Lozach, L. Meijer, B. Baldeyrou, A. Lansiaux and S. Routier, Eur. J. Med. Chem. 2012, 49, 379; R. Boulahjar ; A. Ouach, M. Chiurato, S. Bourg, M. Ravache, R. Le Guével, S. Marionneau-Lambot, T. Oullier, O. Lozach, L. Meijer, C. Guguen-Guillouzo, S. Lazar, M. Akssira, Y. Troin, G. Guillaumet and S. Routier, J. Med. Chem., 2012, 55, 9589;
3. Routier, S. ; Suzenet, F. ; Pin, F. ; Chalon, S. ; Vercouillie, J. ; Guilloteau, D. WO 2012143526 ; F. Pin, J.Vercouillie, A. Ouach, S. Mavel, Z. Gulhan, G. Chicheri, C. Jarry, S. Massip, J.-B. Deloye, D. Guilloteau, F. Suzenet, S. Chalon S. Routier, Euj J. Med; Chem. . 2014, 83, 214-224.

Research Support: ANR Malz MInAlpha 7,the Labex Iron (ANR-11-LABX-18-01), the Région Centre (IMAD), the FEDER and Cyclopharma Laboratories.

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