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Imidazoline I2 receptors (I2-IR), widely distributed in the CNS and altered in patients that suffer from neurodegenerative disorders, are orphans from a structural point of view, and new I2-IR ligands are urgently required for improving their pharmacological characterization. We report the synthesis and three-dimensional quantitative structure−activity relationship (3D-QSAR) studies of a new family of bicyclic α-iminophosphonates endowed with relevant affinities for human brain I2-IR. Acute treatment in mice with a selected compound significantly decreased Fas-associated protein with death domain (FADD) in the hippocampus, a key signaling mediator of neuroprotective actions. Additionally, in vivo studies in the familial Alzheimer’s disease 5xFAD murine model revealed beneficial effects in behavior and cognition. These results are supported by changes in molecular pathways related to cognitive decline and Alzheimer’s disease. Therefore, bicyclic α-iminophosphonates are tools that may open new therapeutic avenues for I2-IR, particularly for unmet neurodegenerative conditions., We strongly acknowledge the advice of Dr Andrés G. Fernández (our mentor in the CaixaImpulse 2018 program) for unvaluable advice. This study was supported by the Ministerio de Economía y Competitividad of Spain (SAF2016-3307) and the Basque Government (IT1211- 19). The project leading to these results has received funding from “la Caixa” Foundation (ID 100010434) under agreement CI18-00002. This activity has received funding from the European Institute of Innovation and Technology (EIT). This body of the European Union receives support from the European Union’s Horizon 2020 research and innovation programme. C.G.-F, F. V., C. E., S. R-A., A. B. and M. P. belong to 2017SGR106 (Generalitat de Catalunya). J. A. G.-S. is a member emeritus of the Institut d’Estudis Catalans. Financial support was provided for F. V. (University of Barcelona, APIF_2017), S. R.-A. (Generalitat de Catalunya, 2018FI_B_00227), A. B. (Institute of Biomedicine UB_2018), C. M. (Marie Sklodowska-Curie Actions Individual Fellowships H2020-MSCA-IF-2016, ID747487), and E. H.-H. (Consejería de Innovación, Investigación y Turismo del Gobierno de las Islas Baleares y del Fondo Social Europeo, FPI/2102/2018). MR, TD and KN kindly acknowledge Ministry of Science and Technological Development of the Republic of Serbia, Project Contract No. 172033, and HORISON2020- COST-Action CA18133 ERNEST: European Research Network on Signal Transduction.