*Article* **Synthesis of Novel Pyrido[1,2-***c***]pyrimidine Derivatives with 6-Fluoro-3-(4-piperidynyl)-1,2-benzisoxazole Moiety as Potential SSRI and 5-HT1A Receptor Ligands**

**Marek Król 1 , Grzegorz Slifirski ´ 1,\* , Jerzy Kleps <sup>1</sup> , Szymon Ulenberg <sup>2</sup> , Mariusz Belka <sup>2</sup> , Tomasz B ˛aczek <sup>2</sup> , Agata Siwek <sup>3</sup> , Katarzyna Stachowicz <sup>4</sup> , Bernadeta Szewczyk <sup>4</sup> , Gabriel Nowak 3,4, Beata Duszy ´nska <sup>4</sup> and Franciszek Herold <sup>1</sup>**


**Abstract:** Two series of novel 4-aryl-2H-pyrido[1,2-c]pyrimidine (6a–i) and 4-aryl-5,6,7,8 tetrahydropyrido[1,2-c]pyrimidine (**7a–i**) derivatives were synthesized. The chemical structures of the new compounds were confirmed by <sup>1</sup>H and <sup>13</sup>C NMR spectroscopy and ESI-HRMS spectrometry. The affinities of all compounds for the 5-HT1A receptor and serotonin transporter protein (SERT) were determined by in vitro radioligand binding assays. The test compounds demonstrated very high binding affinities for the 5-HT1A receptor of all derivatives in the series (**6a–i** and **7a–i**) and generally low binding affinities for the SERT protein, with the exception of compounds **6a** and **7g**. Extended affinity tests for the receptors D<sup>2</sup> , 5-HT2A, 5-HT<sup>6</sup> and 5-HT<sup>7</sup> were conducted with regard to selected compounds (**6a**, **7g**, **6d** and **7i**). All four compounds demonstrated very high affinities for the D<sup>2</sup> and 5-HT2A receptors. Compounds **6a** and **7g** also had high affinities for 5-HT<sup>7</sup> , while **6d** and **7i** held moderate affinities for this receptor. Compounds **6a** and **7g** were also tested in vivo to identify their functional activity profiles with regard to the 5-HT1A receptor, with **6a** demonstrating the activity profile of a presynaptic agonist. Metabolic stability tests were also conducted for **6a** and **6d**.

**Keywords:** antidepressants; pyrido[1,2-*c*]pyrimidines; dual 5-HT1A/SERT activity; drug design
