Exploring the Neuroleptic Substituent in Octoclothepin: Potential Ligands for Positron Emission Tomography with Subnanomolar Affinity for α1-Adrenoceptors

A series of 1-(10.11-dihydrodthenzo[b,f]thiepin-(10-y-l)-4-methylpiperazine analogues substituted in the 8-position of the 10,11-dihydrodibenzo[b,f]thiepine scaffold with aryl, heteroaryl. amine, and amide substituents are described. The compounds were: designed using the previously reported Liljefors-Bogeso pharmacophore model for dopamine 1)2 and alpha(1)-adrenocetor antagonists. with the aim of obtaining selective alpha(1)-adrenoceptors antagonists suitable for development as radioligands for imaging of central alpha(1)-adrenoceptors by positron emission tomography. Sixteen aryl and heteroaryl substituted octoclothepin analogues were prepared by a convergent synthesis via coupling of 1-methyl-4-(8-(4,4.5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-10,11-dihydrodibenzo[b,f]thiepin-10yl-piperazine with aryl and heteroaryl halides under palladium catalysis. The most selective compound obtained, (S)-N-(11-(4-methylpiperazin- -yl)-10,11-dihydrodibenzo[b,f]thiepin-2-yl)methyl)isobutyramide (S)-35, showed a similar subnanomolar affinity compared to alpha(1a), alpha(1b,) and alpha(1d)-adrenoceptors and a selectivity ratio of 20, 440, and 20 with respect to D-2, 5-HT2C, and H-1 receptors. respectively.