Synthesis, radiofluorination and first evaluation of [¹⁸F]fluorophenylsulfonyl- and [¹⁸F]fluorophenylsulfinyl-piperidines as serotonin 5-HT_2A receptor antagonists for PET

Abstract 

In psychiatric disorders, 5-HT_2A receptors play an important role. In order to study these receptors in vivo by positron emission tomography (PET), there is an increasing interest for subtype selective and high affinity radioligands. Up to now, no optimal radiotracer is available. Thus, 1-(2,4-difluorophenethyl)-4-(4-fluorophenylsulfonyl)piperidine (9), possessing high affinity and sufficient subtype selectivity for 5-HT_2A receptors, and 1-(2,4-difluorophenethyl)-4-(4-fluorophenylsulfinyl)piperidine (15) have been ¹⁸F-labelled by a nucleophilic one-step reaction. Both radiotracers could be prepared and isolated within 45 min, [¹⁸F]9 in a radiochemical yield (RCY) of 34.5±8% and [¹⁸F]15 of 9.5±2.5%. The K_i values of 9 and 15 at 5-HT_2A receptors towards [³H]ketanserin were determined to be 1.9±0.6 and 198±8 nM, respectively. Autoradiography with [¹⁸F]9 and [¹⁸F]15 on rat brain sections showed a very high nonspecific binding of >80% for [¹⁸F]9 and 30% to 40% nonspecific binding for [¹⁸F]15; however, it is still too high in order to compensate for its lower affinity. Even though the affinity of 9 is more promising compared with 15, the high nonspecific binding of both radiofluorinated tracers in rat brain does not recommend those as an in vivo PET imaging agent for serotonin 5-HT_2A receptors in humans.

Keywords: Radiofluorination, 5-HT_2A antagonist, PET, Radioligand, Autoradiography