Synthesis, radiofluorination and first evaluation of [18F]fluorophenylsulfonyl- and [18F]fluorophenylsulfinyl-piperidines as serotonin 5-HT2A receptor antagonists for PET

In psychiatric disorders, 5-HT2A 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-HT2A receptors, and 1-(2,4-difluorophenethyl)-4-(4-fluorophenylsulfinyl)piperidine (15) have been F-18-labelled by a nucleophilic one-step reaction. Both radiotracers could be prepared and isolated within 45 min, [F-18]9 in a radiochemical yield (RCY) of 34.5 +/- 8% and [F-18]5 of 9.5 +/- 2.5%. The K-i values of 9 and 15 at 5-HT2A receptors towards [H-3]ketanserin were determined to be 1.9 +/- 0.6 and 198 +/- 8 nM, respectively. Autoradiography with [F-18]9 and [F-18]15 on rat brain sections showed a very high nonspecific binding of >80% for [F-18]9 and 30% to 40% nonspecific binding for [F-18]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-HT2A receptors in humans. (C) 2010 Elsevier Inc. All rights reserved.