Synthesis and biological evaluation of potential 5-HT7 receptor PET radiotracers

Brain serotonin 7 receptor (5-HT7) is involved in several mood disorders and drug candidates targeting this subtype are currently in development. Positron emission tomography (PET) is a molecular imaging modality offering great promise for accelerating the process from preclinical discovery to clinical phases. As no PET radiopharmaceutical has yet been used successfully to study the 5-HT7 receptor in vivo, our objective is to develop the first 5-HT7 fluorine-18 labeled radiotracer. Four structural analogs of SB269970, a specific 5-HT7 receptor antagonist, divided in FP3 series and FPMP series were synthesized. Their antagonist effects were investigated by cellular functional assay. Nitro-precursors of these analogs were radiolabeled via a [F-18(-)]nucleophilic substitution and in vitro autoradiographies were performed in rat brain. Chemical and radiochemical purities of fluorine radiotracers were >99% with specific activities in 40 -129 GBq/mu mole range. The four derivates presented antagonism potencies toward 5-HT7 receptors (PKB) between 7.8 and 8.8. The four PET radiotracers had suitable characteristic for 5-HT7 receptor probing in vitro even if the FP3 series seemed to be more specific for this receptor. These results encourage us to pursue in vivo studies. (C) 2011 Elsevier Masson SAS. All rights reserved.