Synthesis and biological evaluation of potential 5-HT(7) receptor PET radiotracers

Brain serotonin 7 receptor (5-HT(7)) 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-HT(7) receptor in vivo, our objective is to develop the first 5-HT(7) fluorine-18 labeled radiotracer. Four structural analogs of SB269970, a specific 5-HT(7) 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 [(18)F(-)]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/μmole range. The four derivates presented antagonism potencies toward 5-HT(7) receptors (pK(B)) between 7.8 and 8.8. The four PET radiotracers had suitable characteristic for 5-HT(7) 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.